Tetrahedral antibodies

Abstract

This invention provides a tetrahedral antibody comprising a first, second, third, and fourth domain, wherein each of the first and second domains are selected from the group consisting of a Fab domain and an Fc domain, wherein each of the first and second domains comprise a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain, and wherein the first domain and the second domain are joined to each other by a non-peptidyl linkage between the first N-terminus of the first domain and the first N-terminus of the second domain, between first C-terminus of the first domain and the first C-terminus of the second domain, between the first N-terminus of the first domain and the first C-terminus of the second domain, or between the first C-terminus of the first domain and the first N-terminus of the second domain.

What is claimed is: 
     
         1 . A tetrahedral antibody comprising a first, second, third, and fourth domain, wherein:
 a) each of the first and second domains are selected from the group consisting of a Fab domain and an Fc domain,   b) each of the first and second domains comprise:
 i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and 
 ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain, 
   c) the first domain and the second domain are joined to each other by a non-peptidyl linkage wherein the non-peptidyl linkage is:
 i) a covalent linkage
 (1) attached to the first N-terminus of the first domain and the first N-terminus of the second domain, 
 (2) attached to the first C-terminus of the first domain and the first C-terminus of the second domain, 
 (3) attached to the first N-terminus of the first domain and the first C-terminus of the second domain, or 
 (4) attached to the first C-terminus of the first domain and the first N-terminus of the second domain, or 
 
 ii) a non-covalent linkage
 (1) between a first dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the first domain, and a second dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the second domain, 
 (2) between a first dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the first domain, and a second dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the second domain, 
 (3) between a first dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the first domain, and a second dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the second domain, or 
 (4) between a first dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the first domain, and a second dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the second domain, 
 
 wherein the first and second dimerizing polypeptides are not immunoglobulin polypeptides, 
   d) if the first domain is joined to the second domain via a covalent linkage attached to the first N-terminus of the first domain, then the third domain is attached at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker,   e) if the first domain is joined to the second domain via a covalent linkage attached to the first C-terminus of the first domain then the third domain is attached at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker,   f) if the first domain is joined to the second domain via a first dimerizing polypeptide attached to the first N-terminus of the first domain, then the third domain is attached at its C-terminus by a peptide bond or via a peptide linker to
 i) the N-terminus of the first dimerizing polypeptide, 
 ii) the second N-terminus of the first domain, or 
 iii) the N-terminus of a third dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the first domain, 
   g) if the first domain is joined to the second domain via a first dimerizing polypeptide attached to the first C-terminus of the first domain, then the third domain is attached at its N-terminus by a peptide bond or via a peptide linker to
 i) the C-terminus of the first dimerizing polypeptide, 
 ii) the second C-terminus of the first domain, or 
 iii) the C-terminus of a third dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its N-terminus by a peptide bond or via a peptide linker to the second C-terminus of the first domain, 
   h) if the second domain is joined to the first domain via a covalent linkage attached to the first N-terminus of the second domain, then the fourth domain is attached at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker,   i) if the second domain is joined to the first domain via a covalent linkage attached to the first C-terminus of the second domain then the fourth domain is attached at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker,   j) if the second domain is joined to the first domain via a second dimerizing polypeptide attached to the first N-terminus of the second domain, then the fourth domain is attached at its C-terminus by a peptide bond or via a peptide linker to
 i) the N-terminus of the second dimerizing polypeptide, 
 ii) the second N-terminus of the second domain, or 
 iii) the N-terminus of a fourth dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the second domain, 
   k) if the second domain is joined to the first domain via a second dimerizing polypeptide attached to the first C-terminus of the second domain, then the fourth domain is attached at its N-terminus by a peptide bond or via a peptide linker to
 i) the C-terminus of the second dimerizing polypeptide, 
 ii) the second C-terminus of the second domain, or 
 iii) the C-terminus of a fourth dimerizing polypeptide, wherein the fourth dimerizing polypeptide is attached at its N-terminus by a peptide bond or via a peptide linker to the second C-terminus of the second domain. 
   
     
     
         2 . The tetrahedral antibody of  claim 1 , wherein:
 a) the first domain is an Fc domain and the second domain is a Fab domain,   b) the first and second domains are Fc domains,   c) the first and second domains are Fab domains,   d) the third and fourth domains are Fab domains,   e) the third and/or fourth domain are selected from the group consisting of (i) a secreted protein, and (ii) the extracellular domain of a transmembrane protein,   f) the third domain is selected from the group of (i) a secreted protein, and (ii) the extracellular domain of a transmembrane protein, and the fourth domain is a Fab,   g) the third domain is IL-15,   h) the third domain is IL-15 and the fourth domain is an IL-15Rα sushi domain,   i) the third domain is IL-15 and the fourth domain is a Fab,   j) the third and fourth domains are each the ACE2 peptidase domain (PD),   k) the first and second domains are Fc domains, and the third and fourth domains are selected from the group consisting of (i) a secreted protein, and (ii) the extracellular domain of a transmembrane protein,   l) the first and second domains are Fc domains, the third domain is selected from the group consisting of (i) a secreted protein, and (ii) the extracellular domain of a transmembrane protein, and the fourth domain is Fab,   m) the first and second domains are Fc domains and the third and fourth domains are Fab domains,   n) the first and second domains are Fc domains and the third and fourth domains are each the ACE2 peptidase domain (PD),   o) the first domain is an Fc domain and the second, third and fourth domains are Fab domains,   p) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is an IL-15Rα sushi domain, or   q) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is a Fab.   
     
     
         3 . The tetrahedral antibody of  claim 1  or  claim 1 .k)iii), wherein the non-peptidyl linkage between first domain and the second domain is a covalent linkage. 
     
     
         4 . The tetrahedral antibody of  claim 3 , wherein the covalent linkage comprises the structure: 
       
         
           
           
               
               
           
         
         wherein R 2  represents an organic structure which connects to the first or second domain and R 4  represents an organic structure which connects to the other of the first or second domain, wherein R 1  is H or is part of an additional structure that is a cyclic structure, wherein the additional cyclic structure comprises R 1  or a portion of R 1 , and may also comprise R 2  or a portion of R 2 , and the carbon between R 2  and the alkene double bond. 
       
     
     
         5 . The tetrahedral antibody of  claim 4 , wherein R 1  and R 2  are linked via at least one direct bond so as to form a cyclic structure comprising
 a) a portion of R 1 ,   b) a portion of R 2 ,   c) the carbon between R 2  and the alkene double bond, and   d) the alkene double bond.   
     
     
         6 . The tetrahedral antibody of  claim 5 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         which is optionally substituted at any position. 
       
     
     
         7 . The tetrahedral antibody of any one of  claims 4  to  6 , wherein the carbon between R 2  and the alkene double bond is directly bonded to R 2  via a double bond and a single bond. 
     
     
         8 . The tetrahedral antibody of  claim 7 , wherein R 2  is 
       
         
           
           
               
               
           
         
         which is optionally substituted at any position, 
         wherein R 2  is attached to R 1  via the nitrogen atom of R 2 , and 
         wherein J is a bond or an organic structure comprising or consisting of a chain of 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 4  alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4  acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl and an amino acid, 
         wherein [PEG(y)]z is: 
       
       
         
           
           
               
               
           
         
         wherein y=1-100 and z=1-10. 
       
     
     
         9 . The tetrahedral antibody of  claim 7 , wherein R 1  and R 2  taken together are: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         which is optionally substituted at any position, 
         wherein J is a bond or an organic structure comprising or consisting of a chain of 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 4  alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4  acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl and an amino acid, 
         wherein [PEG(y)]z is: 
       
       
         
           
           
               
               
           
         
         wherein y=1-100 and z=1-10. 
       
     
     
         10 . The tetrahedral antibody of any one of  claim 4  to  7  or  9 , wherein the covalent linkage comprises the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         which is optionally substituted at any position, 
         wherein J is a bond or an organic structure comprising or consisting of a chain of 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 4  alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4  acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl and an amino acid, 
         wherein [PEG(y)]z is: 
       
       
         
           
           
               
               
           
         
         wherein y=1-100 and z=1-10. 
       
     
     
         11 . The tetrahedral antibody of  claim 3 , wherein the covalent linkage comprises the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         a) X a  is a chemical structure selected from the group consisting of:
 i) a chemical structure which comprises a cyclooctane fused to a dihydropyridazine, 
 ii) a chemical structure which comprises a cyclooctene fused to a pyridazine, 
 
         b) R a  is a bond or a chemical structure which connects X a  to the first N-terminus of the first domain, and 
         c) R b  is a bond or a chemical structure which connects X a  to the first N-terminus of the second domain. 
       
     
     
         12 . The tetrahedral antibody of  claim 11 , wherein X a  comprises the structure 
       
         
           
           
               
               
           
         
       
       wherein R c  is H, alkyl, or aryl, or a tautomer thereof. 
     
     
         13 . The tetrahedral antibody of any of  claims 11 - 12 , wherein the covalent linkage comprises the structure 
       
         
           
           
               
               
           
         
       
       wherein R c  is H, alkyl, or aryl, or a tautomer thereof. 
     
     
         14 . The tetrahedral antibody of any of  claims 11 - 13 , wherein R a  and R b  are, independently, a bond, or a chemical structure comprising or consisting of a chain of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties, wherein each moiety is independently selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 10  alkyl, C 3 -C 10  cycloalkane, C 2 -C 10  alkene, C 5 -C 10  cycloalkene, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 2 -C 5  acyl, C 2 -C 5  acylamino, C 2 -C 5  acyloxy, succinyl, malonyl, glutaryl, phthalyl, adipoyl, an amino acid, an aryl group, a heteroaryl group, a carbamate, a chemical structure containing a cyclooctane fused to a dihydropyridazine, a chemical structure containing a cyclooctene fused to a triazole, a chemical structure containing a cyclooctene fused to a isoxazolidine, a dibenzocyclooctyne. a dibenzoazacyclooctene, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein X 1  is CH or N, X 2  is CH 2  or a carbonyl group, and R 5  is an aryl or alkyl group, wherein [PEG(y)]z is: 
       
         
           
           
               
               
           
         
       
       wherein y=1-100 and z=1-10. 
     
     
         15 . The tetrahedral antibody of  claim 14 , wherein R a  and/or R b  each independently:
 a) comprise a [PEG(y)]z group;   b) comprise a polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), or polysaccharide group;   c) comprise a C 1 -C 4  alkyl group;   d) comprise a succinimide;   e) comprise an amine;   f) comprise a succinyl, malonyl, glutaryl, phthalyl or adipoyl;   g) comprise a malonyl;   h) comprise an amino acid;   i) comprise a cysteine;   j) comprise a lysine;   k) consist of a chain of 3 moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 10  alkyl, C 3 -C 10  cycloalkane, C 2 -C 10  alkene, C 5 -C 10  cycloalkene, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 2 -C 5  acyl, C 2 -C 5  acylamino, C 2 -C 5  acyloxy, succinyl, malonyl, glutaryl, phthalyl, adipoyl, an amino acid, an aryl group, a heteroaryl group, a carbamate, a chemical structure containing a cyclooctane fused to a dihydropyridazine, a chemical structure containing a cyclooctene fused to a triazole, a chemical structure containing a cyclooctene fused to a isoxazolidine, a dibenzocyclooctene, a dibenzoazacyclooctene,   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         l) consist of a chain of 4 moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 10  alkyl, C 3 -C 10  cycloalkane, C 2 -C 10  alkene, C 5 -C 10  cycloalkene, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 2 -C 5  acyl, C 2 -C 5  acylamino, C 2 -C 5  acyloxy, succinyl, malonyl, glutaryl, phthalyl, adipoyl, an amino acid, an aryl group, a heteroaryl group, a carbamate, a chemical structure containing a cyclooctane fused to a dihydropyridazine, a chemical structure containing a cyclooctene fused to a triazole, a chemical structure containing a cyclooctene fused to a isoxazolidine, a dibenzocyclooctene, a dibenzoazacyclooctene, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         m) consist of a chain of 5 moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 10  alkyl, C 3 -C 10  cycloalkane, C 2 -C 10  alkene, C 5 -C 10  cycloalkene, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 2 -C 5  acyl, C 2 -C 5  acylamino, C 2 -C 5  acyloxy, succinyl, malonyl, glutaryl, phthalyl, adipoyl, an amino acid, an aryl group, a heteroaryl group, a carbamate, a chemical structure containing a cyclooctane fused to a dihydropyridazine, a chemical structure containing a cyclooctene fused to a triazole, a chemical structure containing a cyclooctene fused to a isoxazolidine, a dibenzocyclooctene, a dibenzoazacyclooctene, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         n) comprise a [PEG(y)]z group bonded to a lysine; 
         o) comprise a C 1 -C 4  acyl group bonded to a succinimide group; 
         p) comprise a lysine bonded to a C 1 -C 4  acyl 
         q) comprise a [PEG(y)]z group, which is bonded to a glutaryl; 
         r) consist of a chain of three, four or five moieties selected from the group consisting of [PEG(y)]z, C 2 -C 5  acyl, succinyl, malonyl, glutaryl, an amino acid, a chemical structure containing a cyclooctane fused to a dihydropyridazine, a chemical structure containing a cyclooctene fused to a triazole, a chemical structure containing a cyclooctene fused to a isoxazolidine, a dibenzocyclooctene, a dibenzoazacyclooctene, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein X 1  is CH or N, X 2  is CH 2  or a carbonyl group, and R 5  is an aryl or alkyl group, wherein [PEG(y)]z is: 
       
       
         
           
           
               
               
           
         
       
       wherein y=1-100 and z=1-10;
 s) is a bond; 
 t) is a cysteine; 
 u) has a linear structure; or 
 v) has a branched structure; 
 w) has the structure: 
 
       
         
           
           
               
               
           
         
         x) is: 
       
       
         
           
           
               
               
           
         
       
       wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50;
 y) is: 
 
       
         
           
           
               
               
           
         
       
       wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50 and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50;
 z) is: 
 
       
         
           
           
               
               
           
         
       
       wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50 and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50; or
 aa) is: 
 
       
         
           
           
               
               
           
         
       
       wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50. 
     
     
         16 . The tetrahedral antibody of  claim 14  or  15 , wherein R a  and/or R b  comprise the moiety 
       
         
           
           
               
               
           
         
       
       wherein X 1  is CH or N and X 2  is CH 2  or a carbonyl group. 
     
     
         17 . The tetrahedral antibody of  claim 1  or  claim 1 .k)iii), wherein the non-peptidyl linkage is a non-covalent linkage between a first dimerizing polypeptide attached to the first domain and a second dimerizing polypeptide attached to the second domain. 
     
     
         18 . The tetrahedral antibody of  claim 17 , wherein the first and second dimerizing polypeptides are selected from the group consisting of:
 a) dimerizing domains of an extracellular protein dimer, and   b) dimerizing domains of an intracellular protein dimer.   
     
     
         19 . The tetrahedral antibody of  claim 17 , wherein the first and second dimerizing polypeptides are selected from the group consisting of:
 a) a leucine zipper domain,   b) a collectrin-like domain (CLD),   c) a collectrin domain (CD),   d) a CD8 alpha extracellular domain, and   e) a CD8 beta extracellular domain.   
     
     
         20 . The tetrahedral antibody of any one of  claims 17  to  19 , wherein:
 a) the first dimerizing polypeptide is the same as the second dimerizing polypeptide, and 
 b) the dimerizing polypeptides form a homodimer. 
 
     
     
         21 . The tetrahedral antibody of any one of  claims 17  to  19 , wherein:
 a) the first dimerizing polypeptide is different than the second dimerizing polypeptide, and 
 b) the first and second dimerizing polypeptides form a heterodimer. 
 
     
     
         22 . The tetrahedral antibody of  claim 21 , wherein:
 a) the dimerizing polypeptides are collectrin-like domain (CLD), and wherein:
 i) the CLD comprises substitutions that disrupt homodimer formation in the CLD dimerizing polypeptide, preferably wherein the substitutions are at Arg652, Arg710, Tyr641, Tyr633, Asn638, Glu639, Gln653, Asn636, Ser709, Asp713, and/or Arg716, more preferably wherein Tyr641 and Tyr633 are substituted with positively charged amino acids lysine, arginine or histidine and Arg652 and Arg710 are substituted with the negatively charged amino acids glutamic acid or aspartic acid or the positively amino acid lysine; or 
   b) the dimerizing polypeptides are collectrin, and wherein:
 i) the collecting dimerizing polypeptide comprises substitutions that disrupt homodimer formation in the collectrin dimerizing polypeptide, preferably wherein the substitutions are at Arg59, Arg111, Tyr48, and/or Tyr40, more preferably wherein Tyr48 and/or Tyr40 are substituted with positively charged amino acids lysine, arginine or histidine and Arg59 and/or Arg111 are substituted with the negatively charged amino acids glutamic acid or aspartic acid or the positively charge amino acid lysine. 
   
     
     
         23 . The tetrahedral antibody of  claim 22 , wherein:
 a) the dimerizing polypeptides are collectrin-like domain (CLD), and wherein:
 i) the CLD comprises substitutions that promote heterodimer formation in the CLD dimerizing polypeptide, preferably wherein:
 (1) Tyr633 on the first CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg710 on the second CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (2) Tyr633 on the second CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg710 on the first CLD dimerizing polypeptide is substituted. with the other of a positively charge or negatively charged amino acid; 
 (3) Tyr641 on the first CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg652 on the second CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (4) Tyr641 on the second CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg652 on the first CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (5) Arg652 on the first CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Asn638 on the second CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (6) Arg652 on the second CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg638 on the first CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (7) Arg710 on the first CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Glu639 on the second CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (8) Arg710 on the second CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Glu639 on the first CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (9) Ser709 on the first CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg716 on the second CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (10) Ser709 on the second CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg716 on the first CLD dimerizing polypeptide is substituted. with the other of a positively charge or negatively charged amino acid; 
 (11) Asp713 on the first CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg716 on the second CLD dimerizing polypeptide is substituted. with the other of a positively charge or negatively charged amino acid; and/or 
 (12) Asp713 on the second CLD dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg716 on the first CLD dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; or 
 
   b) the dimerizing polypeptides are collectrin, and wherein:
 i) the collectrin dimerizing polypeptide comprises substitutions that promote heterodimer formation in the collectrin dimerizing polypeptide, preferably wherein:
 (1) Tyr40 on the first collectrin dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg111 on the second collectrin dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (2) Tyr40 on the second collectrin dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg111 on the first collectrin dimerizing polypeptide is substituted with the other of a positively charge or negatively charged amino acid; 
 (3) Tyr48 on the first collectrin dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg59 on the second collectrin dimerizing polypeptide is substituted with the other of a positively charge or negatively, charged amino acid; and/or 
 (4) Tyr48 on the second collectrin dimerizing polypeptide is substituted with either a positively charge or negatively charged amino acid, and Arg59 on the first collectrin dimerizing polypeptide is substituted with the other of a positively charge or negatively, charged amino acid. 
 
   
     
     
         24 . The tetrahedral antibody of  claim 17 , wherein:
 a) the first and second dimerizing polypeptides are selected from the group consisting of:
 i) a T cell receptor alpha and T cell receptor beta extracellular domain, 
 ii) a T cell receptor gamma and T cell receptor extracellular domain, 
 iii) an WIC class I alpha extracellular domain and beta-2 microglobulin 
 iv) an WIC class II alpha and WIC class II beta extracellular domain, and 
 v) a CD8 alpha and CD8 beta extracellular domain, 
   b) the first dimerizing polypeptide is different from the second dimerizing polypeptide, and   c) the first and second dimerizing polypeptides form a heterodimer.   
     
     
         25 . The tetrahedral antibody of any one of  claims 21  to  24 , wherein the first and second dimerizing polypeptides, when in the presence of each other, form less than 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1% homodimers. 
     
     
         26 . The tetrahedral antibody of any one of  claims 17  to  25 , wherein the first dimerizing polypeptide comprises one or more disulfide bonds with the second dimerizing polypeptide, preferably wherein:
 a) the one or more disulfide bonds are at the interface between the first and second dimerizing polypeptides, more preferably wherein:
 i) if the first and second dimerizing polypeptides are collectrin-like domain or collectrin, and the one or more disulfide bonds are in the second and fourth helices of the collectrin-like domain or corresponding region in collectrin, or 
 
 b) the one or more disulfide bonds are between an immunoglobulin hinge region, or portion thereof comprising at least one cysteine, appended at the N-terminus and/or C-terminus of the first and second dimerizing polypeptides, wherein said hinge regions are appended directly to the first and second dimerizing polypeptides or via peptide linkers, preferably wherein the first and second dimerizing polypeptides are collectrin-like domain or collectrin. 
 
     
     
         27 . The tetrahedral antibody of any of  claims 17 - 20 , wherein:
 a) the third and fourth domains are each the ACE2 peptidase domain (PD), and   b) the first and second dimerizing polypeptides are each the ACE2 collectrin-like domain (CLD) preferably wherein the first and second domains are Fc domains and wherein each polypeptide chain of the tetrahedral antibody comprises the amino acid sequence set forth in any one of SEQ ID NOs: 74-119, more preferably SEQ ID NO: 78.   
     
     
         28 . The tetrahedral antibody of  claim 17 - 27 , wherein the first and second domains are Fc domains. 
     
     
         29 . The tetrahedral antibody of any of  claims 17 - 27 , wherein:
 a) the first and second domains are Fc domains and the third domain is a first type of Fab domain,   b) the first and second domains are Fc domains and the third and fourth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,   c) the first domain is an Fc domain, and the second and third domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain, or   d) the first domain is an Fc domain, and the second, third, and fourth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain.   
     
     
         30 . The tetrahedral antibody of any of  claims 17 - 29 , additionally comprising a fifth domain, wherein the fifth domain is attached at its C-terminus by a peptide bond or via a peptide linker to:
 a) the N-terminus of the first dimerizing polypeptide,   b) the second N-terminus of the first domain, or   c) the N-terminus of a third dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the first domain.   
     
     
         31 . The tetrahedral antibody of  claim 30 , wherein:
 a) the first and second domains are Fc domains and the fifth domain is a first type of Fab domain,   b) the first and second domains are Fc domains, and the third and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,   c) the first and second domains are Fc domains, and the fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,   d) the first and second domains are Fc domains, and the third, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain,   e) the first domain is an Fc domain, and the second and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,   f) the first domain is an Fc domain, and the second, third, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain,   g) the first domain is an Fc domain, and the second, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain, or   h) the first domain is an Fc domain, and the second, third, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, a third type of Fab domain, and a fourth type of Fab domain.   
     
     
         32 . The tetrahedral antibody of any of  claims 17 - 31 , additionally comprising a fifth and/or sixth domain, wherein:
 a) the first domain is joined to the second domain via a first dimerizing polypeptide attached to the first N-terminus of the first domain, and wherein
 i) the fifth domain is attached at its C-terminus by a peptide bond or via a peptide linker to:
 (1) the N-terminus of the first dimerizing polypeptide, 
 (2) the second N-terminus of the first domain, or 
 (3) the N-terminus of a third dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the first domain, 
 
   b) the first domain is joined to the second domain via a first dimerizing polypeptide attached to the first C-terminus of the first domain, and wherein
 i) the fifth domain is attached at its N-terminus by a peptide bond or via a peptide linker to:
 (1) the C-terminus of the first dimerizing polypeptide, 
 (2) the second C-terminus of the first domain, or 
 (3) the C-terminus of a third dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its N-terminus by a peptide bond or via a peptide linker to the second C-terminus of the first domain, 
 
   c) the second domain is joined to the first domain via a second dimerizing polypeptide attached to the first N-terminus of the second domain, and wherein
 i) the sixth domain is attached at its C-terminus by a peptide bond or via a peptide linker to:
 (1) the N-terminus of the second dimerizing polypeptide, 
 (2) the second N-terminus of the second domain, or 
 (3) the N-terminus of a fourth dimerizing polypeptide, wherein the fourth dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the second domain, or 
 
   d) the second domain is joined to the first domain via a second dimerizing polypeptide attached to the first C-terminus of the second domain, and wherein
 i) the sixth domain is attached at its N-terminus by a peptide bond or via a peptide linker to:
 (1) the C-terminus of the second dimerizing polypeptide, 
 (2) the second C-terminus of the second domain, or 
 (3) the C-terminus of a fourth dimerizing polypeptide, wherein the fourth dimerizing polypeptide is attached at its N-terminus by a peptide bond or via a peptide linker to the second C-terminus of the second domain. 
 
   
     
     
         33 . The tetrahedral antibody of  claim 32 , wherein:
 a) the first and second domains are Fc domains and the fifth domain is a first type of Fab domain,   b) the first and second domains are Fc domains, and the third and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,   c) the first and second domains are Fc domains, and the fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,   d) the first and second domains are Fc domains, and the third, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain,   e) the first domain is an Fc domain, and the second and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,   f) the first domain is an Fc domain, and the second, third, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain,   g) the first domain is an Fc domain, and the second, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain,   h) the first domain is an Fc domain, and the second, third, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, a third type of Fab domain, and a fourth type of Fab domain, or   i) the first and second domains are Fc domains, the third and fourth domains are the ACE2 peptidase domain (PD), and the fifth and sixth domains are Fab domains.   
     
     
         34 . The tetrahedral antibody of  claim 32 , wherein:
 a) the third, fourth, fifth and sixth domains are each the ACE2 PD and the dimerizing polypeptides are each the ACE2 CLD,   b) the first and second domains are Fc domains, the third, fourth, fifth and sixth domains are each the ACE2 PD and the dimerizing polypeptides are each the ACE2 CLD, preferably wherein the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker,   c) the third and fourth domains are each the ACE2 PD, the fifth and sixth domains are each Fab domains, and the dimerizing polypeptides are each the ACE2 CLD,   d) the first and second domains are Fc domains, the third and fourth domains are each the ACE2 PD, the fifth and sixth domains are each Fab domains, and the dimerizing polypeptides are each the ACE2 CLD, preferably wherein the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker,   e) the third and fourth domains are each Fab domains, the fifth and sixth domains are each the ACE2 PD, and the dimerizing polypeptides are each the ACE2 CLD,   f) the first and second domains are Fc domains, the third and fourth domains are each Fab domains, the fifth and sixth domains are each the ACE2 PD, and the dimerizing polypeptides are each the ACE2 CLD, preferably wherein the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker, or   g) the first and second domains are Fc domains, the third and fourth domains are the ACE2 PD, the fifth and sixth domains are Fab domains, the dimerizing polypeptides are each the ACE2 CLD, and the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker,   preferably wherein such domains and linkers, if present, are characterized by one or more or all of the following features:
 i) the Fc domains are characterized by one or more or all of the following features:
 (1) are heterodimers, 
 (2) are IgG1 Fc domains, 
 (3) comprise a silencing mutation such that the Fc domain lacks Fc gamma receptor binding activity, preferably wherein such mutation is one of the following combinations of mutations:
 (a) P329G/L234A/L235A (PGLALA), 
 (b) L234A/L235A (LALA), 
 (c) P331 S/L234A/L235A, 
 (d) L234F/L235E/P331S, and 
 (e) L234F/L235E/P329G, 
 
 (4) comprise a mutation that enhances FcRn activity, preferably wherein such mutation extends the half-life of the tetrahedral antibody, preferably wherein the mutation is:
 (a) a combination the following mutations: L309D/Q311H/N434S (DHS), 
 (b) a combination of the following mutations: S239D/I298E, 
 (c) S239D, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises the I298E mutation, or 
 (d) I298E, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises the S239D mutation, and 
 
 (5) comprise a mutation that ablates their Protein A binding site, preferably wherein such mutation is H435R/Y436F (HY/RF), 
 
 ii) the ACE2 peptidase domains comprise a mutation which blocks its angiotensin converting enzyme activity, preferably wherein such mutation is an H378A mutation, 
 iii) the Fab domains are chimeric Fab domains comprising a murine variable region, and 
 iv) the peptide linkers each have a length of 23 amino acids and are derived from the stalk region of a TNF receptor, preferably wherein the TNF receptor is TNF receptor 1B, still more preferably wherein the peptide linker consists of the amino acid sequence set forth in SEQ ID NO: 4468, and 
 v) such domains and peptide linkers are formed by two or three different types of polypeptide chains. 
   
     
     
         35 . The tetrahedral antibody of  claim 32 , wherein:
 a) the third and fourth domains are each the ACE2 PD,   b) the fifth domain, if present, is attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of a third dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the first domain,   c) the sixth domain, if present, is attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of a fourth dimerizing polypeptide, wherein the fourth dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the second domain, and   d) the first, second, third, and fourth dimerizing polypeptides are each the ACE2 CLD.   
     
     
         36 . The tetrahedral antibody of any of  claims 27  and  34 - 35 , wherein the ACE2 PD comprises or consists of amino acids 18-615 of the ACE2 protein or a portion thereof. 
     
     
         37 . The tetrahedral antibody of any of  claims 27  and  34 - 35 , wherein the ACE2 CLD comprises or consists of amino acids 616-740 of the ACE2 protein or a portion thereof. 
     
     
         38 . The tetrahedral antibody of any of  claims 27  and  34 - 37 , wherein the ACE2 PD is catalytically active. 
     
     
         39 . The tetrahedral antibody of any of  claims 27  and  34 - 37 , wherein ACE2 PD is catalytically inactive. 
     
     
         40 . The tetrahedral antibody of  claim 39 , wherein ACE2 PD comprises a R 273 Q or a H378A mutation. 
     
     
         41 . The tetrahedral antibody of any of  claims 28 ,  29 ,  31  and  33 - 40 , wherein the Fc domains lack Fc gamma receptor binding activity. 
     
     
         42 . The tetrahedral antibody of  claim 41 , wherein the Fc domains comprise:
 a) a P329G mutation, a L234A mutation and a L235A mutation (PGLALA);   b) a L234A mutation and a L235A mutation (LALA),   c) a P331S mutation, a L234A mutation, and a L235A mutation,   d) a L234F mutation, a L235E mutation, and a P331S mutation, or   e) a L234Fmutation, a L235E mutation, and a P329G mutation.   
     
     
         43 . The tetrahedral antibody of any of  claims 27 - 42 , wherein the tetrahedral antibody comprises one or more Fab domains and the one or more Fab domains comprise the complementarity-determining region (CDR) of the Fab domain of the B13A antibody. 
     
     
         44 . The tetrahedral antibody of  claim 43 , wherein the one or more Fab domains comprise the VH and VL regions from the B13A antibody, preferably wherein the VH and VL regions comprise the amino acid sequences set forth in SEQ ID NOs 463 and 464 or variants thereof with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences. 
     
     
         45 . The tetrahedral antibody of  claim 43  or  44 , wherein the one or more Fab domains are humanized. 
     
     
         46 . The tetrahedral antibody of  claim 34 , wherein the first and second domains are Fc domains, the third and fourth domains are the ACE2 PD, the fifth and sixth domains are Fab domains, the dimerizing polypeptides are each the ACE2 CLD, and the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker, and wherein the domains and peptide linkers of the tetrahedral antibody are formed by three different types of polypeptide chains. 
     
     
         47 . The tetrahedral antibody of  claim 46 , wherein the three different types of polypeptide chains are denoted H1, L2, and H2, and wherein:
 a) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 524, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 535, or wherein the H1, L2 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   b) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 473, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 485, or wherein the H1, L2 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   c) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 526, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 527, or wherein the H1, L2 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   d) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 514, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 528, or wherein the H1, L2 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   e) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 529, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 530, or wherein the H1, L2 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   f) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 518, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 531; or wherein the H1, L2 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences,   g) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 532, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 533, or wherein the H1, L2 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or   h) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 522, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 534, or wherein the H1, L2 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.   
     
     
         48 . The tetrahedral antibody of  claim 34 , wherein the first and second domains are Fc domains, the third, fourth, fifth and sixth domains are each the ACE2 PD and the dimerizing polypeptides are each the ACE2 CLD, wherein the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker, and wherein the domains and peptide linkers of the tetrahedral antibody are formed by two different types of polypeptide chains. 
     
     
         49 . The tetrahedral antibody of  claim 48 , wherein the two different types of polypeptide chains are denoted H1 and H2, and wherein:
 a) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 509, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 510 or wherein the H1 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   b) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 512, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 513 or wherein the H1 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   c) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 516, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 517 or wherein the H1 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   d) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 520, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 521 or wherein the H1 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   e) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 542, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 543 or wherein the H1 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   f) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 545, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 546 or wherein the H1 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   g) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 548, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 549 or wherein the H1 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or   h) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 551, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 552 or wherein the H1 and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.   
     
     
         50 . The tetrahedral antibody of  claim 35 , wherein:
 a) the third domain, first dimerizing polypeptide, and first polypeptide chain of the first domain are part of a first stretch of consecutive amino acids,   b) the fourth domain, second dimerizing polypeptide, and first polypeptide chain of the second domain are part of a second stretch of consecutive amino acids,   c) the fifth domain, third dimerizing polypeptide, and second polypeptide chain of the first domain are part of a third stretch of consecutive amino acids, and   d) the sixth domain, fourth dimerizing polypeptide, and second polypeptide chain of the second domain are part of a fourth stretch of consecutive amino acids,   
       wherein each stretch of consecutive amino acids consists of the sequence of amino acids selected from the group consisting of SEQ ID NOs: 74-119 or wherein each such stretch of consecutive amino acids are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences. 
     
     
         51 . A polynucleotide which encodes a polypeptide of  claim 27 , wherein the polypeptide comprises the amino acid sequence set forth in any one of SEQ ID NOs: 74-119. 
     
     
         52 . A polynucleotide which encodes a polypeptide comprising any one of the polypeptide chains of  claim 47  or  49 . 
     
     
         53 . A polynucleotide which encodes a polypeptide comprising any one of the stretches of consecutive amino acids of  claim 50 . 
     
     
         54 . A vector comprising polynucleotides which encode polypeptides comprising the three different types of polypeptide chains of  claim 47 , wherein each polynucleotide is operably linked to a promoter which directs expression of the polynucleotide in a host cell. 
     
     
         55 . A vector comprising polynucleotides which encode polypeptides comprising the two different types of polypeptide chains of  claim 49 , wherein each polynucleotide is operably linked to a promoter which directs expression of the polynucleotide in a host cell. 
     
     
         56 . A vector comprising one or more polynucleotides of any one of  claims 51  to  53 , wherein each polynucleotide is operably linked to a promoter which directs expression of the polynucleotide in a host cell. 
     
     
         57 . A host cell comprising the vector of any one of  claims 54  to  56 . 
     
     
         58 . The host cell of  claim 57  for use in a method of producing a tetrahedral antibody. 
     
     
         59 . A method of producing a tetrahedral antibody, the method comprising recombinantly expressing the two different types of polypeptide chains of  claim 47  in a host cell. 
     
     
         60 . A method of producing a tetrahedral antibody, the method comprising recombinantly expressing the two different types of polypeptide chains of  claim 49  in a host cell. 
     
     
         61 . A method of producing a tetrahedral antibody, the method comprising recombinantly expressing the vector of any one of  claims 54  to  56  in a host cell. 
     
     
         62 . A method of producing a tetrahedral antibody comprising two, three, or four different types of polypeptide chains, the method comprising expressing the two, three, or four different types of polypeptide chains in the host cell of  claim 57 . 
     
     
         63 . A pharmaceutical composition comprising any one of the tetrahedral antibodies of  claims 27  and  34 - 49  and one or more pharmaceutically acceptable excipients. 
     
     
         64 . A method of treating Covid-19 in a subject, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 63 . 
     
     
         65 . The tetrahedral antibody of any of  claims 1  to  33 , further comprising a seventh and/or eight domain, wherein:
 a) the first domain is joined to the second domain via a covalent linkage attached to the first N-terminus of the first domain or via a first dimerizing polypeptide attached to the first N-terminus of the first domain, and wherein
 i) the seventh domain is attached at its N-terminus by a peptide bond or via a peptide linker to:
 (1) the first C-terminus of the first domain, or 
 (2) the second C-terminus of the first domain, 
 
 
 b) the first domain is joined to the second domain via a covalent linkage attached to the first C-terminus of the first domain or via a first dimerizing polypeptide attached to the first C-terminus of the first domain, and wherein
 i) the seventh domain is attached at its C-terminus by a peptide bond or via a peptide linker to:
 (1) the first N-terminus of the first domain, or 
 (2) the second N-terminus of the first domain, 
 
 
 c) the second domain is joined to the first domain via a covalent linkage attached to the first N-terminus of the second domain or via a second dimerizing polypeptide attached to the first N-terminus of the second domain, and wherein
 i) the eighth domain is attached at its N-terminus by a peptide bond or via a peptide linker to:
 (1) the first C-terminus of the second domain, or 
 (2) the second C-terminus of the second domain, or 
 
 
 d) the second domain is joined to the first domain via a covalent linkage attached to the first C-terminus of the second domain or via a second dimerizing polypeptide attached to the first C-terminus of the second domain, and wherein
 i) the eighth domain is attached at its C-terminus by a peptide bond or via a peptide linker to:
 (1) the first N-terminus of the second domain, or 
 (2) the second N-terminus of the second domain. 
 
 
 
     
     
         66 . The tetrahedral antibody of  claim 32 , wherein:
 a) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains and the fifth and sixth domains are anti-CD19 Fab domains;   b) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains and the fifth and sixth domains are anti-CD20 Fab domains;   c) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, and each dimerizing polypeptide is an ACE2 CLD;   d) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains and the fifth and sixth domains are anti-CD20 Fab domains, and each dimerizing polypeptide is an ACE2 CLD;   e) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker;   f) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains and the fifth and sixth domains are anti-CD20 Fab domains, each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker.   
     
     
         67 . The tetrahedral antibody of  claim 66 , wherein:
 a) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains and the fifth and sixth domains are anti-CD19 Fab domains, and the seventh and eighth domains are single chain 4-1BB ligands;   b) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, the fifth and sixth domains are anti-CD20 Fab domains, and the seventh and eighth domains are single chain 4-1BB ligands;   c) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, the seventh and eighth domains are single chain 4-1BB ligands, and each dimerizing polypeptide is an ACE2 CLD;   d) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains and the fifth and sixth domains are anti-CD20 Fab domains, the seventh and eighth domains are single chain 4-1BB ligands, and each dimerizing polypeptide is an ACE2 CLD;   e) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, the seventh and eighth domains are single chain 4-1BB ligands, each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker; or   f) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains and the fifth and sixth domains are anti-CD20 Fab domains, the seventh and eighth domains are single chain 4-1BB ligands, each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each connected to their respective dimerizing polypeptides via a peptide linker.   
     
     
         68 . The tetrahedral antibody of  claim 66  or  67 , wherein:
 a) the anti-CD19 Fab domain comprises
 i) the CDRs of each of the heavy and lights chains of FMC63, preferably wherein the anti-CD19 Fab is the Fab domain of FMC63; 
 ii) the CDRs of each of the heavy and lights chains of FMC60, preferably wherein the anti-CD19 Fab is the Fab domain of FMC60; or 
 iii) the CDRs of each of the heavy and lights chains of FMC59, preferably wherein the anti-CD19 Fab is the Fab domain of FMC59; and/or 
 
 b) the anti-CD20 Fab domain comprises the CDR of rituximab, preferably wherein the anti-CD20 Fab is the Fab domain of rituximab. 
 
     
     
         69 . The tetrahedral antibody of any one of  claims 66  to  68 , wherein the Fc domains are characterized by one or more or all of the following features:
 a) are heterodimers, 
 b) are IgG1 Fc domains, 
 c) comprise a silencing mutation such that the Fc domain lacks Fc gamma receptor binding activity, preferably wherein such mutation is one of the following combinations of mutations:
 i) P329G/L234A/L235A (PGLALA), 
 ii) L234A/L235A (LALA), 
 iii) P331S/L234A/L235A, 
 iv) L234F/L235E/P331S, and 
 v) L234F/L235E/P329G, 
 
 d) comprise a mutation that enhances FcRn activity, preferably wherein such mutation extends the half-life of the tetrahedral antibody, preferably wherein the mutation is a combination the following mutations: L309D/Q311H/N434S (DHS), and 
 e) comprise a mutation that ablates their Protein A binding site, preferably wherein such mutation is H435R/Y436F (HY/RF). 
 
     
     
         70 . The tetrahedral antibody of any one of  claims 66  to  69 , wherein the peptide linkers each have a length of 23 amino acids and are derived from the stalk region of a TNF receptor, preferably wherein the TNF receptor is TNF receptor 1B, still more preferably wherein the peptide linker consists of the amino acid sequence set forth in SEQ ID NO: 4468, and 
     
     
         71 . The tetrahedral antibody of any one of  claims 66  to  70 , wherein the dimerizing polypeptides are each an ACE2 CLD, and wherein each ACE2 CLD comprises or consists of amino acids 616-740 of the ACE2 protein. 
     
     
         72 . The tetrahedral antibody of  claim 66 , wherein such domains and peptide linkers are formed by four different types of polypeptide chains, preferably wherein the four different types of polypeptide chains are denoted L1, H1, L2, and H2, and wherein:
 a) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 707, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 708, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   b) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 710, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   c) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 711, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   d) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 712, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 713, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   e) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 715, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or   f) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 716, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   g) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4801, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4721, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4802, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4722, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   h) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4804, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4724, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   i) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4805, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4725, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   j) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4806, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4726, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4807, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4727, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   k) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4808, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   l) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4808, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   m) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4772, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   n) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4773, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   o) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4772, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   p) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4773, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   q) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4816, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   r) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4816, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   s) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4817, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   t) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4817, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   u) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4794, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   v) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4793, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   w) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4794, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   x) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4819, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences   y) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4819, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   z) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4820, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or   aa) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4820, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.   
     
     
         73 . The tetrahedral antibody of  claim 67 , wherein such domains and peptide linkers are formed by four different types of polypeptide chains, preferably wherein the four different types of polypeptide chains are denoted L1, H1, L2, and H2, and wherein:
 a) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 707, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 717, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   b) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 718, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   c) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 719, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   d) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 712, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 720, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   e) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 721, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   f) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 722, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   g) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 724, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   h) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 725, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 726, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   i) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 725, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 727, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   j) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 729, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;   k) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 731, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or   l) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 732, or wherein the L1, H1, L2, and H2 chains are variants with at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.   
     
     
         74 . A polynucleotide which encodes a polypeptide comprising any one of the polypeptide chains of  claim 72  or  73 . 
     
     
         75 . A vector comprising polynucleotides which encode polypeptides comprising the four different types of polypeptide chains of  claim 72  or  73 , wherein each polynucleotide is operably linked to a promoter which directs expression of the polynucleotide in a host cell. 
     
     
         76 . A vector comprising one or more polynucleotides of  claim 74 , wherein each polynucleotide is operably linked to a promoter which directs expression of the polynucleotide in a host cell. 
     
     
         77 . A host cell comprising the vector of  claim 75  or  76 . 
     
     
         78 . The host cell of  claim 77  for use in a method of producing a tetrahedral antibody. 
     
     
         79 . A method of producing a tetrahedral antibody, the method comprising recombinantly expressing the four different types of polypeptide chains of  claim 72  or  73  in a host cell. 
     
     
         80 . A method of producing a tetrahedral antibody, the method comprising recombinantly expressing the vector of  claim 75  or  76  in a host cell. 
     
     
         81 . A method of producing a tetrahedral antibody comprising four different types of polypeptide chains, the method comprising expressing the four different types of polypeptide chains in the host cell of  claim 77 . 
     
     
         82 . A pharmaceutical composition comprising any one of the tetrahedral antibodies of  claims 66 - 73  and one or more pharmaceutically acceptable excipients. 
     
     
         83 . A method of treating cancer or inflammatory disease in a subject, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 82 , preferably wherein the cancer is B cell cancer. 
     
     
         84 . A tetrahedral molecule comprising a first, second, third, and fourth domain, wherein:
 a) the first and second domains each independently comprise:
 i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and 
 ii) optionally a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain, 
   b) the first domain and the second domain are joined to each other by a non-covalent linkage
 (1) between a first dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the first domain, and a second dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the second domain, 
 (2) between a first dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the first domain, and a second dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the second domain, 
 (3) between a first dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the first domain, and a second dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the second domain, or 
 (4) between a first dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the first domain, and a second dimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the second domain, 
 wherein the first and second dimerizing polypeptides are not immunoglobulin polypeptides, 
   c) if the first domain is joined to the second domain via a first dimerizing polypeptide attached to the first N-terminus of the first domain, then the third domain is attached at its C-terminus by a peptide bond or via a peptide linker to
 i) the N-terminus of the first dimerizing polypeptide, 
 ii) the second N-terminus of the first domain if present, or 
 iii) the N-terminus of a third dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the first domain if present, 
   d) if the first domain is joined to the second domain via a first dimerizing polypeptide attached to the first C-terminus of the first domain, then the third domain is attached at its N-terminus by a peptide bond or via a peptide linker to
 i) the C-terminus of the first dimerizing polypeptide, 
 ii) the second C-terminus of the first domain if present, or 
 iii) the C-terminus of a third dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its N-terminus by a peptide bond or via a peptide linker to the second C-terminus of the first domain if present, 
   e) if the second domain is joined to the first domain via a second dimerizing polypeptide attached to the first N-terminus of the second domain, then the fourth domain is attached at its C-terminus by a peptide bond or via a peptide linker to
 i) the N-terminus of the second dimerizing polypeptide, 
 ii) the second N-terminus of the second domain if present, or 
 iii) the N-terminus of a fourth dimerizing polypeptide, wherein the third dimerizing polypeptide is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the second domain if present, and 
   f) if the second domain is joined to the first domain via a second dimerizing polypeptide attached to the first C-terminus of the second domain, then the fourth domain is attached at its N-terminus by a peptide bond or via a peptide linker to
 i) the C-terminus of the second dimerizing polypeptide, 
 ii) the second C-terminus of the second domain if present, or 
 iii) the C-terminus of a fourth dimerizing polypeptide, wherein the fourth dimerizing polypeptide is attached at its N-terminus by a peptide bond or via a peptide linker to the second C-terminus of the second domain if present. 
   
     
     
         85 . The tetrahedral molecule of  claim 84 , wherein
 a) the first domain is an Fc domain or Fab domain,   b) the first domain is an Fc domain or Fab domain and the second domain is not an Fc domain or Fab domain,   c) the first domain is an Fc domain and the second domain is a Fab domain,   d) the first and second domains are Fc domains,   e) the first and second domains are Fab domain,   f) the second, third and/or fourth domain are selected from the group consisting of (i) a secreted protein, and (ii) the extracellular domain of a transmembrane protein,   g) the third domain is selected from the group of (i) a secreted protein, and (ii) the extracellular domain of a transmembrane protein, and the fourth domain is a Fab,   h) the third domain is IL-15,   i) the third domain is IL-15 and the fourth domain is an IL-15Rα sushi domain,   j) the third domain is IL-15 and the fourth domain is a Fab,   k) the third and fourth domains are each the ACE2 peptidase domain (PD),   l) the first and second domains are Fc domains, and the third and fourth domains are selected from the group consisting of (i) a secreted protein, and (ii) the extracellular domain of a transmembrane protein,   m) the first and second domains are Fc domains, the third domain is selected from the group consisting of (i) a secreted protein, and (ii) the extracellular domain of a transmembrane protein, and the fourth domain is Fab,   n) the first and second domains are Fc domains and the third and fourth domains are Fab domains,   o) the first and second domains are Fc domains and the third and fourth domains are each the ACE2 peptidase domain (PD),   p) the first domain is an Fc domain and the second, third and fourth domains are Fab domains,   q) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is an IL-15Rα sushi domain, or   r) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is a Fab.   
     
     
         86 . The tetrahedral molecule of  claim 84  or  85 , wherein the first and second dimerizing polypeptides are selected from the group consisting of:
 a) dimerizing domains of an extracellular protein dimer, and 
 b) dimerizing domains of an intracellular protein dimer. 
 
     
     
         87 . The tetrahedral molecule of  claim 84  or  85 , wherein the first and second dimerizing polypeptides are selected from the group consisting of:
 a) a leucine zipper domain, 
 b) a collectrin-like domain (CLD), 
 c) a collectrin domain (CD), 
 d) a CD8 alpha extracellular domain, and 
 e) a CD8 beta extracellular domain. 
 
     
     
         88 . The tetrahedral molecule of any one of  claims 84  to  87 , wherein:
 a) the first dimerizing polypeptide is the same as the second dimerizing polypeptide, and 
 b) the dimerizing polypeptides form a homodimer. 
 
     
     
         89 . The tetrahedral molecule of any one of  claims 84  to  87 , wherein:
 a) the first dimerizing polypeptide is different than the second dimerizing polypeptide, and 
 b) the first and second dimerizing polypeptides form a heterodimer. 
 
     
     
         90 . The tetrahedral molecule of  claim 84  or  85 , wherein:
 a) the first and second dimerizing polypeptides are selected from the group consisting of:
 i) a T cell receptor alpha and T cell receptor beta extracellular domain, 
 ii) a T cell receptor gamma and T cell receptor extracellular domain, 
 iii) an WIC class I alpha extracellular domain and beta-2 microglobulin 
 iv) an WIC class II alpha and WIC class II beta extracellular domain, and 
 v) a CD8 alpha and CD8 beta extracellular domain, 
 
 b) the first dimerizing polypeptide is different from the second dimerizing polypeptide, and 
 c) the first and second dimerizing polypeptides form a heterodimer. 
 
     
     
         91 . The tetrahedral molecule of  claim 89  or  90 , wherein the first and second dimerizing polypeptides, when in the presence of each other, form less than 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1% homodimers. 
     
     
         92 . A non-naturally occurring fusion protein dimer comprising a dimer of a first dimerizing polypeptide and a second dimerizing polypeptide, wherein:
 a) the first dimerizing polypeptide is attached by a peptide bond or via a peptide linker at its N-terminus or C-terminus to a first domain, the second dimerizing polypeptide is optionally attached by a peptide bond or via a peptide linker at its N-terminus or C-terminus to a second domain,   b) the first and second dimerizing polypeptides are selected from the group consisting of:
 i) a collectrin-like domain (CLD), and 
 ii) a collectrin domain (CD), 
   c) the first dimerizing polypeptide is optionally attached by a peptide bond or via a peptide linker at its remaining free N-terminus or C-terminus to a third domain, and   d) the second dimerizing polypeptide is optionally attached by a peptide bond or via a peptide linker at its remaining free N-terminus or C-terminus to a fourth domain, and.   
     
     
         93 . The tetrahedral molecule of any one of  claims 84 - 91 , or the non-naturally occurring fusion protein dimer of  claim 92 , which:
 i) does not comprise an ACE2 PD at the N-terminal side of either dimerizing polypeptide; and/or   ii) does not comprise an ACE2 transmembrane domain at the C-terminal side of either dimerizing polypeptide.   
     
     
         94 . An octahedral antibody comprising a first, second, third, fourth, fifth and sixth domain, wherein:
 a) each of the first, second and third domains are selected from the group consisting of a Fab domain and an Fc domain,   b) each of the first, second and third domains comprise:
 i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and 
 ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain, 
   c) the first N-terminus of the first domain, the first N-terminus of the second domain and the first N-terminus of the third domain are joined to each other by a non-peptidyl linkage wherein the non-peptidyl linkage is:
 i) a branched covalent linkage, or 
 ii) a non-covalent linkage between
 (1) a first trimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the first domain, 
 (2) a second trimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the second domain, and 
 (3) a third trimerizing polypeptide attached by a peptide bond or via a peptide linker to the first N-terminus of the third domain, 
 wherein the first, second, and third trimerizing polypeptides are not immunoglobulin polypeptides, 
 
   d) the fourth domain is attached at its C-terminus by a peptide bond or via a peptide linker to:
 i) the second N-terminus of the first domain, or 
 ii) the N-terminus terminus of the first trimerizing polypeptide, 
   e) the fifth domain is attached at its C-terminus by a peptide bond or via a peptide linker to:
 i) the second N-terminus of the second domain, or 
 ii) the N-terminus of the second trimerizing polypeptide, and 
   f) the sixth domain is attached at its C-terminus by a peptide bond or via a peptide linker to:
 i) the second N-terminus of the third domain, or 
 ii) the N-terminus of the third trimerizing polypeptide. 
   
     
     
         95 . The octahedral antibody of  claim 94 , wherein the non-peptidyl linkage is a non-covalent linkage between a first trimerizing polypeptide attached to the first N-terminus of the first domain, a second trimerizing polypeptide attached to the first N-terminus of the second domain, and a third trimerizing polypeptide attached to the first N-terminus of the third domain, wherein the first, second, and third trimerizing polypeptides are selected from the group consisting of TNF ligand superfamily members OX40L/TNFLSF4, CD40L/TNFLSF5, FASL/TNFLSF6, CD70L/TNFLSF7, CD30L/TNFLSF8, 4-1BBL/TNFLSF9, TRAIL/TNFLSF10, RANKL/TNFLSF11, TWEAK/TNFLSF12, APRIL/TNFLSF13, BAFF/TNFLSF13B, LIGHT/TNFLSF14, VEG1/TNFLSF15, GITRL/TNFLSF18, EctodyplasinATNFLSF19, TNF/TNFLSF2, lymphotoxin alpha/TNFLSF1, and lymphotoxin beta/TNFLSF3. 
     
     
         96 . The octahedral antibody of  claim 94  or  95 , further comprising a seventh, eighth, and/or ninth domain, wherein:
 a) the seventh domain is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the first domain, 
 b) the eighth domain is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the second domain, and/or 
 c) the ninth domain is attached at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the third domain. 
 
     
     
         97 . The octahedral antibody of any one of  claims 94  to  96 , further comprising a tenth, eleventh, and/or twelfth domain, wherein:
 a) the tenth domain is attached at its N-terminus by a peptide bond or via a peptide linker to:
 i) the first C-terminus of the first domain, or 
 ii) the second C-terminus of the first domain, 
 
 b) the eleventh domain is attached at its N-terminus by a peptide bond or via a peptide linker to:
 i) the first C-terminus of the second domain, or 
 ii) the second C-terminus of the second domain, 
 
 c) the twelfth domain is attached at its N-terminus by a peptide bond or via a peptide linker to:
 i) the first C-terminus of the third domain, or 
 ii) the second C-terminus of the third domain. 
 
 
     
     
         98 . The tetrahedral or octahedral antibody, non-naturally occurring fusion protein dimer, or tetrahedral molecule of any of  claims 1  to  97 , wherein:
 a) one or more of the first, second, third, fourth, fifth, sixth, seventh, and eighth domains of the tetrahedral antibody, or one or more of the first, second, third, fourth, fifth, sixth domains, seventh, eighth, ninth, tenth, eleventh, and twelfth domains of the octahedral antibody are Fc domains, wherein the one or more Fc domains are independently selected from any of the Fc domains disclosed herein, 
 b) one or more of the first, second, third, fourth, fifth, sixth, seventh and eighth domains of the tetrahedral antibody, or one or more of the first, second, third, fourth, fifth, sixth domains, seventh, eighth, ninth, tenth, eleventh, and twelfth domains of the octahedral antibody are Fab domains, wherein the one or more Fab domains are independently selected from any of the Fab domains disclosed herein, 
 c) one or more of the third, fourth, fifth, sixth, seventh, and eighth domains of the tetrahedral antibody, or one or more of the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, and twelfth domains of the octahedral antibody are a secreted protein, wherein the one or more secreted protein are independently selected from any of the secreted proteins disclosed herein, 
 d) one or more of the third, fourth, fifth, sixth, seventh, and eighth domains of the tetrahedral antibody, or one or more of the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, and twelfth domains of the octahedral antibody are extracellular domains of a transmembrane protein, wherein the one or more extracellular domains of a transmembrane protein are independently selected from any of the extracellular domains of a transmembrane protein disclosed herein, 
 e) one or more of the third, fourth, fifth, sixth, seventh, and eighth domains of the tetrahedral or one or more of the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, and twelfth domains of the octahedral antibody:
 i) comprise the structure of a compound that is a drug approved for treating a subject afflicted with a disease, 
 ii) comprise the structure of an organic compound having a molecular weight less than 1000 Daltons, a DNA aptamer, an RNA aptamer, an oligonucleotide, or a protein that is biologically active, 
 iii) comprise a primary or a secondary amine, 
 iv) are aripiprazole or oseltamivir, 
 v) are a respiratory drug, an antiasthmatic agent, an analgesic agent, an antidepressant, an antianginal agent, an antiarrhythmic agent, an antihypertensive agent, an antidiabetic agent, an antihistamine, an anti-infective agent, an antibiotic, an antiinflamatory agent, an antiparkinsonism drug, an antipsychotics, an antipyretic agent, an antiulcer agent, an attention deficit hyperactivity disorder (ADHD) drug, a central nervous system stimulant, a decongestant, or a psychostimulant, 
 vi) are alprenolol, acebutolol, amidephrine, amineptine, amosulalol, amoxapine, amphetaminil, atenolol, atomoxetine, balofloxacin, bamethan, befunolol, benazepril, benfluorex, benzoctamine, betahistine, betaxolol, bevantolol, bifemelane, bisoprolol, brinzolamide, bufeniode, butethamine, camylofine, carazolol, carticaine, carvedilol, cephaeline, ciprofloxacin, cloZapine, clobenZorex, clorprenaline, cyclopentamine, delapril, demexiptiline, denopamine, desipramine, desloratadine, diclofenac, dimetofrine, dioxadrol, dobutamine, dopexamine, doripenem, dorzolamide, droprenilamine, duloxetine, eltopraZine, enalapril, enoxacin, epinephrine, ertapenem, esapraZole, esmolol, etoxadrol, fasudil, fendiline, fenethylline, fenfluramine, fenoldopam, fenoterol, fenproporex, flecamide, fluoxetine, formoterol, frovatriptan, gaboxadol, garenoxacin, gatifloxacin, grepafloxacin, hexoprenaline, imidapril, indalpine, indecainide, indeloxazine hydrochloride, isoxsuprine, ispronicline, labetalol, landiolol, lapatinib, levophacetoperane, lisinopril, lomefloxacin, lotrafiban, maprotiline, mecamylamine, mefloquine, mepindolol, meropenem, metapramine, metaproterenol, methoxyphenamine, dextrorotary methylphenidate, methylphenidate, metipranolol, metoprolol, mitoxantrone, mivazerol, moexipril, moprolol, moxifloxacin, nebivolol, nifenalol, nipradilol, norfloxacin, nortriptyline, nylidrin, olanZapine, oxamniquine, oxprenolol, oxyfedrine, paroxetine, perhexyline, phenmetrazine, phenylephrine, phenylpropylmethylamine, pholedrine, picilorex, pimethylline, pindolol, pipemidic acid, piridocaine, practolol, pradofloxacin, pramipexole, pramiverin, prenalterol, prenylamine, prilocalne, procaterol, pronethalol, propafenone, propranolol, propylhexedrine, protokylol, protriptyline, pseudoephedrine, reboxetine, rasagiline, (r)-rasagiline, repinotan, reproterol, rimiterol, ritodrine, safinamide, salbutamol/albuterol, salmeterol, sarizotan, sertraline, silodosin, sotalol, soterenol, sparfloxacin, spirapril, sulfinalol, synephrine, tamsulosin, tebanicline, tianeptine, tirofiban, tretoquinol, trimetazidine, troxipide, varenicline, vildagliptin, viloxazine, viquidil or xamoterol, 
 vii) comprise a protein that is biologically active, 
 viii) are biologically active such that it has target-binding activity, 
 ix) are an independently-folding protein or a portion thereof, 
 x) are a glycosylated protein, 
 xi) comprise intra-chain disulfide bonds, 
 xii) binds a cytokine, 
 xiii) binds to a cytokine, wherein the cytokine is TNFα, 
 xiv) comprise Atrial Natriuretic Peptide (ANP), Calcitonin, Corticotropin Releasing Hormone (CRH), Endothelin, Exenatide, Gastric Inhibitory Peptide (GIP), Glucagon-Like Peptide-1 (GLP-1), Glucagon-Like Peptide-2 (GLP-2), an analog of GLP-1 or GLP-2, Glucagon Vasoactive Intestinal Peptide (GVIP), Ghrelin, Peptide YY or Secretin, or a portion thereof, 
 xv) comprise a stretch of consecutive amino acids in the sequence HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRG (SEQ ID NO: 4657), 
 xvi) comprise at least one stretch of consecutive amino acids which are identical to a stretch of consecutive amino acids present in the heavy chain of a Fab or a Fab′ of an antibody, 
 xvii) comprise at least one at least one stretch of consecutive amino acids which are identical to a stretch of consecutive amino acids present in the light chain of a Fab or a Fab′ of an antibody, 
 xviii) comprise at least one Fab or Fab′ of an antibody, or a portion of at least one Fab or Fab′, 
 xix) comprise Fab-1 or Fab′1, or a portion thereof of an antibody, 
 xx) comprise Fab-2 or Fab′2, or a portion thereof of an antibody, 
 xxi) comprise two Fab or Fab′ hands of an antibody, 
 xxii) comprise at least one stretch of consecutive amino acids which are identical to a stretch of consecutive amino acids present in a single chain antibody, or 
 xxiii) comprise at least one stretch of consecutive amino acids which are identical to a stretch of consecutive amino acids present in a TNFα receptor. 
 
 f) the tetrahedral or octahedral antibody comprises a covalent linkage, wherein the covalent linkage is selected from any covalent linkage disclosed herein, or comprises any heterobifunctional crosslinker disclosed herein, and/or 
 g) the tetrahedral or octahedral antibody comprises one or more peptide linkers, wherein the one or more peptide linkers are independently selected from:
 i) a stretch of consecutive amino acids which is, or is present in, the sequence TSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSF LLPMGPSPPAEGSTGD (SEQ ID NO: 3227), 
 ii) a stretch of consecutive amino acids which is, or is present in, the sequence GGGGAGGGGAGGGGAGGGGAGGGGAGGG (SEQ ID NO: 3226), or 
 iii) any peptide linker disclosed herein. 
 
 
     
     
         99 . A composition comprising at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the tetrahedral or octahedral antibody of any of  claims 1  to  98  as a proportion (w/w) of peptide-containing molecules in the composition. 
     
     
         100 . A pharmaceutical composition comprising the composition of  claim 99  and one or more pharmaceutically acceptable excipients. 
     
     
         101 . A method of making the tetrahedral antibody of any one of  claims 17  to  31 , wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerizing polypeptide attached to the first N-terminus of first domain and a second dimerizing polypeptide attached to the first N-terminus of the second domain, the method comprising:
 a) recombinantly expressing each of the following polypeptides in a host cell:
 i) a first polypeptide comprising, from its N-terminus to its C-terminus,
 (1) optionally, the third domain, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the first dimerizing polypeptide, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the first polypeptide chain of the first domain, 
 
 ii) a second polypeptide comprising, from its N-terminus to its C-terminus,
 (1) optionally, the fourth domain, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the second dimerizing polypeptide, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the first polypeptide chain of the second domain, 
 
 iii) a third polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the third domain if not present on the first polypeptide, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a third dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain, or 
 (b) the N-terminus of the second polypeptide chain of the first domain, 
 
 
 iv) a fourth polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the fourth domain if not present on the second polypeptide, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a fourth dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain, or 
 (b) the N-terminus of the second polypeptide chain of the first domain, and 
 
 
 v) optionally one or more additional polypeptides comprising a second polypeptide chain of the third and/or fourth domains, if present. 
 
 
     
     
         102 . A method of making the tetrahedral antibody of any one of  claims 17  to  31 , wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerizing polypeptide attached to the first C-terminus of first domain and a second dimerizing polypeptide attached to the first N-terminus of the second domain, the method comprising:
 a) recombinantly expressing each of the following polypeptides in a host cell:
 i) a first polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the first polypeptide chain of the first domain which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the first dimerizing polypeptide, which is in turn optionally attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the third domain, 
 
 ii) a second polypeptide comprising, from its N-terminus to its C-terminus,
 (1) optionally, the fourth domain which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the second dimerizing polypeptide which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the first polypeptide chain of the second domain, 
 
 iii) a third polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the second polypeptide chain of the first domain, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a third dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the third domain if not present on the first polypeptide, or 
 (b) the N-terminus of the third domain if not present on the first polypeptide, 
 
 
 iv) a fourth polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the fourth domain if not present on the second polypeptide, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a fourth dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain, or 
 (b) the N-terminus of the second polypeptide chain of the first domain, and 
 
 
 v) optionally one or more additional polypeptides comprising a second polypeptide chain of the third and/or fourth domains, if present. 
 
 
     
     
         103 . A method of making the tetrahedral antibody of any one of  claims 17  to  31 , wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerizing polypeptide attached to the first N-terminus of first domain and a second dimerizing polypeptide attached to the first C-terminus of the second domain, the method comprising:
 a) recombinantly expressing each of the following polypeptides in a host cell:
 i) a first polypeptide comprising, from its N-terminus to its C-terminus,
 (1) optionally, the third domain attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the first dimerizing polypeptide attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the first polypeptide chain of the first domain, 
 
 ii) a second polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the first polypeptide chain of the second domain attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the second dimerizing polypeptide, which is in turn optionally attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the third domain, 
 
 iii) a third polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the third domain if not present on the first polypeptide, attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a third dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain, or 
 (b) the N-terminus of the second polypeptide chain of the first domain, 
 
 
 iv) a fourth polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the second polypeptide chain of the first domain, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a fourth dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the fourth domain if not present on the second polypeptide, or 
 (b) the N-terminus of the fourth domain if not present on the second polypeptide, and 
 
 
 v) optionally one or more additional polypeptides comprising a second polypeptide chain of the third and/or fourth domains, if present. 
 
 
     
     
         104 . A method of making the tetrahedral antibody of any one of  claims 17  to  31 , wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerizing polypeptide attached to the first C-terminus of first domain and a second dimerizing polypeptide attached to the first C-terminus of the second domain, the method comprising:
 a) recombinantly expressing each of the following polypeptides in a host cell:
 i) a first polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the first polypeptide chain of the first domain which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the first dimerizing polypeptide, which is in turn optionally attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the third domain, 
 
 ii) a second polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the first polypeptide chain of the second domain attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the second dimerizing polypeptide, which is in turn optionally attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the third domain, 
 
 iii) a third polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the second polypeptide chain of the first domain, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a third dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the third domain if not present on the first polypeptide, or 
 (b) the N-terminus of the third domain if not present on the first polypeptide, 
 
 
 iv) a fourth polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the second polypeptide chain of the first domain, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a fourth dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the fourth domain if not present on the second polypeptide, or 
 (b) the N-terminus of the fourth domain if not present on the second polypeptide, and 
 
 
 v) optionally one or more additional polypeptides comprising a second polypeptide chain of the third and/or fourth domains, if present. 
 
 
     
     
         105 . A method of making the tetrahedral antibody of any one of  claims 32  to  50 , wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerizing polypeptide attached to the first N-terminus of first domain and a second dimerizing polypeptide attached to the first N-terminus of the second domain, the method comprising:
 a) recombinantly expressing each of the following polypeptides in a host cell:
 i) a first polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the third domain, or fifth domain if present, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the first dimerizing polypeptide, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the first polypeptide chain of the first domain, 
 
 ii) a second polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the fourth domain, or sixth domain if present, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the second dimerizing polypeptide which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the first polypeptide chain of the second domain, 
 
 iii) a third polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the third domain if not present on the first polypeptide, or the fifth domain if present, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a third dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain, or 
 (b) the N-terminus of the second polypeptide chain of the first domain, 
 
 
 iv) a fourth polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the fourth domain if not present on the second polypeptide, or the sixth domain if present, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a fourth dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain, or 
 (b) the N-terminus of the second polypeptide chain of the first domain, and 
 
 
 v) optionally one or more additional polypeptides comprising a second polypeptide chain of the third, fourth, fifth, and/or sixth domains, if present. 
 
 
     
     
         106 . A method of making the tetrahedral antibody of any one of  claims 32  to  46 , wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerizing polypeptide attached to the first C-terminus of first domain and a second dimerizing polypeptide attached to the first N-terminus of the second domain, the method comprising:
 a) recombinantly expressing each of the following polypeptides in a host cell:
 i) a first polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the first polypeptide chain of the first domain which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the first dimerizing polypeptide which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the third domain, or fifth domain if present, 
 
 ii) a second polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the fourth domain, or sixth domain if present, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the second dimerizing polypeptide which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the first polypeptide chain of the second domain, 
 
 iii) a third polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the second polypeptide chain of the first domain which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a third dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the third domain if not present on the first polypeptide, or the fifth domain if present, or 
 (b) the N-terminus of the third domain if not present on the first polypeptide, or the fifth domain if present, 
 
 
 iv) a fourth polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the fourth domain if not present on the second polypeptide, or the sixth domain if present, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a fourth dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain, or 
 (b) the N-terminus of the second polypeptide chain of the first domain, and 
 
 
 v) optionally one or more additional polypeptides comprising a second polypeptide chain of the third, fourth, fifth, and/or sixth domains, if present. 
 
 
     
     
         107 . A method of making the tetrahedral antibody of any one of  claims 32  to  46 , wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerizing polypeptide attached to the first N-terminus of first domain and a second dimerizing polypeptide attached to the first C-terminus of the second domain, the method comprising:
 a) recombinantly expressing each of the following polypeptides in a host cell:
 i) a first polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the third domain, or fifth domain if present, which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the first dimerizing polypeptide which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the first polypeptide chain of the first domain, 
 
 ii) a second polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the first polypeptide chain of the second domain which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the second dimerizing polypeptide which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the fourth domain, or sixth domain if present, 
 
 iii) a third polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the third domain if not present on the first polypeptide, or the fifth domain if present, attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a third dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain, or 
 (b) the N-terminus of the second polypeptide chain of the first domain, and 
 
 
 iv) a fourth polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the second polypeptide chain of the first domain, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a fourth dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the fourth domain if not present on the second polypeptide, or the sixth domain if present, or 
 (b) the N-terminus of the fourth domain if not present on the second polypeptide, or the sixth domain if present, and 
 
 
 v) optionally one or more additional polypeptides comprising a second polypeptide chain of the third, fourth, fifth, and/or sixth domains, if present. 
 
 
     
     
         108 . A method of making the tetrahedral antibody of any one of  claims 32  to  46 , wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerizing polypeptide attached to the first C-terminus of first domain and a second dimerizing polypeptide attached to the first C-terminus of the second domain, the method comprising:
 a) recombinantly expressing each of the following polypeptides in a host cell:
 i) a first polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the first polypeptide chain of the first domain which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the first dimerizing polypeptide which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the third domain, or fifth domain if present, 
 
 ii) a second polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the first polypeptide chain of the second domain which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (2) the N-terminus of the second dimerizing polypeptide which is attached at its C-terminus by a peptide bond or via a peptide linker to 
 (3) the N-terminus of the fourth domain, or sixth domain if present, 
 
 iii) a third polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the second polypeptide chain of the first domain which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a third dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the third domain if not present on the first polypeptide, or the fifth domain if present, or 
 (b) the N-terminus of the third domain if not present on the first polypeptide, or the fifth domain if present, and 
 
 
 iv) a fourth polypeptide comprising, from its N-terminus to its C-terminus,
 (1) the second polypeptide chain of the first domain, which is attached at its C-terminus by a peptide bond or via a peptide linker to
 (a) the N-terminus of a fourth dimerizing polypeptide which is in turn attached at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the fourth domain if not present on the second polypeptide, or the sixth domain if present, or 
 (b) the N-terminus of the fourth domain if not present on the second polypeptide, or the sixth domain if present, and 
 
 
 v) optionally one or more additional polypeptides comprising a second polypeptide chain of the third, fourth, fifth, and/or sixth domains, if present. 
 
 
     
     
         109 . The tetrahedral antibody of any one of  claims 17 - 25 , wherein the first domain is an Fc domain, and the second, third, and fourth domains are Fab domain, wherein:
 a) the third and fourth domains comprise a first type of Fab and the second domain comprise a second type of Fab,
 i) the first type of Fab is formed by a VH-CH on a H1 or H2 chain, and a VL-CL on a L1 chain, and the second type of Fab is formed by a VL-CH on a H1 chain, and a VH-CL domain on a L2 chain; 
 ii) the first type of Fab is formed by a VL-CH on a H1 or H2 chain, and a VH-CL on a L1 chain, and the second type of Fab is formed by a VH-CH on a H2 chain, and a VL-CL domain on a L2 chain, or 
 iii) the first type of Fab is formed by a VH-CH on a H1 or H2 chain, and VL-CL on a L1 chain, and the second type of Fab is formed by a VH-CH on a H2 chain, and a VL-CL domain on a L2 chain, 
   wherein VL is a kappa and/or lambda light chain V region.   
     
     
         110 . The tetrahedral antibody of  claim 32 , wherein the third, fourth, fifth, and sixth domains are Fab domains, wherein
 a) the third and fourth domain comprise a first type of Fab, and the fifth and/or sixth domain comprise a second type of Fab, and
 i) the first type of Fab is formed by a VH-CH on a H1 chain, and a VL-CL domain on a L1 chain, and the second type of Fab is formed by a VL-CH on a H2 chain, and a VH-CL on a L2 chain; 
 ii) the first type of Fab is formed by a VL-CH on a H1 chain, and a VH-CL domain on a L1 chain, and the second type of Fab is formed by a VH-CH on a H2 chain, and a VL-CL on a L2 chain; or 
 iii) the first type of Fab is formed by a VH-CH on a H1 chain, and a VL-CL domain on a L1 chain, and the second type of Fab is formed by a VH-CH on a H2 chain, and a VL-CL on a L2 chain, 
   wherein VL is a kappa and/or lambda light chain V region.   
     
     
         111 . The tetrahedral antibody of  claim 109  or  110 , wherein:
 a) one type of Fab comprises the mutations Q39K and S183E in its heavy chain portion, and the mutations Q38E and V133K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38E in its heavy chain portion, and the mutations V133E and Q39K in its light chain portion; 
 b) one type of Fab comprises the mutations Q39K and S183E in its heavy chain portion, and the mutations Q38E and V133K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38K in its heavy chain portion, and the mutations V133E and Q39E in its light chain portion; 
 c) one type of Fab comprises the mutations Q39E and S183E in its heavy chain portion, and the mutations Q38E and V133K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38E in its heavy chain portion, and the mutations V133E and Q39K in its light chain portion; 
 d) one type of Fab comprises the mutations Q39E and S183E in its heavy chain portion, and the mutations Q38K and V133K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38K in its heavy chain portion, and the mutations S176E and Q39E in its light chain portion; 
 e) one type of Fab comprises the mutations Q39K and S183E in its heavy chain portion, and the mutations Q38E and S176K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38E in its heavy chain portion, and the mutations S176E and Q39K in its light chain portion; 
 f) one type of Fab comprises the mutations Q39K and S183E in its heavy chain portion, and the mutations Q38E and S176K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38K in its heavy chain portion, and the mutations S176E and Q39E in its light chain portion; 
 g) one type of Fab comprises the mutations Q39E and S183E in its heavy chain portion, and the mutations Q38E and S176K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38E in its heavy chain portion, and the mutations S176E and Q39K in its light chain portion; or 
 h) one type of Fab comprises the mutations Q39E and S183E in its heavy chain portion, and the mutations Q3 8K and S176K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38K in its heavy chain portion, and the mutations S176E and Q39E in its light chain portion.