Monovalent Antigen Binding Proteins

Abstract

The present invention relates to monovalent antigen binding proteins with a CH1-CL domain exchange, methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.

1 . A monovalent antigen binding protein comprising
 a) a modified heavy chain of an antibody which specifically binds to an antigen, wherein the VH domain is replaced by the VL domain of said antibody; and   b) a modified heavy chain of said antibody, wherein the CH1 domain is replaced by the CL domain of said antibody.   
     
     
         2 . The monovalent antigen binding protein according to  claim 1 , comprising
 the CH3 domain of the modified heavy chain of the antibody of a) and the CH3 domain of the modified heavy chain of the antibody of b) each meet at an interface which comprises an original interface between the antibody CH3 domains;   wherein said interface is altered to promote the formation of the monovalent antigen binding protein, wherein the alteration comprises:   i) a CH3 domain of one heavy chain is altered,   so that within the original interface the CH3 domain of one heavy chain that meets the original interface of the CH3 domain of the other heavy chain within the monovalent antigen binding protein,   an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the interface of the CH3 domain of one heavy chain which is positionable in a cavity within the interface of the CH3 domain of the other heavy chain   and   ii) the CH3 domain of the other heavy chain is altered,   so that within the original interface of the second CH3 domain that meets the original interface of the first CH3 domain within the monovalent antigen binding protein,   an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the interface of the second CH3 domain within which a protuberance within the interface of the first CH3 domain is positionable.   
     
     
         3 . The monovalent antigen binding protein according to  claim 2 , comprising said amino acid residue having a larger side chain volume is selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), tryptophan (W), and said amino acid residue having a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), valine (V). 
     
     
         4 . The monovalent antigen binding protein according to  claim 3 , comprising both CH3 domains are further altered by the introduction of cysteine (C) as amino acid in the corresponding positions of each CH3 domain such that a disulfide bridge between both CH3 domains can be formed. 
     
     
         5 . The monovalent antigen binding protein according to  claims 1  to  4 , comprising is of human IgG1 isotype. 
     
     
         6 . The monovalent antigen binding protein according to  claim 1 , characterized in comprising
 a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:1; and   b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:2; or   a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:3; and   b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:4; or   a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:5; and   b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:6; or   a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:7; and   b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:8; or   a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:9; and   b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:10; or   a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:11; and   b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:12.   
     
     
         7 . The monovalent antigen binding protein according to  claim 1 ,  2 ,  3 ,  4  or  6 , comprising the modified heavy chains of a) and b) are of IgG1 isotype, and the antigen binding protein is afucosylated with an amount of fucose of 80% or less of the total amount of oligosaccharides (sugars) at Asn297 is of human IgG1 isotype. 
     
     
         8 . A pharmaceutical composition of a monovalent antigen binding protein according to  claims 1  to  7 . 
     
     
         9 . A pharmaceutical composition comprising a monovalent antigen binding protein according to  claims 1  to  7  and at least one pharmaceutically acceptable excipient. 
     
     
         10 . The monovalent antigen binding protein according to  claims 1  to  7  for use in the treatment of cancer. 
     
     
         11 . Use of the monovalent antigen binding protein according to  claims 1  to  7  for the manufacture of a medicament for the treatment of cancer. 
     
     
         12 . A method for the treatment of a patient in need of therapy, characterized by administering to the patient a therapeutically effective amount of a monovalent antigen binding protein according to  claims 1  to  7 . 
     
     
         13 . A method for the preparation of a monovalent antigen binding protein according to  claims 1  to  7 
 comprising the steps of 
 a) transforming a host cell with vectors comprising nucleic acid molecules encoding a monovalent antigen binding protein according to  claims 1  to  7 , 
 b) culturing the host cell under conditions that allow synthesis of said monovalent antigen binding protein molecule; and 
 c) recovering said monovalent antigen binding protein molecule from said culture. 
 
     
     
         14 . Nucleic acid encoding the monovalent antigen binding protein according to  claims 1  to  7 . 
     
     
         15 . A vector comprising nucleic acid according to  claim 14 . 
     
     
         16 . A host cell comprising the vector according to  claim 15 .