Igf-1r monoclonal antibodies and uses thereof

Abstract

The present invention relates to conjugates including a chelating moiety of a metal complex thereof and a therapeutic or targeting moiety, methods for their production, and uses thereof.

What is claimed is: 
     
         1 . A compound having a structure of Formula I, or a pharmaceutically acceptable salt thereof:
   A-L 1 -(L 2 ) n -B   Formula I
   wherein A is a chelating moiety or a metal complex thereof;   L 1  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted aryl or heteroaryl;   B is a cross-linking group selected from the group consisting of an amino-reactive cross-linking group, a methionine-reactive cross-linking group, a thiol-reactive cross-linking group, and a sortase-mediated coupling sequence;   n is 1-5; and   each L 2 , independently, has a structure of Formula II:
   (—X 1 -L 3 -Z 1 —)   Formula II
 
   wherein X 1  is C═O(NR 1 ), C═S(NR 1 ), OC═O(NR 1 ), NR 1 C═O(O), NR 1 C═O(NR 1 ), —CH 2 PhC═O(NR 1 ), —CH 2 Ph(NH)C═S(NR 1 ), 0, or NR 1 , in which R 1  is H or optionally substituted C 1 -C 6  alkyl or optionally substituted C 1 -C 6  heteroalkyl, optionally substituted aryl or heteroaryl;   L 3  is optionally substituted C 1 -C 50  alkyl or optionally substituted C 1 -C 50  heteroalkyl or C 5 -C 20  polyethylene glycol; and   Z 1  is CH 2 , C═0, C═S, OC═O, NR 1 C═O, or NR 1 , in which R 1  is hydrogen or optionally substituted C 1 -C 6  alkyl, or pyrrolidine-2,5-dione.   
     
     
         2 . The compound in  claim 1 , wherein the chelating moiety is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (1R,4R,7R,10R)-α, α′, α″, α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid), DOTA-GA anhydride (2,2′,2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid)), DOTMP (1,4,6,10-tetraazacyclodecane-1,4,7,10-tetramethylene phosphonic acid, DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamido-methylenephosphonic acid), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NOTP (1,4,7-triazacyclononane-1,4,7-tri(methylene phosphonic acid), TETPA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetra acetic acid), HEHA (1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid), PEPA (1,4,7,10,13-pentaazacyclopentadecane-N,N′,N″,N′″, N″″-pentaacetic acid), H 4 octapa (N,N′-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N′-diacetic acid), H 2 dedpa (1,2-[[6-(carboxy)-pyridin-2-yl]-methylamino]ethane), H 6 phospa (N,N′-(methylenephosphonate)-N,N′-[6-(methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane), TTHA (triethylenetetramine-N,N,N′,N″,N′″, N′″-hexaacetic acid), DO2P (tetraazacyclododecane dimethanephosphonic acid), HP-DO3A (hydroxypropyltetraazacyclododecanetriacetic acid), EDTA (ethylenediaminetetraacetic acid), Deferoxamine, DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (diethylenetriaminepentaacetic acid-bismethylamide), or porphyrin. 
     
     
         3 . The compound of  claim 2 , wherein the structure of Formula I is: 
       
         
           
           
               
               
           
         
         wherein Y 1  is —CH 2 OCH 2 (L 2 ) n -B, C═O(L 2 ) n -B, or C═S(L 2 ) n -B and Y 2  is —CH 2 CO 2 H; or 
         wherein Y 1  is H, and Y 2  is L 1 -(L 2 ) n -B. 
       
     
     
         4 . The compound of  claim 1 , wherein L 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein R 2  is hydrogen or —CO 2 H. 
       
     
     
         5 . The compound of  claim 1 , wherein the metal of said metal complex is selected from the group consisting of Bi, Pb, Y, Mn, Cr, Fe, Co, Zn, Ni, Tc, In, Ga, Cu, Re, a lanthanide, and an actinide; or
 the metal of said metal complex is a radionuclide selected from the group consisting of  47 Sc,  55 Co,  60 Cu,  61 Cu,  62 Cu,  64 Cu,  67 Cu,  66 Ga,  67 Ga,  68 Ga,  82 Rb,  86 Y,  87 Y,  90 Y,  97 Ru,  99m Tc,  105 Rh,  109 Pd,  111 In,  117m Sn,  149 Pm,  149 Tb,  153 Sm,  177 Lu,  186 Re,  188 Re,  199 Au,  201 Tl,  203 Pb,  212 Pb,  212 Bi,  213 Bi,  225 Ac, and  227 Th.   
     
     
         6 . The compound of  claim 1 , wherein the cross-linking group is an amino-reactive, a methionine-reactive, or a thiol-reactive cross-linking group. 
     
     
         7 . The compound of  claim 6 , wherein the amino-reactive, methionine-reactive, or thiol-reactive cross-linking group comprises an activated ester, imidate, anhydride, thiol, disulfide, maleimide, azide, alkyne, strained alkyne, strained alkene, halogen, sulfonate, haloacetyl, amine, hydrazide, diazirine, phosphine, tetrazine, isothiocyanate, or oxaziridine. 
     
     
         8 . The compound of  claim 7 , wherein the activated ester is a hydroxysuccinimide ester, 2,3,5,6-tetrafluorophenol ester, or 4-nitrophenol ester. 
     
     
         9 . The compound of  claim 1 , wherein the cross-linking group is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A conjugate having the following structure, or a pharmaceutically acceptable salt thereof:
   A-L 1 -(L 2 ) n -B   wherein the conjugate is formed by reacting a compound of  claim 1  with a human or humanized IgG antibody or an antigen binding fragment thereof,   wherein, with respect to the conjugate,   A is a chelating moiety or a metal complex thereof;   B is a human or humanized IgG antibody or an antigen binding fragment thereof;   L 1  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  heteroalkyl, optionally substituted aryl or heteroaryl;   n is 1-5; and   each L 2 , independently, has a structure of Formula II:
   (—X 1 -L 3 -Z 1 —)   Formula II
 
   wherein X 1  is C═O(NR 1 ), C═S(NR 1 ), OC═O(NR 1 ), NR 1 C═O(O), NR 1 C═O(NR 1 ), —CH 2 PhC═O(NR 1 ), —CH 2 Ph(NH)C═S(NR 1 ), 0, or NR 1 , in which R 1  is H or optionally substituted C 1 -C 6  alkyl or optionally substituted C 1 -C 6  heteroalkyl, optionally substituted aryl or heteroaryl;   L 3  is optionally substituted C 1 -C 50  alkyl or optionally substituted C 1 -C 50  heteroalkyl or C 5 -C 20  polyethylene glycol; and   Z 1  is CH 2 , C═O, C═S, OC═O, NR 1 C═O, or NR 1 , in which R 1  is hydrogen or optionally substituted C 1 -C 6  alkyl, or pyrrolidine-2,5-dione.   
     
     
         12 . The conjugate of  claim 11 , wherein the human or humanized IgG antibody is an IGF-1R antibody.