Humanized or chimeric cd3 antibodies

Abstract

The present invention relates to humanized or chimeric antibodies binding CD3. It furthermore relates to bispecific antibodies, compositions, pharmaceutical compositions, use of said antibodies in the treatment of a disease, and method of treatment.

1 - 77 . (canceled) 
     
     
         78 . A method of treating cancer, an infectious disease, or an autoimmune disease, the method comprising administering to a subject in need thereof an effective amount of a chimeric or humanized antibody which binds to human CD3, a bispecific antibody comprising the antigen binding region of the antibody, or a composition comprising the antibody or bispecific antibody and a carrier, wherein the antibody comprises a heavy chain variable (VH) region, wherein said VH region comprises a mutation in one of the three CDR sequences of a reference antibody having the CDR sequences set forth in SEQ ID NOs: 1, 2, and 3, which mutation is in one of the positions selected from the group consisting of: T31M, T31P, N57, H101, G105, S110 and Y114, wherein the positions are numbered according to the reference sequence of SEQ ID NO: 4. 
     
     
         79 . The method according to  claim 78 , wherein the antibody comprises an H101G or an H101N mutation. 
     
     
         80 . The method according to  claim 78 , wherein the VH region of the antibody comprises the CDR1, CDR2, and CDR3 sequences selected from the group consisting of:
 a) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 54, 2, 3 [T31M];   b) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 58, 2, 3 [T31P];   c) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 106, 3 [N57E];   d) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 176 [H101G];   e) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 184 [H101N];   f) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 220 [G105P];   g) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 236 [S110A];   h) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 244 [S110G];   i) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 284 [Y114M];   j) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 292 [Y114R];   k) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, 298 [Y114V]; and   l) CDR1, CDR2 and CDR3 sequences having at least 90% or at least 95% amino acid sequence identity, in total across the three CDR sequences or to any one of the three CDR sequences as set forth in a) to k), or at most 5 further mutations or substitutions in total across the three CDR sequences, provided that the CDR1, CDR2 and CDR3 sequences do not have the sequences as set forth in SEQ ID NO: 1, 2, 3, and wherein the mutations or substitutions preferably do not modify the binding affinity of the antibody to human CD3.   
     
     
         81 . The method according to  claim 78 , wherein the VH region of the antibody comprises an amino acid sequence selected from the group consisting of:
 a) a VH sequence as set forth in SEQ ID NO: 55[T31M],   b) a VH sequence as set forth in SEQ ID NO: 59 [T31P],   c) a VH sequence as set forth in SEQ ID NO: 107 [N57E]   d) a VH sequence as set forth in SEQ ID NO: 177 [H101G],   e) a VH sequence as set forth in SEQ ID NO: 185 [H101N],   f) a VH sequence as set forth in SEQ ID NO: 221 [G105P],   g) a VH sequence as set forth in SEQ ID NO: 237 [S110A],   h) a VH sequence as set forth in SEQ ID NO: 245 [S110G],   i) a VH sequence as set forth in SEQ ID NO: 285 [Y114M],   j) a VH sequence as set forth in SEQ ID NO: 293 [Y114R],   k) a VH sequence as set forth in SEQ ID NO: 299 [Y114V], and   l) a VH sequence having at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence identity to any one of the sequences as set forth in a) to k).   
     
     
         82 . The method according to  claim 78 , wherein the antibody comprises a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO:6, GTN, and 7, respectively. 
     
     
         83 . The method according to  claim 78 , wherein the antibody comprises a variable light chain (VL) region, wherein said VL region is selected from the group consisting of:
 a) a VL sequence as set forth in SEQ ID NO:8,   b) a VL sequence as set forth in SEQ ID NO:10, and   c) a VL sequence having at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence identity to any one of the sequences as set forth in a) to b).   
     
     
         84 . The method according to  claim 82 , wherein the antibody comprises a VH region comprising CDR1, CDR2, and CDR3 sequences selected from the group consisting of:
 a) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 54, 2, and 3 [T31M];   b) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 58, 2, and 3 [T31P];   c) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 106, and 3 [N57E];   d) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, and 176 [H101G];   e) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, and 184 [H101N];   f) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, and 220 [G105P];   g) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, and 236 [S110A];   h) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, and 244 [S110G];   i) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, and 284 [Y114M];   j) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, and 292 [Y114R]; and   k) CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 1, 2, and 298 [Y114V].   
     
     
         85 . The method according to  claim 78 , wherein the antibody is a full-length antibody. 
     
     
         86 . The method according to  claim 78 , wherein the antibody is chimeric or humanized. 
     
     
         87 . The method according to  claim 78 , wherein the antibody is of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         88 . The method according to  claim 78 , wherein the antibody is monovalent, bivalent or multivalent. 
     
     
         89 . The method according to  claim 78 , wherein the antibody comprises a first heavy chain and a second heavy chain. 
     
     
         90 . The method according to  claim 78 , wherein the antibody comprises a first heavy chain and a second heavy chain, wherein in at least one of said first and second heavy chains, one or more amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain according to EU numbering, are not L, L, D, N, and P, respectively. 
     
     
         91 . The method according to  claim 89 , wherein in at least one of said first and second heavy chains of the antibody,
 (a) the amino acid in the position corresponding to position D265 in a human IgG1 heavy chain is not D;   (b) the amino acid in the position corresponding to position N297 in a human IgG1 heavy chain is not N;   (c) the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain are not L and L, respectively;   (d) the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain are F and E; or A and A, respectively;   (e) the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain are F and E, respectively;   (f) the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain are A and A, respectively;   (g) the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are not L, L, and D, respectively;   (h) the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A; or A, A, and A, respectively;   (i) the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A, respectively;   (j) the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain, are A, A, and A, respectively; or   (k) the amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain are F, E, A, Q, and S, respectively.   
     
     
         92 . The method according to  claim 89 , wherein each of said first and second heavy chain of the antibody comprises at least a hinge region, a CH2 region, and a CH3 region, wherein in said first heavy chain, at least one of the amino acids in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain has been substituted, and in said second heavy chain, at least one of the amino acids in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain has been substituted, and wherein said first and said second heavy chains are not substituted in the same positions. 
     
     
         93 . The method according to  claim 92 , wherein (a) the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said first heavy chain, and the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said second heavy chain, or (b) the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said second heavy chain, and the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said first heavy chain. 
     
     
         94 . The method according to  claim 78 , wherein the subject has cancer. 
     
     
         95 . The method according to  claim 94 , wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, gastric cancer, colorectal cancer, esophageal cancer and squamous cell carcinoma of the head & neck, cervical cancer, pancreatic cancer, testis cancer, malignant melanoma, a soft-tissue cancer, an indolent or aggressive form of B-cell lymphoma, chronic lymphatic leukemia, and acute lymphatic leukemia. 
     
     
         96 . The method according to  claim 78 , wherein the subject has an infectious disease. 
     
     
         97 . The method according to  claim 78 , wherein the subject has an autoimmune disease.