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 - 49 . (canceled) 
     
     
         50 . A nucleic acid construct encoding the heavy and/or light chain variable region of a humanized or chimeric antibody which binds to human CD3, wherein said antibody comprises heavy chain variable (VH) region CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain variable (VL) region CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NO: 4, GTN, and SEQ ID NO: 5, respectively. 
     
     
         51 . An expression vector comprising the nucleic acid of  claim 50 . 
     
     
         52 . A host cell comprising the expression vector of  claim 51 . 
     
     
         53 . A method for producing an anti-CD3 antibody comprising: (a) culturing the host cell of  claim 52 , and (b) purifying the antibody from the culture media. 
     
     
         54 . A method of diagnosing a disease characterized by involvement or accumulation of CD3-expressing cells, comprising administering a humanized or chimeric antibody which binds to human CD3, wherein said antibody comprises heavy chain variable (VH) region CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain variable (VL) region CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NO: 4, GTN, and SEQ ID NO: 5, respectively, optionally wherein the antibody is labeled with a detectable agent. 
     
     
         55 . A method for detecting the presence of CD3 antigen, or a cell expressing CD3, in a sample comprising the steps of;
 a) contacting the sample with a humanized or chimeric antibody which binds to human CD3, wherein said antibody comprises heavy chain variable (VH) region CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain variable (VL) region CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NO: 4, GTN, and SEQ ID NO: 5, respectively, under conditions that allow for formation of a complex between said antibody or bispecific antibody and CD3; and   b) analyzing whether a complex has been formed.   
     
     
         56 . A method of treating cancer, an infectious disease, or an autoimmune disease comprising administering to a subject in need thereof a humanized or chimeric antibody which binds to human CD3, wherein said antibody comprises heavy chain variable (VH) region CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain variable (VL) region CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NO: 4, GTN, and SEQ ID NO: 5, respectively. 
     
     
         57 . The method of  claim 56 , wherein the antibody comprises VH and VL regions comprising the amino acid sequences selected from the group consisting of:
 a) SEQ ID NOs: 6 and 10, respectively;   b) SEQ ID NOs: 8 and 10, respectively;   c) SEQ ID NOs: 9 and 10, respectively;   d) SEQ ID NOs: 6 and 11, respectively;   e) SEQ ID NOs: 6 and 12, respectively;   f) SEQ ID NOs: 7 and 10, respectively;   g) SEQ ID NOs: 7 and 11, respectively;   h) SEQ ID NOs: 7 and 12, respectively;   i) SEQ ID NOs: 8 and 11, respectively;   j) SEQ ID NOs: 8 and 12, respectively;   k) SEQ ID NOs: 9 and 11, respectively; and   l) SEQ ID NOs: 9 and 12, respectively.   
     
     
         58 . The method of  claim 56 , wherein the antibody is a full-length antibody. 
     
     
         59 . The method of  claim 56 , wherein the antibody comprises an Fc region comprising a first and a second immunoglobulin heavy chain. 
     
     
         60 . The method of  claim 56 , wherein the first and the second heavy chains are of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         61 . The method of  claim 56 , wherein the antibody comprises an Fc region which has been modified so that:
 (a) binding of C1q to the antibody is reduced compared to a wild-type antibody by at least 70%, wherein C1q binding is determined by ELISA;   (b) the antibody mediates reduced Fc-mediated T-cell proliferation compared to a wild-type antibody by at least 50%, wherein said T-cell proliferation is measured in a peripheral blood mononuclear cell (PBMC)-based functional assay; or   (c) the antibody reduces Fc-mediated CD69 expression by at least 50%, when compared to a wild-type antibody wherein said Fc-mediated CD69 expression is determined in a PBMC-based functional assay.   
     
     
         62 . The method of  claim 56 , wherein the antibody comprises a first and a second immunoglobulin heavy chain, wherein in at least one of the first and second immunoglobulin 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, are not L, L, D, N, and P, respectively. 
     
     
         63 . The method of  claim 62 , wherein in
 (a) at least one of the first and second heavy chains 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;   (b) at least one of the first and second heavy chains 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; or   (c) at least one of said first and second heavy chains 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; and   (d) at least one of said first and second heavy chains 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.   
     
     
         64 . The method of  claim 63 , wherein in at least one of the first and second heavy chains 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.