US2014193405A1PendingUtilityA1

Humanized anti-cd40 antibodies

59
Assignee: PRESTA LEONARD GPriority: May 26, 2005Filed: Mar 10, 2014Published: Jul 10, 2014
Est. expiryMay 26, 2025(expired)· nominal 20-yr term from priority
Inventors:Leonard G. PrestaLori Y. O'ConnellSvetlana O. Doronina
A61P 37/02A61P 35/02A61P 35/00A61P 37/06A61P 37/00A61P 29/00A61P 19/02C07K 2317/24C07K 16/2878A61K 2039/505C07K 2317/55A61K 39/3955C07K 2317/73C07K 2317/56A61K 39/395C07K 16/00C07K 16/18
59
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Claims

Abstract

Provided are humanized anti-CD40 antibodies and antigen-binding fragments and methods for treating disease characterized by expression of CD40 antigen.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . An isolated antibody or antigen-binding fragment that specifically binds to human CD40, comprising a humanized heavy chain variable domain comprising a framework region having an amino acid sequence at least 90% identical to the amino acid sequence of the framework region of the human variable domain heavy chain subgroup III concensus amino acid sequence of SEQ ID NO:2, and comprising at least one CDR having an amino acid sequence at least 90% identical to a corresponding heavy chain CDR of SEQ ID NO:3. 
     
     
         2 . An isolated antibody or antigen-binding fragment that specifically binds to human CD40, comprising a humanized light chain variable domain comprising a framework region having an amino acid sequence at least 90% identical to the framework region of the human variable domain light chain subgroup kappa I concensus amino acid sequence of SEQ ID NO:13, and comprising at least one CDR having an amino acid sequence at least 90% identical to a corresponding light chain CDR of SEQ ID NO:14. 
     
     
         3 . The antibody or antigen-binding fragment of  claim 1 , further comprising humanized light chain variable domain comprising a framework region comprising an amino acid sequence at least 90% identical to the framework region of the human variable domain light chain subgroup kappa I concensus amino acid sequence of SEQ ID NO:13 comprising at least one CDR having an amino acid sequence at least 90% identical to a corresponding light chain CDR of SEQ ID NO:14. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 1 , wherein each heavy chain CDR is at least 90% identical to the corresponding heavy chain CDR of SEQ ID NO:3. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 4 , wherein the heavy chain CDRs comprise the amino acid sequences of the corresponding heavy chain CDRs of SEQ ID NO:3. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 2  or  3 , wherein each light chain CDR is at least 90% identical to the corresponding light chain CDR of SEQ ID NO:14. 
     
     
         7 . The antibody or antigen-binding fragment of  claim 6 , wherein the light chain CDRs comprise the amino acid sequences of the light chain CDRs of SEQ ID NO:14. 
     
     
         8 . The antibody or antigen-binding fragment of  claim 1 , comprising the heavy chain variable domain amino acid sequence of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, or SEQ ID NO:11. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 2 , comprising the light chain variable domain amino acid sequence of SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:16. 
     
     
         10 . The antibody or antigen-binding fragment of  claim 3 , comprising the heavy chain variable domain amino acid sequence of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, or SEQ ID NO:11, and the light chain variable domain amino acid sequence of SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:16. 
     
     
         11 . The antibody or antigen-binding fragment of  claim 1  or  3 , further comprising a human IgG constant region. 
     
     
         12 . The antibody or antigen-binding fragment of  claim 11 , wherein the isotype of the IgG constant region is IgG1, IgG2, IgG3, or IgG4. 
     
     
         13 . The antibody or antigen-binding fragment of  claim 12 , wherein the isotype of the IgG constant region is IgG1. 
     
     
         14 . The antibody or antigen-binding fragment of  claim 2  or  3 , further comprising a light chain constant domain. 
     
     
         15 . The antibody or antigen-binding fragment of  claim 14 , wherein the light chain constant domain is a kappa constant domain. 
     
     
         16 . The antibody or antigen-binding fragment of  claim 10 , wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:3 and SEQ ID NO:14, respectively; SEQ ID NO:4 and SEQ ID NO:14, respectively; SEQ ID NO:5 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:14, respectively; SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:8 and SEQ ID NO:14, respectively; SEQ ID NO:9 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:15, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:7 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:14, respectively; SEQ ID NO:11 and SEQ ID NO:14, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO:11 and SEQ ID NO:16, respectively. 
     
     
         17 . The antibody or antigen-binding fragment of  claim 10 , wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:7 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:14, respectively; SEQ ID NO:11 and SEQ ID NO:14, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO: 11 and SEQ ID NO:16, respectively. 
     
     
         18 . The antibody or antigen-binding fragment of  claim 10 , wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO: 11 and SEQ ID NO:16, respectively. 
     
     
         19 . The antibody or antigen-binding fragment of  claim 10 , wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:3 and SEQ ID NO:14, respectively. 
     
     
         20 . The antibody or antigen-binding fragment of  claim 10 , wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:10 and SEQ ID NO:16, respectively. 
     
     
         21 . The antibody of any one of  claims 16 - 20 , wherein the antibody further comprises a human immunoglobulin constant region. 
     
     
         22 . The antibody of  claim 21 , comprising the heavy chain and the light chain amino acid sequences set forth in SEQ ID NO:19 and SEQ ID NO:22, respectively. 
     
     
         23 . The antibody of  claim 21 , which is hu sgn-0, hu sgn-1, hu sgn-2, hu sgn-4, hu sgn-14, hu sgn-15, hu sgn-16, hu sgn-17, hu sgn-18, hu sgn-19, hu sgn-22, hu sgn-23, hu sgn-26 or hu sgn-27. 
     
     
         24 . The antibody or antigen-binding fragment of any one of  claims 1 - 3 , which is an antigen-binding antibody fragment. 
     
     
         25 . The antigen binding fragment of  claim 24 , wherein the antibody fragment is a Fab, a Fab′, a F(ab′) 2 , a Fv fragment, a diabody, a single-chain antibody, an scFv fragment or an scFv-Fc. 
     
     
         26 . The antibody or antigen-binding fragment of any one of  claims 1 - 3 , further comprising a detectable label. 
     
     
         27 . The antibody or antigen-binding fragment of any one of  claims 1 - 3 , wherein the antibody is conjugated to a chemotherapeutic agent. 
     
     
         28 . The antibody or antigen-binding fragment of  claim 27 , wherein the chemotherapeutic agent is an auristatin. 
     
     
         29 . The antibody or antigen-binding fragment of  claim 28 , wherein the auristatin is MMAE or MMAF. 
     
     
         30 . A kit comprising in a container the antibody or antigen binding fragment of any one of  claims 1 - 3 , and optionally instructions for using the antibody to detect CD40 protein in a biological sample. 
     
     
         31 . A method for inhibiting the growth of cells expressing human CD40 antigen, comprising administering the antibody or antigen-binding fragment of any one of  claims 1 - 3  to the cells, which antibody or antigen-binding fragment specifically binds to the human cell surface CD40 antigen, wherein the binding of the antibody or antigen-binding fragment to the CD40 antigen inhibits the growth or differentiation of the cells. 
     
     
         32 . A method for treating a subject having a CD40-associated disorder, comprising administering to the subject the antibody or antigen-binding fragment of any one of  claims 1 - 3 , which antibody or antigen-binding fragment specifically binds to human CD40, wherein the binding of the antibody or antigen-binding fragment to CD40 inhibits the growth or differentiation of cells of the CD40-associated disorder. 
     
     
         33 . The method of  claim 32 , wherein the cells of the CD40-associated disorder are B lymphoblastoid cells, pancreatic, lung cells, breast cells, ovarian cells, colon cells, prostate cells, skin cells, head and neck cells, bladder cells, bone cells or kidney cells. 
     
     
         34 . The method of  claim 32 , wherein the CD40-associated disorder is chronic lymphocytic leukemia, Burkitt's lymphoma, multiple myeloma, a T cell lymphoma, Non-Hodgkin's Lymphoma, Hodgkin's Disease, Waldenstrom's macroglobulinemia or Kaposi's sarcoma. 
     
     
         35 . A method for inducing depletion of peripheral B cells, comprising administering to the cells the antibody or antigen-binding fragment of any one of  claims 1 - 3 , which antibody or antigen-binding fragment specifically binds to a human cell surface CD40 antigen, wherein the binding of the antibody or antigen-binding fragment to the CD40 antigen induces depletion of the cells. 
     
     
         36 . The method of  claim 35 , wherein the antibody or antigen-binding fragment is administered to a subject having an immune disorder. 
     
     
         37 . The method of  claim 36 , wherein the immune disorder is rheumatoid arthritis or systemic lupus erythematosus. 
     
     
         38 . The antibody or antigen-binding fragment of any one of  claims 1 - 3 , wherein the antibody or antigen-binding fragment competes for binding with monoclonal antibody S2C6 that is secreted by a hybridoma having ATCC Accession No. PTA-110. 
     
     
         39 . A pharmaceutical composition comprising:
 (i) the antibody or antigen-binding fragment of any one of  claims 1 - 3 ; and   (ii) a pharmaceutically acceptable excipient.   
     
     
         40 . An isolated polynucleotide encoding the humanized heavy chain variable region of the antibody or antigen-binding fragment of  claim 1 . 
     
     
         41 . An isolated polynucleotide encoding the humanized light chain variable region of the antibody or antigen-binding fragment of  claim 2 . 
     
     
         42 . The isolated polynucleotide of  claim 40 , further encoding a humanized light chain variable region comprising a framework region comprising an amino acid sequence at least 90% identical to the framework region of the human variable region light chain subgroup kappa I concensus amino acid sequence of SEQ ID NO:13 and comprising at least one CDR having an amino acid sequence at least 90% identical to a corresponding heavy chain CDR of SEQ ID NO:3. 
     
     
         43 . The isolated polynucleotide of  claim 40  or  42 , wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, or SEQ ID NO:11. 
     
     
         44 . The isolated polynucleotide of  claim 41  or  42 , wherein the polynucleotide encodes the light chain variable domain amino acid sequence of SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:16. 
     
     
         45 . The isolated polynucleotide of  claim 43 , wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of SEQ ID NO:3 and SEQ ID NO:14, respectively; SEQ ID NO:4 and SEQ ID NO:14, respectively; SEQ ID NO:5 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:14, respectively; SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:8 and SEQ ID NO:14, respectively; SEQ ID NO:9 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:15, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:7 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:14, respectively; SEQ ID NO:11 and SEQ ID NO:14, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO:11 and SEQ ID NO:16, respectively. 
     
     
         46 . The isolated polynucleotide of  claim 43 , wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:7 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:14, respectively; SEQ ID NO:11 and SEQ ID NO:14, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO: 11 and SEQ ID NO:16, respectively. 
     
     
         47 . The isolated polynucleotide of  claim 43 , wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO: 11 and SEQ ID NO:16, respectively. 
     
     
         48 . The isolated polynucleotide of  claim 43 , wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of SEQ ID NO:3 and SEQ ID NO:14, respectively. 
     
     
         49 . The isolated polynucleotide of  claim 43 , wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of SEQ ID NO:10 and SEQ ID NO:16, respectively.

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