Nucleic acids encoding human antibodies to sialyl-lewis a

Abstract

The present invention provides compositions for the production of an antibody or functional fragment thereof directed against Sialyl-Lewis a (sLe a ). The compositions of the invention include polynucleotides encoding a heavy chain and/or a light chain variable domain that binds to sLe a . The invention also provides an isolated antibody or functional fragment thereof and methods of treating or preventing a disease, such as cancer or tumor formation, wherein the antibody or functional fragment includes a variable heavy chain domain and a variable light chain domain that has an amino acid sequence provided herein. The invention further provides a conjugate of an antibody or functional fragment thereof conjugated or recombinantly fused to a diagnostic agent, detectable agent or therapeutic agent, and methods of treating, preventing or diagnosing a disease in a subject in need thereof.

1 .- 24 . (canceled) 
     
     
         25 . A method of cancer treatment, the method comprising a step of:
 co-administering to a subject having cancer first and second therapeutic agents,   wherein the first therapeutic agent is or comprises an antibody or antigen binding fragment thereof that binds to sialyl-Lewis a , which antibody or antigen binding fragment thereof comprises:
 a variable heavy chain domain having at least one CDR selected from the group consisting of (i) CDR1 represented by amino acid residues 55-62 of SEQ ID NO: 2; (ii) CDR2 represented by amino acid residues 70-77 of SEQ ID NO: 2; and (iii) CDR3 represented by amino acid residues 116-131 of SEQ ID NO: 2; and/or 
 a variable light chain domain having at least one CDR selected from the group consisting of (i) CDR1 represented by amino acid residues 45-52 of SEQ ID NO: 4; (ii) CDR2 represented by amino acid residues 70-72 of SEQ ID NO: 4; and (iii) CDR3 represented by amino acid residues 109-120 of SEQ ID NO: 4; and 
   wherein the second therapeutic agent is or comprises a chemotherapeutic agent.   
     
     
         26 . The method of  claim 25 , wherein the first and second therapeutic agents are administered concurrently. 
     
     
         27 . The method of  claim 25 , wherein the first and second therapeutic agents are administered successively. 
     
     
         28 . The method of  claim 27 , wherein the step of co-administering comprises administering the first therapeutic agent to a subject who is receiving the second therapeutic agent. 
     
     
         29 . The method of  claim 27 , wherein the step of co-administering comprises administering the second therapeutic agent to a subject who is receiving the first therapeutic agent. 
     
     
         30 . The method of  claim 25 , wherein the first therapeutic agent is administered intravenously. 
     
     
         31 . The method of  claim 25 , wherein the cancer is a sialyl-Lewis a -positive cancer. 
     
     
         32 . The method of  claim 31 , wherein the cancer is selected from the group consisting of a tumor of the gastrointestinal tract, colon cancer, colorectal adenocarcinoma, metastatic colon cancer, colorectal cancer, pancreatic cancer, pancreatic adenocarcinoma, small cell carcinoma of the lung, bladder adenocarcinoma, signet ring ovarian cancer, ovarian cancer, metastatic carcinoma, adenocarcinoma of the stomach, adenocarcinoma of the esophagus, adenocarcinoma of the throat, adenocarcinoma of the urogenital tract, and adenocarcinoma of the breast. 
     
     
         33 . The method of  claim 25 , wherein the subject is suffering from pancreatic cancer. 
     
     
         34 . The method of  claim 25 , wherein the subject is suffering from colorectal cancer. 
     
     
         35 . The method of  claim 25 , wherein the subject is suffering from small cell lung cancer. 
     
     
         36 . The method of  claim 25 , wherein the subject is suffering from or susceptible to cancer metastasis. 
     
     
         37 . The method of  claim 25 , wherein the variable heavy chain domain has an amino acid sequence represented by amino acid residues 20-142 of SEQ ID NO: 2 or a derivative thereof comprising less than 10 amino acid substitutions relative to the amino acid sequence represented by amino acid residues 20-142 of SEQ ID NO: 2. 
     
     
         38 . The method of  claim 25 , wherein the variable light chain domain has an amino acid sequence represented by amino acid residues 20-130 of SEQ ID NO: 4 or a derivative thereof comprising less than 10 amino acid substitutions relative to the amino acid sequence represented by amino acid residues 20-130 of SEQ ID NO: 4. 
     
     
         39 . The method of  claim 25 , wherein the first therapeutic agent is or comprises the antibody that binds to sialyl-Lewis a . 
     
     
         40 . The method of  claim 39 , wherein the antibody is a human antibody. 
     
     
         41 . The method of  claim 39 , wherein the antibody is a monoclonal antibody. 
     
     
         42 . The method of  claim 39 , wherein the antibody is an IgG isotype. 
     
     
         43 . The method of  claim 42 , wherein the IgG isotype is IgG1. 
     
     
         44 . The method of  claim 25 , wherein the first therapeutic agent is or comprises the antigen binding fragment thereof that binds to sialyl-Lewis a . 
     
     
         45 . The method of  claim 44 , wherein the antigen binding fragment is selected from the group consisting of a Fab, a Fab′, a F(ab′) 2 , a scFv, a diabody, a triabody, a minibody and a single-domain antibody (sdAB). 
     
     
         46 . The method of  claim 25 , wherein the chemotherapeutic agent is or comprises a taxane. 
     
     
         47 . The method of  claim 46 , wherein the taxane is or comprises paclitaxel (Taxol).