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.

What is claimed is: 
     
         1 . An isolated polynucleotide encoding an antibody heavy chain or a functional fragment thereof, wherein said antibody heavy chain or functional fragment thereof comprises a variable heavy chain (VH) domain having an amino acid sequence selected from the group consisting of residues 20-142 of SEQ ID NO: 2, residues 20-142 of SEQ ID NO: 6, residues 20-142 of SEQ ID NO: 10, and residues 20-145 of SEQ ID NO: 14. 
     
     
         2 . The isolated polynucleotide of  claim 1 , wherein said VH domain amino acid sequence is encoded by the nucleic acid sequence selected from the group consisting of residues 58-426 of SEQ ID NO: 1, residues 58-426 of SEQ ID NO: 5, residues 58-426 of SEQ ID NO: 9 and residues 58-435 of SEQ ID NO: 13. 
     
     
         3 . An isolated polynucleotide encoding an antibody light chain or a functional fragment thereof, wherein said antibody light chain or functional fragment thereof comprises a variable light chain (VL) domain having an amino acid sequence selected from the group consisting of residues 20-130 of SEQ ID NO: 4, residues 20-129 of SEQ ID NO: 8, residues 20-130 of SEQ ID NO: 12, and residues 23-130 of SEQ ID NO: 16. 
     
     
         4 . The isolated polynucleotide of  claim 3 , wherein said VL domain amino acid sequence is encoded by the nucleic acid sequence selected from the group consisting of residues 58-390 of SEQ ID NO: 3, residues 58-387 of SEQ ID NO: 7, residues 58-390 of SEQ ID NO: 11 and residues 67-390 of SEQ ID NO: 15. 
     
     
         5 . An isolated antibody or functional fragment thereof that binds to Sialyl-Lewis a , said antibody or functional fragment thereof comprising a variable heavy chain (VH) domain, said VH domain comprising an amino acid sequence selected from the group consisting of residues 20-142 of SEQ ID NO: 2, residues 20-142 of SEQ ID NO: 6, residues 20-142 of SEQ ID NO: 10, and residues 20-145 of SEQ ID NO: 14. 
     
     
         6 . An isolated antibody or functional fragment thereof that binds to Sialyl-Lewis a , said antibody or functional fragment thereof comprising a variable light chain (VL) domain, said VL domain comprising an amino acid sequence selected from the group consisting of residues 20-130 of SEQ ID NO: 4, residues 20-129 of SEQ ID NO: 8, residues 20-130 of SEQ ID NO: 12, and residues 23-130 of SEQ ID NO: 16. 
     
     
         7 . An isolated antibody or functional fragment thereof that binds to Sialyl-Lewis a , said antibody or functional fragment thereof comprising a variable heavy chain (VH) domain and a variable light chain (VL) domain, where said VH domain and said VL domain respectively comprise an amino acid sequence selected from the group consisting of residues 20-142 of SEQ ID NO: 2 and residues 20-130 of SEQ ID NO: 4; residues 20-142 of SEQ ID NO: 6 and residues 20-129 of SEQ ID NO: 8; residues 20-142 of SEQ ID NO: 10 and residues 20-130 of SEQ ID NO: 12; and residues 20-145 of SEQ ID NO: 14 and residues 23-130 of SEQ ID NO: 16. 
     
     
         8 . The isolated antibody or functional fragment thereof of any one of  claims 5 - 7 , wherein said antibody is a human antibody. 
     
     
         9 . The isolated antibody or functional fragment thereof of any one of  claims 5 - 7 , wherein said antibody functional 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). 
     
     
         10 . The antibody or functional fragment thereof of  claim 9 , wherein said antibody functional fragment is a diabody. 
     
     
         11 . The antibody or functional fragment of  claim 10 , wherein said diabody comprises the amino acid sequence of SEQ ID NO: 18 or 20. 
     
     
         12 . The isolated antibody or functional fragment thereof of any one of  claims 5 - 7 , wherein said antibody is a monoclonal antibody. 
     
     
         13 . The isolated antibody or functional fragment thereof of any one of  claims 5 - 7 , wherein said antibody is an IgG or IgM isotype. 
     
     
         14 . The isolated antibody or functional fragment thereof of  claim 13 , wherein said IgG antibody is an IgG1 subclass. 
     
     
         15 . An conjugate comprising an isolated antibody or functional fragment of any one of  claims 5 - 7  conjugated or recombinantly fused to a diagnostic agent, detectable agent or therapeutic agent. 
     
     
         16 . The conjugate of  claim 15 , wherein said conjugate comprises a detectable agent. 
     
     
         17 . The conjugate of  claim 16 , wherein said detectable agent is zirconium ( 89 Zr). 
     
     
         18 . A pharmaceutical composition comprising the antibody or functional fragment of any one of  claims 5 - 7  and a pharmaceutically acceptable carrier. 
     
     
         19 . A method for treating or preventing a disease comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 18  to a subject in need thereof. 
     
     
         20 . The method of  claim 19 , wherein said disease is cancer or a tumor formation, wherein the cells of said cancer or said tumor expresses sLe a . 
     
     
         21 . The method of  claim 19 , wherein said cancer or tumor 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. 
     
     
         22 . The method of  claim 19 , wherein said method further comprises administering concurrently or successively a second therapeutic agent. 
     
     
         23 . The method of  claim 22 , wherein said second therapeutic agent is a chemotherapeutic agent or an immunotherapeutic agent. 
     
     
         24 . A method for detecting a tumor in a subject comprising administering an effective amount of the conjugate of  claim 16  to a subject in need thereof.