Nucleic acids encoding human antibodies to sialyl-lewis
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. An isolated antibody or antigen binding fragment thereof that binds to Sialyl-Lewis a , said antibody or antigen binding 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.
2. The isolated antibody or antigen binding fragment thereof of claim 1 , wherein said antibody is a human antibody.
3. The isolated antibody or antigen binding fragment thereof of claim 1 , wherein said antibody 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).
4. The antibody or antigen binding fragment thereof of claim 3 , wherein said antibody antigen binding fragment is a diabody.
5. The antibody or antigen binding fragment of claim 4 , wherein said diabody comprises the amino acid sequence of SEQ ID NO: 18 or 20.
6. The isolated antibody or antigen binding fragment thereof of claim 1 , wherein said antibody is a monoclonal antibody.
7. The isolated antibody or antigen binding fragment thereof of claim 1 , wherein said antibody is an IgG or IgM isotype.
8. The isolated antibody or antigen binding fragment thereof of claim 7 , wherein said IgG antibody is an IgG1 subclass.
9. An conjugate comprising an isolated antibody or antigen binding fragment of claim 1 conjugated or recombinantly fused to a diagnostic agent, detectable agent or therapeutic agent.
10. The conjugate of claim 9 , wherein said conjugate comprises a detectable agent.
11. The conjugate of claim 10 , wherein said detectable agent is zirconium ( 89 Zr).
12. A pharmaceutical composition comprising the antibody or antigen binding fragment of claim 1 and a pharmaceutically acceptable carrier.
13. A method for treating or preventing a disease comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 12 to a subject in need thereof, wherein said disease is cancer or a tumor formation having cells expressing sLe a , and wherein preventing is the forestalling of a clinical symptom indicative of cancer or tumor formation or guarding against tumor metastasis.
14. The method of claim 13 , 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.
15. The method of claim 13 , wherein said method further comprises administering concurrently or successively a second therapeutic agent.
16. The method of claim 15 , wherein said second therapeutic agent is a chemotherapeutic agent or an immunotherapeutic agent.
17. A method for detecting a tumor in a subject comprising administering an effective amount of the conjugate of claim 10 to a subject in need thereof, wherein the tumor expresses sLe a .
18. An isolated polynucleotide encoding the VH domain of claim 1 .
19. An isolated polynucleotide encoding the VL domain of claim 1 .
20. An isolated polynucleotide encoding the VH and the VL domain of claim 1 .