Human antibodies specific for gastrin materials and methods
View Patent ↗The present invention relates to materials and methods for human antibodies specific for the peptide hormone gastrin and uses of these antibodies in the treatment of subjects having cancer and other conditions or disorders related to gastrin expression.
1. An isolated antibody that binds gastrin (gastrin 17) with an affinity kd of 10 −7 M or less that comprises:
(a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33, a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution, or a consensus sequence thereof;
(b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution or a consensus sequence thereof;
(c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33 or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution, or a consensus sequence thereof;
(d) a light chain CDR1 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution;
(e) a light chain CDR2 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution; and
(f) a light chain CDR3 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution.
2. The antibody of claim 1 wherein one or more of said heavy chain CDR1, CDR2 or CDR3 amino acid sequences is a consensus sequence set forth in SEQ ID NO: 11.
3. The antibody of claim 1 wherein
(a) an amino acid in a heavy chain CDR1 amino acid sequence is replaced with an amino acid from a corresponding position within a different heavy chain CDR1 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33; or
(b) an amino acid in a heavy chain CDR2 amino acid sequence is replaced with an amino acid from a corresponding position within a different heavy chain CDR2 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33; or
(c) an amino acid in a heavy chain CDR3 amino acid sequence is replaced with an amino acid from a corresponding position within a different heavy chain CDR3 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33.
4. The antibody of claim 1 that comprises a heavy chain variable region amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33.
5. The antibody of claim 1 in which one or more heavy chain framework amino acids have been replaced with corresponding amino acid(s) from another human antibody amino acid sequence.
6. The antibody of claim 1 further comprising a human heavy chain constant region attached to said heavy chain variable region.
7. The antibody of claim 1 wherein one or more of said light chain CDR1, CDR2 or CDR3 amino acid sequences is a consensus sequence set forth in SEQ ID NO: 12.
8. The antibody of claim 1 wherein
(a) an amino acid in a light chain CDR1 amino acid sequence is replaced with an amino acid from a corresponding position within a different light chain CDR1 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12; or
(b) an amino acid in a light chain CDR2 amino acid sequence is replaced with an amino acid from a corresponding position within a different light chain CDR2 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12; or
(c) an amino acid in a light chain CDR3 amino acid sequence is replaced with an amino acid from a corresponding position within a different light chain CDR3 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12.
9. The antibody of claim 1 that comprises a light chain variable region amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12.
10. The antibody of claim 1 in which one or more light chain framework amino acids have been replaced with corresponding amino acid(s) from another human antibody amino acid sequence.
11. The antibody of claim 1 further comprising a human light chain constant region attached to said light chain variable region.
12. An antibody of claim 1 that exhibits at least 70% neutralization of calcium flux in an assay using AGS-TR cells, wherein the tested antibody is at a concentration in 100 molar excess over gastrin, and wherein gastrin is at the EC50 concentration (1 nM).
13. The antibody of claim 1 that comprises 6 CDRs of any of XPA061 (SEQ ID NO: 1 and 2), XPA063 (SEQ ID NO: 3 and 4), XPA065 (SEQ ID NO: 5 and 6), XPA067 (SEQ ID NO: 7 and 8), and XPA081 (SEQ ID NO: 9 and 10).
14. The antibody of claim 1 which is a single chain antibody.
15. The antibody of claim 1 that is conjugated to another diagnostic or therapeutic agent.
16. A pharmaceutical composition comprising an antibody of claim 1 and a pharmaceutically acceptable carrier.
17. A kit comprising an antibody of claim 4 and instructions for use.
18. An isolated monoclonal antibody that binds gastrin (gastrin 17) with an affinity kd of 10 −8 M or less that comprises:
(a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33, a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution, or a consensus sequence thereof;
(b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution or a consensus sequence thereof;
(c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11 or 23-33, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution, or a consensus sequence thereof;
(d) a light chain CDR1 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution;
(e) a light chain CDR2 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution; and
(f) a light chain CDR3 amino acid sequence set forth in SEQ ID NOs: 2, 4, 6, 8, 10 or 12, or a variant thereof in which one or two amino acids have been changed by conservative amino acid substitution.
19. The antibody of claim 1 wherein the heavy chain CDR2 and CDR3 amino acid sequences are from the same heavy chain variable region as the CDR1 amino acid sequence.
20. The antibody of claim 1 wherein the light chain CDR2 and CDR3 amino acid sequences are from the same light chain variable region as the CDR1 amino acid sequence.
21. The antibody of claim 1 that comprises heavy chain CDR1, CDR2 and CDR3 of any of XPA067.06 (SEQ ID NO: 23) and XPA067.18 (SEQ ID NO: 29).
22. A method for treating a condition or disorder selected from the group consisting of pancreatic cancer, esophageal cancer, gastric cancer, colorectal cancer, small lung cell carcinoma, gastric ulcer, duodenal ulcer, other ulcers or conditions associated with H. Pylori , gastroesophageal reflux disease, autoimmune gastritis, atrophic body gastritis, Zollinger-Ellison syndrome associated with tumor of the pancreas (gastrinoma), or inflammatory bowel disease comprising the step of administering to a subject in need a therapeutically effective amount of the pharmaceutical composition of claim 16 .
23. The method of claim 22 wherein the antibody is administered in conjunction with a second therapeutic agent.