ErbB interface peptidomimetics and methods of use thereof
Peptides, mimetics and antibodies of erbB, TNF, and IgSF receptors and pharmaceutical compositions comprising the same are described. Methods of using such antibodies, peptides, and mimetics in therapeutic, prophylactic, imaging and diagnostic applications are disclosed.
1. An isolated antibody which binds an amino acid sequence selected from the group consisting of Y-C-F-P-D-E-E-G-A-C-Y (SEQ ID NO:3); C-K-V-E-L-M-Y-P-P-P-Y-F-V-G-M-G-N-G-T-Q-I-Y-V-I-D-P-E-P-C (SEQ ID NO: 28); C-K-I-E-F-M-Y-P-P-P-Y-L-D-N-E-R-S-N-G-T-I-I-H-I-K-E-K-H-L-C (SEQ ID NO: 29); C-S-L-S-I-F-D-P-P-P-F-Q-E-R-N-L-S-G-G-Y-L-H-I-Y-E-S-Q-L-C (SEQ ID NO: 30); Y-C-P-I-W-K-F-P-D-E-E-C-Y (SEQ ID NO: 31); Y-C-L-V-W-K-Y-A-D-A-G-C-Y (SEQ ID NO: 32); Y-C-P-I-Y-K-Y-P-D-V-Q-C-Y (SEQ ID NO: 33); Y-C-F-I-F-K-Y-A-D-P-D-C-Y (SEQ ID NO: 34); Y-C-F-P-D-E-E-G-A-C-Y (SEQ ID NO: 35).
2. The isolated antibody of claim 1 wherein the antibody binds to a cystine knot of an erbB receptor.
3. The isolated antibody of claim 2 wherein the cystine knot is in subdomain IV of an erbB receptor.
4. The isolated antibody of claim 3 wherein the cystine knot is selected from the group consisting of the S22 loop and the S23 loop.
5. The isolated antibody of claim 1 wherein the antibody binds to an interaction surface in the extracellular domain of an erbB receptor.
6. The isolated antibody of claim 1 wherein the antibody is conjugated to a radioactive agent or a chemotherapeutic compound.
7. The isolated antibody of claim 6 wherein the antibody is conjugated to 18 F, 47 Sc, 67 Cu, 86 Y, 90 Y, 109 Pd, 123 I, 125 I, 131 I, 186 Re, 188 Re, 199 Au, 211 At, 212 Pb and 212 Bi.
8. The isolated antibody of claim 6 wherein the antibody is conjugated to methotrexate (amethopterin), doxorubicin (adrimycin), daunorubicin, cytosinarabinoside, etoposide, 5-4 fluorouracil, melphalan, chlorambucil, cyclophosphamide, cis-platin, vindesine, mitomycin, bleomycin, tamoxiphen, taxol, ricin, ricin A chain, Pseudomonas exotoxin (PE), diphtheria toxin (DT), Clostridium perfringens phospholipase C (PLC), bovine pancreatic ribonuclease (BPR), pokeweed antiviral protein (PAP), abrin, abrin A chain, cobra venom factor (CVF), gelonin (GEL), saporin (SAP), modeccin, viscumin or volkensin.
9. A recombinant antibody which binds an amino acid sequence selected from the group consisting of Y-C-F-P-D-E-E-G-A-C-Y (SEQ ID NO:3); C-K-V-E-L-M-Y-P-P-P-Y-F-V-G-M-G-N-G-T-Q-I-Y-V-I-D-P-E-P-C (SEQ ID NO: 28); C-K-I-E-F-M-Y-P-P-P-Y-L-D-N-E-R-S-N-G-T-I-I-H-I-K-E-K-H-L-C (SEQ ID NO: 29); C-S-L-S-I-F-D-P-P-P-F-Q-E-R-N-L-S-G-G-Y-L-H-I-Y-E-S-Q-L-C (SEQ ID NO: 30); Y-C-P-I-W-K-F-P-D-E-E-C-Y (SEQ ID NO: 31); Y-C-L-V-W-K-Y-A-D-A-G-C-Y (SEQ ID NO: 32); Y-C-P-I-Y-K-Y-P-D-V-Q-C-Y (SEQ ID NO: 33); Y-C-F-I-F-K-Y-A-D-P-D-C-Y (SEQ ID NO: 34); Y-C-F-P-D-E-E-G-A-C-Y (SEQ ID NO: 35).
10. The recombinant antibody of claim 9 wherein the antibody binds to a cystine knot of an erbB receptor.
11. The recombinant antibody of claim 10 wherein the cystine knot is in subdomain IV of an erbB receptor.
12. The recombinant antibody of claim 11 wherein the cystine knot is selected from the group consisting of the S22 loop and the S23 loop.
13. The recombinant antibody of claim 9 wherein the antibody binds to an interaction surface in the extracellular domain of an erbB receptor.
14. The recombinant antibody of claim 9 wherein the antibody is conjugated to a radioactive agent or a chemotherapeutic compound.
15. The recombinant antibody of claim 14 wherein the antibody is conjugated to 18 F, 47 Sc, 67 Cu, 86 Y, 90 Y, 109 Pd, 123 I, 125 I, 131 I, 186 Re, 188 Re, 199 Au, 211 At, 212 Pb and 212 Bi.
16. The recombinant antibody of claim 14 wherein the antibody is conjugated to methotrexate (amethopterin), doxorubicin (adrimycin), daunorubicin, cytosinarabinoside, etoposide, 5-4 fluorouracil, melphalan, chlorambucil, cyclophosphamide, cis-platin, vindesine, mitomycin, bleomycin, tamoxiphen, taxol, ricin, ricin A chain, Pseudomonas exotoxin (PE), diphtheria toxin (DT), Clostridium perfringens phospholipase C (PLC), bovine pancreatic ribonuclease (BPR), pokeweed antiviral protein (PAP), abrin, abrin A chain, cobra venom factor (CVF), gelonin (GEL), saporin (SAP), modeccin, viscumin or volkensin.
17. A pharmaceutical composition comprising the antibody of claim 1 or claim 9 .
18. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is an injectable pharmaceutical composition.
19. The pharmaceutical composition of claim 17 further comprising a chemotherapeutic agent.
20. The pharmaceutical composition of claim 19 wherein the chemotherapeutic agent is methotrexate (amethopterin), doxorubicin (adrimycin), daunorubicin, cytosinarabinoside, etoposide, 5-4 fluorouracil, melphalan, chlorambucil, cyclophosphamide), cis-platin, vindesine, mitomycin, bleomycin, tamoxiphen, or taxol.
21. The isolated antibody of claim 1 , wherein said antibody binds an amino acid sequence selected from the group consisting of Y-C-F-P-D-E-E-G-A-C-Y (SEQ ID NO:3); C-K-I-E-F-M-Y-P-P-P-Y-L-D-N-E-R-S-N-G-T-I-I-H-I-K-E-K-H-L-C (SEQ ID NO: 29); C-S-L-S-I-F-D-P-P-P-F-Q-E-R-N-L-S-G-G-Y-L-H-I-Y-E-S-Q-L-C (SEQ ID NO: 30); Y-C-P-I-W-K-F-P-D-E-E-C-Y (SEQ ID NO: 31); Y-C-L-V-W-K-Y-A-D-A-G-C-Y (SEQ ID NO: 32); Y-C-P-I-Y-K-Y-P-D-V-Q-C-Y (SEQ ID NO: 33); Y-C-F-I-F-K-Y-A-D-P-D-C-Y (SEQ ID NO: 34); Y-C-F-P-D-E-E-G-A-C-Y (SEQ ID NO: 35).
22. The recombinant antibody of claim 9 , wherein said antibody binds an amino acid sequence selected from the group consisting of Y-C-F-P-D-E-E-G-A-C-Y (SEQ ID NO:3); C-K-I-E-F-M-Y-P-P-P-Y-L-D-N-E-R-S-N-G-T-I-I-H-I-K-E-K-H-L-C (SEQ ID NO: 29); C-S-L-S-I-F-D-P-P-P-F-Q-E-R-N-L-S-G-G-Y-L-H-I-Y-E-S-Q-L-C (SEQ ID NO: 30); Y-C-P-I-W-K-F-P-D-E-E-C-Y (SEQ ID NO: 31); Y-C-L-V-W-K-Y-A-D-A-G-C-Y (SEQ ID NO: 32); Y-C-P-I-Y-K-Y-P-D-V-Q-C-Y (SEQ ID NO: 33); Y-C-F-I-F-K-Y-A-D-P-D-C-Y (SEQ ID NO: 34); Y-C-F-P-D-E-E-G-A-C-Y (SEQ ID NO: 35).