Endotrophin neutralization and use thereof
Aspects of the present invention relate to methods and reagents for increasing chemosensitivity to platinum-based chemotherapy. In one aspect, a method of increasing chemosensitivity to platinum-based chemotherapy is provided, comprising administering to a patient in need thereof an effective amount of an endotrophin-neutralizing agent. The agent can be a monoclonal antibody, or fragment thereof, capable of binding to the C5 domain of the alpha3 chain of collagen VI. In some embodiments, the method can further include administering an effective amount of thiazolidinedione to said patient.
1. A polynucleotide that encodes a monoclonal antibody, or fragment thereof, that specifically binds to the C5 domain of the alpha3 chain of human collagen VI (SEQ ID NO: 5) or mouse collagen VI (SEQ ID NO: 6), wherein the antibody comprises:
(a) a first V H CDR comprising the sequence GYTFTSYE (SEQ ID NO: 9);
(b) a second V H CDR comprising the sequence IYPESGST (SEQ ID NO: 10);
(c) a third V H CDR comprising the sequence TRGLRVLGYVMDV (SEQ ID NO: 11);
(d) a first V L CDR comprising the sequence QNINKY (SEQ ID NO: 7);
(e) a second V L CDR comprising the sequence NTN; and
(f) a third V L CDR comprising the sequence LQHSSLYT (SEQ ID NO: 8).
2. The polynucleotide of claim 1 , wherein the monoclonal antibody, or fragment thereof further comprises a light chain framework sequence from an immunoglobulin light chain and a heavy chain framework sequence from an immunoglobulin heavy chain.
3. The polynucleotide of claim 2 , wherein the monoclonal antibody, or fragment thereof, comprises i) the light chain variable region with the amino acid sequence of SEQ ID NO: 2; and ii) the heavy chain variable region with the amino acid sequence of SEQ ID NO: 4.
4. The polynucleotide of claim 1 , wherein the monoclonal antibody, or fragment thereof, is recombinant.
5. The polynucleotide of claim 1 , wherein the fragment of the monoclonal antibody is an Fab′, a F(ab′)2, a F(ab′)3, a monovalent scFv, a bivalent scFv, or a single domain antibody.
6. The polynucleotide of claim 1 , wherein the antibody or antibody fragment is a human, humanized antibody or de-immunized antibody.
7. A method of treating a cancer patient comprising administering an effective amount of an antibody encoded by a polynucleotide in accordance with claim 1 , said cancer patient determined to express an elevated level of endotrophin relative to control patient.
8. The method of claim 7 , further defined as a method for inhibiting angiogenesis or increasing chemosensitivity to platinum-based chemotherapy in the patient.
9. The method of claim 8 , further comprising administering a platinum-based chemotherapy to the patient.
10. The method claim 7 , wherein the cancer is a breast cancer or colon cancer.
11. The method of claim 7 , wherein the antibody is conjugated or fused to an imaging agent or a cytotoxic agent.
12. The method of claim 7 , further comprising administering at least a second anti-cancer therapy.
13. The method of claim 12 , wherein the second anti-cancer therapy is a chemotherapy, radiotherapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy or cytokine therapy.
14. The method of claim 13 , wherein the chemotherapy comprises a platinum-based chemotherapy.
15. The method of claim 14 , wherein the platinum-based chemotherapy is cisplatin, oxaliplatin or carboplatin.
16. The method of claim 14 , further comprising administering thiazolidinedione to the patient.