Antigen-binding proteins that antagonize leptin receptor
The present invention provides antibodies and antigen-binding fragments of antibodies that bind to leptin receptor (LEPR), and methods of using the same. According to certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR and antagonize LEPR signaling. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR in the presence or absence of leptin. In other embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that exhibit partial agonism of LEPR signaling. The antibodies and antigen-binding fragments of the present invention are useful for the treatment of various conditions, including but not limited to congestive heart failure cachexia, pulmonary cachexia and cancer cachexia, autoimmune disorders such as inflammatory bowel disease, lupus erythematosus, multiple sclerosis, psoriasis, cardiovascular diseases, elevated blood pressure, neurodegenerative disorders, depression, cancer such as hepatocellular carcinoma, melanoma, breast cancer, and other diseases and disorders associated with or caused by elevated leptin signaling.
1. A method for treating a disease associated with or caused by elevated human leptin receptor (LEPR) signaling in a subject in need thereof, the method comprising administering, to the subject, a pharmaceutical composition that comprises a pharmaceutically acceptable carrier or diluent and an isolated antibody or antigen-binding fragment thereof that binds human LEPR, wherein the antibody or antigen-binding fragment thereof comprises:
(a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 42, and SEQ ID NO: 58; and
(b) the CDRs of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 10.
2. The method of claim 1 , wherein the disease or condition associated with or caused by leptin signaling is selected from the group consisting of anorexia, a psychiatric eating disorder, cachexia, chronic kidney disease cachexia, congestive heart failure cachexia, pulmonary cachexia, radiation cachexia, cancer cachexia, an autoimmune disorder, inflammatory bowel disease, lupus erythematosus, multiple sclerosis, psoriasis, a cardiovascular disease, elevated blood pressure, nonalcoholic fatty liver disease, cancer, hepatocellular carcinoma, melanoma and breast cancer.
3. The method of claim 1 , further comprising administering a second therapeutic agent to the subject.
4. The method of claim 3 wherein the second therapeutic agent is selected from the group consisting of a 5-aminosalicylic acid; an angiotensin receptor blocker; an angiotensin-converting enzyme inhibitor; an anthracycline; an anti-cancer therapy; an anticholinergic; an anti-depressant; a corticosteroid; a diuretic; a fumarate; an immunosuppressant; an iron-deficient anemia treatment; a long- or short-acting bronchodilator; a long-acting nitrate; a long-term antibiotic; a loop diuretic; a macrolide; a methylxanthine; a monoclonal antibody that binds CD20; a nonsteroidal anti-inflammatory drug; a potassium-sparing diuretic; a proline-rich peptide; a relapsing-remitting multiple sclerosis therapy; a retinoid; a smooth muscle relaxant; a statin; a taxane; a thiazide-like diuretic; a TNF-alpha antagonist; a topical agent for psoriasis treatment; and a vitamin D analogue.
5. The method of claim 3 wherein the second therapeutic agent is selected from the group consisting of a combination of atropine; hyoscyamine, phenobarbital and scopolamine; a combination of simvastatin and ezetimibe; a combination of lovastatin and niacin; a combination of atorvastatin and amlodipine; 5-fluorouracil; 6-mercaptopurine; adalimumab; albuterol; alefacept; alemtuzumab; amitriptyline; arformoterol; aspirin; atorvastatin; atropine; azathioprine; azithromycin; benazepril; betamethasone; budesonide; buphenine; bupropion; captopril; carboplatin; celecoxib; certolizumab pegol; citalopram; clenbuterol; coal tar; coconut oil; cyclophosphamide; cyclosporin; dabrafenib; daclizumab; desoximetasone; desvenlafaxine; dexamethasone; diclofenac; dicyclomine; diflunisal; dimebon; dimethyl fumarate; dithranol; docetaxel; dopexamine; doxorubicin; duloxetine; efalizumab; enalapril; epinephrine; epirubicin; erythromycin; escitalopram; etodolac; fentoterol; fingolimod; flunisolide; fluocinonide; fluocortolone; fluoxetine; fluvastatin; formoterol; fosinopril; glatiramer acetate; golimumab; hydralazine; hydrocortisone; hydrocortisone-17-butyrate; hydrocortisone-17-valerate; hydroxycarbamide; hyoscyamine; ibuprofen; indomethacin; infliximab; interferon beta-1a; interferon beta-1 b; interleukin-2; ipilimumab; isoetarine; isoprenaline; isoproterenol; isosorbide dinitrate; JX-594; ketoprofen; levosalbutamol; lisinopril; lovastatin; mepenzolate; mesalazine; methotrexate; mevastatin; mitoxantrone; moexipril; naproxen; natalizumab; nivolumab; nortriptyline; ocrelizumab; ofatumumab; orciprenaline; oxaprozin; paclitaxel; para-aminobenzoic acid; parenteral iron; paroxetine; pembrolizumab; perindopril; phenobarbital; pirbuterol; piroxicam; pitavastatin; pravastatin; prednisolone; prednisone; procaterol; psoralen; quinapril; ramapril; ritodrine; rituximab; rosuvastatin; salbutamol; salsalate; scopolamine; sertraline; simvastatin; sorafenib; sulindac; terbutaline; teriflunomide; theophylline; tiotropium; tolmetin; trametinib; trandolapril; trazodone; triamcinolone acetonide; triamcinolone alcohol; vemurafenib; venlafacine; venlafaxine; and vitamin D3.
6. The method of claim 1 wherein the isolated antibody or antigen-binding fragment thereof comprises:
a light chain variable region comprising:
an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 12;
an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 14, and
an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16;
and
a heavy chain variable region comprising:
(i)
an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 4;
an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 6; and
an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 8;
(ii)
an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 44;
an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 46; and
an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 48;
or
(iii)
an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 60;
an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 62; and
an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 64.
7. The method of claim 1 wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 2 and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10.
8. The method of claim 7 wherein the antibody or antigen-binding fragment is a monospecific antibody comprising two of said light chain variable regions which are linked to light chain constant regions and two of said heavy chain variable regions which are linked to heavy chain constant regions, inter-connected by disulfide bonds.
9. The method of claim 8 wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.
10. The method of claim 1 wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 42 and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10.
11. The method of claim 10 wherein the antibody or antigen-binding fragment is a monospecific antibody comprising two of said light chain variable regions which are linked to light chain constant regions and two of said heavy chain variable regions which are linked to heavy chain constant regions, inter-connected by disulfide bonds.
12. The method of claim 11 wherein the disease is cachexia.
13. The method of claim 11 wherein the disease is cancer cachexia.
14. The method of claim 11 wherein the disease is congestive heart failure cachexia.
15. The method of claim 11 wherein the disease is pulmonary cachexia.
16. The method of claim 11 wherein the disease is radiation cachexia.
17. The method of claim 11 wherein the disease is a psychiatric eating disorder.
18. The method of claim 11 wherein the disease is anorexia.
19. The method of claim 11 wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.
20. The method of claim 1 wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 58 and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10.
21. The method of claim 20 wherein the antibody or antigen-binding fragment is a monospecific antibody comprising two of said light chain variable regions which are linked to light chain constant regions and two of said heavy chain variable regions which are linked to heavy chain constant regions, inter-connected by disulfide bonds.
22. The method of claim 21 wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.
23. The method of claim 1 wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region comprising:
an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 12;
an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 14; and
an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16;
and
a heavy chain variable region comprising:
an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 4;
an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 6; and
an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 8.
24. The method of claim 1 wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region comprising:
an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 12;
an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 14; and
an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16;
and
a heavy chain variable region comprising:
an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 44;
an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 46; and
an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 48.
25. The method of claim 1 wherein the isolated antibody or antigen-binding fragment thereof comprises a light chain variable region comprising:
an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 12;
an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 14; and
an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16;
and
a heavy chain variable region comprising:
an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 60;
an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 62; and
an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 64.