Methods of treatment using a leptin receptor agonist antibody

1. A method for increasing bone mass in a subject in need thereof having low bone mass which is a symptom of hypoleptinemia from which the subject suffers comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that binds human leptin receptor (LEPR) and activates LEPR signaling comprising:

a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26, and

a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10; and a

pharmaceutically acceptable carrier or diluent, to the subject.

2. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:

a heavy chain variable region that comprises:

an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 28,

an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 30, and

an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 32; and

a light chain variable region that comprises:

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.

3. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 26; and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10.

4. The method of claim 3 , wherein the antibody or antigen-binding fragment thereof is a monospecific antibody that is a tetramer comprising two heavy chains that comprise heavy chain variable regions that comprise the amino acid sequence set forth in SEQ ID NO: 26, and two light chains that comprise light chain variable regions that comprise the amino acid sequence set forth in SEQ ID NO: 10, inter-connected by disulfide bonds.

5. The method of claim 4 wherein the heavy chain variable region is linked to an IgG4 human constant region and the light chain variable region is linked to a kappa light chain constant region.

6. The method of claim 4 , further comprising administering a second therapeutic agent to the subject.

7. The method of claim 6 wherein the second therapeutic agent is selected from the group consisting of: a recombinant human leptin, a PCSK9 inhibitor, a statin, ezetimibe, insulin, an insulin variant, an insulin secretagogue, metformin, a sulfonylurea, a sodium glucose cotransporter 2 (SGLT2) Inhibitor, a GLP-1 agonist/analogue, a glucagon (GCG) inhibitor, a glucagon receptor (GCGR) inhibitor, an angiopoietin-like protein (ANGPTL) inhibitor, phentermine, orlistat, topiramate, bupropion, topiramate/phentermine, bupropion/naltrexone, bupropion/zonisamide, pramlintide/metreleptin, lorcaserin, cetilistat, tesofensine, velneperit, an anticonvulsant, digoxin, coumadin, vitamin D, thyroxine, a thyroid supplement, a vitamin supplement, a calcium supplement, carnitine, coenzyme Q10, an anti-constipation medication, an anti-allergic medications, gabapentin, a narcotic, ketamine, lidocaine, and venlafaxine hydrochloride.

8. The method of claim 4 wherein the subject has amenorrhea.

9. The method of claim 4 wherein the subject has functional hypothalamic amenorrhea.