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NZ741097B2 - Antigen-binding proteins that activate the leptin receptor - Google Patents
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NZ741097B2 - Antigen-binding proteins that activate the leptin receptor - Google Patents

Antigen-binding proteins that activate the leptin receptor

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Publication number
NZ741097B2
NZ741097B2 NZ741097A NZ74109716A NZ741097B2 NZ 741097 B2 NZ741097 B2 NZ 741097B2 NZ 741097 A NZ741097 A NZ 741097A NZ 74109716 A NZ74109716 A NZ 74109716A NZ 741097 B2 NZ741097 B2 NZ 741097B2
Authority
NZ
New Zealand
Prior art keywords
seq
amino acid
acid sequence
set forth
sequence set
Prior art date
Application number
NZ741097A
Other versions
NZ741097A (en
Inventor
Judith ALTAREJOS
Jesper Gromada
Panayiotis Stevis
Original Assignee
Regeneron Pharmaceuticals Inc
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Priority to NZ780754A priority Critical patent/NZ780754B2/en
Priority to NZ780753A priority patent/NZ780753B2/en
Priority claimed from PCT/US2016/056465 external-priority patent/WO2017066204A1/en
Publication of NZ741097A publication Critical patent/NZ741097A/en
Publication of NZ741097B2 publication Critical patent/NZ741097B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2869—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

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 activate LEPR signaling. In other embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind to LEPR and enhance sensitization of LEPR to an antigen. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that bind LEPR in the presence and absence of leptin. In certain embodiments, the invention includes antibodies and antigen-binding fragments of antibodies that induce signaling in cells expressing LEPR mutants that otherwise exhibit defective or impaired signaling in the presence of leptin. The antibodies and antigen-binding fragments of the present invention are useful for the treatment of lipodystrophies and other diseases and disorders associated with or caused by leptin deficiency or leptin resistance.

Claims (41)

What is claimed is:
1. An isolated antibody or antigen-binding fragment thereof that binds human leptin receptor (LEPR) and activates LEPR signaling, wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region (LCVR) 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; a heavy chain variable region (HCVR) that comprises 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; an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 20; an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 22 and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 24; an HCVR 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; an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 36; an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 38 and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 40; an HCVR that comprises 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; an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 52; an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 54 and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 56; an HCVR that comprises 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; an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 68; an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 70 and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 72; an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 76; an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 78 and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 80; an LCVR that comprises an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 92; an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 94 and an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 96; an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 84; an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 86 and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 88; an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100; an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102 and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104; an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108; an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110 and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112.
2. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof exhibits one or more properties selected from the group consisting of: (i) binds monomeric human LEPR at 25ºC with a K of less than about 150 nM as measured by surface plasmon resonance; (ii) binds monomeric human LEPR at 25ºC with a t of greater than about 1 minute as measured by surface plasmon resonance; (iii) binds dimeric human LEPR at 25ºC with a K of less than about 5 nM as measured by surface plasmon resonance; (iv) binds dimeric human LEPR at 25ºC with a t½ of greater than about 15 minutes as measured by surface plasmon resonance; (v) binds human LEPR in complex with human leptin; (vi) does not block the LEPR:leptin interaction; (vii) binds cell surface-expressed LEPR in the presence and absence of human leptin; and (viii) activates LEPR signaling with an EC of less than about 90 pM in a cell- based reporter assay.
3. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: an HCVR 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, and an LCVR 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.
4. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: an HCVR comprising: 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 an LCVR 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.
5. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: an HCVR comprising: an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 36, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 38, and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 40, and an LCVR 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.
6. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment comprises: an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10.
7. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 26, and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10.
8. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 34, and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10.
9. The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: (i) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2; (ii) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 18; (iii) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 26; (iv) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 34; (v) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 42; (vi) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 50; (vii) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 58; (viii) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 66; (ix) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 74; (x) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 90; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 82; (xi) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 90; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 98; (xii) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 90; and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 106.
10. The isolated antibody or antigen-binding fragment thereof of claim 1, which is a full antibody, wherein the HCVR is linked to human IgG1 heavy chain constant domain and the LCVR is linked to human kappa light chain constant domain.
11. The isolated antibody or antigen-binding fragment thereof of claim 1, which is a full antibody, wherein the HCVR is linked to human IgG4 heavy chain constant domain and the LCVR is linked to human kappa light chain constant domain.
12. The isolated antibody or antigen-binding fragment thereof of claim 1, which is a full antibody having two of said heavy chain variable regions linked to human heavy chain constant domains and two of said light chain variable regions linked to human light chain constant domains, which chains are interconnected by disulfide bonds.
13. The isolated antibody or antigen-binding fragment thereof of claim 1 which is bispecific.
14. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof potentiates LEPR to leptin binding.
15. An isolated polynucleotide that encodes an HCVR and an LCVR of an antibody or antigen-binding fragment thereof of any one of claims 1 to 14.
16. A vector comprising the polynucleotide of claim 15.
17. An in vitro host cell comprising the vector of claim 16.
18. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1 to 14, and a pharmaceutically acceptable carrier or diluent.
19. A pen delivery device comprising the pharmaceutical composition of claim 18.
20. The pharmaceutical composition of claim 18 for use in a method for treating a disease or condition associated with or caused by leptin deficiency or leptin resistance, comprising administering the pharmaceutical composition to a subject in need thereof.
21. The pharmaceutical composition of claim 20, wherein the disease or condition associated with or caused by leptin deficiency or leptin resistance is selected from the group consisting of lipodystrophy, obesity, metabolic syndrome, diet-induced food craving, functional hypothalamic amenorrhea, type 1 diabetes, type 2 diabetes, insulin resistance, severe insulin resistance due to mutation in insulin receptor, Alzheimer's disease, leptin deficiency, leptin resistance, Leprechaunism/Donohue syndrome, and Rabson-Mendenhall syndrome.
22. The pharmaceutical composition of claim 18 for use in a method for treating a lipodystrophy condition in a patient, comprising administering the pharmaceutical composition to a patient in need thereof, wherein the lipodystrophy is a condition is selected from the group consisting of congenital generalized lipodystrophy, acquired generalized lipodystrophy, familial partial lipodystrophy, acquired partial lipodystrophy, centrifugal abdominal lipodystrophy, lipoatrophia annularis, localized lipodystrophy, and HIV-associated lipodystrophy.
23. The pharmaceutical composition of claim 18 for use in a method for treating a disease or condition associated with or caused by a signaling-defective or signaling-impaired LEPR mutation, comprising administering the pharmaceutical composition to a subject in need thereof.
24. The pharmaceutical composition of claim 23, wherein the signaling-defective or signaling-impaired LEPR mutation is LEPR-A409E or LEPR-P316T.
25. The pharmaceutical composition of claim 23 or 24, wherein the disease or condition associated with or caused by a signaling-defective or signaling-impaired LEPR mutation is early-onset obesity.
26. The pharmaceutical composition of any one of claims 20 to 25, further comprising administering a second therapeutic agent to the subject, 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/Metrelepin, Lorcaserin, Cetilistat, Tesofensine, and Velneperit.
27. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof binds human LEPR and sensitizes LEPR to leptin.
28. The isolated antibody or antigen-binding fragment thereof of claim 1 in combination with one or more additional therapeutically active components.
29. The isolated antibody or antigen-binding fragment thereof of claim 28, wherein the one or more additional therapeutically active components 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 Inhibitor, a GLP-1 agonist/analogue, a glucagon inhibitor, a glucagon receptor inhibitor, an angiopoietin-like protein inhibitor, Phentermine, Orlistat, Topiramate, Bupropion, Topiramate/Phentermine, Bupropion/Naltrexone, Bupropion/Zonisamide, Pramlintide/Metrelepin, Lorcaserin, Cetilistat, Tesofensine, and Velneperit.
30. Use of an antibody or antigen-binding fragment thereof of any one of claims 1 to 14 and 27 to 29, in the manufacture of a medicament for use in treating a disease or condition associated with or caused by leptin deficiency or leptin resistance.
31. Use of claim 30, wherein the disease or condition associated with or caused by leptin deficiency or leptin resistance is selected from the group consisting of lipodystrophy, obesity, metabolic syndrome, diet-induced food craving, functional hypothalamic amenorrhea, type 1 diabetes, type 2 diabetes, insulin resistance, severe insulin resistance due to mutation in insulin receptor, Alzheimer's disease, leptin deficiency, leptin resistance, Leprechaunism/Donohue syndrome, and Rabson-Mendenhall syndrome.
32. Use of an antibody or antigen-binding fragment thereof of any one of claims 1 to 14 and 27 to 29, in the manufacture of a medicament for use in treating a lipodystrophy condition in a patient, wherein the lipodystrophy is a condition is selected from the group consisting of congenital generalized lipodystrophy, acquired generalized lipodystrophy, familial partial lipodystrophy, acquired partial lipodystrophy, centrifugal abdominal lipodystrophy, lipoatrophia annularis, localized lipodystrophy, and HIV-associated lipodystrophy.
33. Use of an antibody or antigen-binding fragment thereof of any one of claims 1 to 14 and 27 to 29, in the manufacture of a medicament for use in treating a disease or condition associated with or caused by a signaling-defective or signaling-impaired LEPR mutation.
34. The use of claim 33, wherein the signaling-defective or signaling-impaired LEPR mutation is LEPR-A409E or LEPR-P316T.
35. The use of claim 33 or 34, wherein the disease or condition associated with or caused by a signaling-defective or signaling-impaired LEPR mutation is early-onset obesity.
36. The use of any one of claims 30 to 35, wherein the medicament further comprises a second therapeutic agent, 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/Metrelepin, Lorcaserin, Cetilistat, Tesofensine, and Velneperit.
37. The use of any one of claims 30 to 35, wherein the medicament is to be administered, or is in a form for administration, in combination with a second therapeutic agent, 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/Metrelepin, Lorcaserin, Cetilistat, Tesofensine, and Velneperit.
38. An isolated antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 14 and 27 to 29, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
39. A pharmaceutical composition as claimed in any one of claims 18 and 21-26, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
40. A pen as claimed in claim 19, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
41. A use as claimed in any one of claims 30 to 37, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings. Blocking of 10nM hLepR ecto-hFc Binding to hLeptin H4H16650P2 H4H16679P2 IgG4 Isotype control hLeptin -11 -10 -9 -8 -7 -6 Concentration of Antibody or Leptin (Log M) Binding of LepR Absorbance at 450nm P316T A409E -12 -11 -10 -9 -8 -7 -6 Leptin Concentration (M) P316T A409E -12 -11 -10 -9 -8 -7 -6 H4H16650Ab Concentration (M) P316T A409E -12 -11 -10 -9 -8 -7 -6 H4H16679Ab Concentration (M) pSTAT3 Y705/ STAT3 pSTAT3 Y705/ STAT3 pSTAT3 Y705/ STAT3 Densitometry (A.U.) Densitometry (A.U.) Densitometry (A.U.) Fat Mass Pre-mAb (Day 6) * P<0.05 Significance over Isotype Control Pre-mAb (Day 6) Post-mAb (Day 13) 15 P<0.05 Significance over Isotype Control Post-mAb (Day 13) Isotype Control (N=7) H4H16650P2 (N=7) H4H16679P2 (N=7) H4H17319P2 (N=7) H4H17321P2 (N=4) Fat Mass (g) *P<0.05, Isotype Control vs H4H18482P2 P<0.05, Isotype Control vs H4H18487P2 P<0.05, Isotype Control vs H4H18492P2 P<0.05, H4H18492P2 vs H4H18482P2 P<0.05, H4H18492P2 vs H4H18487P2 Isotype Control Isotype Control *P<0.05, vs REGN1945
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