Immunoglobulins and uses thereof

Patent metadata

Field	Value
Publication number	US-12134636-B2
Application number	US-202017085128-A
Country	US
Kind code	B2
Filing date	Oct 30, 2020
Priority date	Oct 27, 2016
Publication date	Nov 5, 2024
Grant date	Nov 5, 2024

Abstract

The present invention relates to a monoclonal antibody platform designed to be coupled to therapeutic peptides to increase the half-life of the therapeutic peptide in a subject. The invention also relates to pharmaceutical compositions and methods for use thereof.

First claim

It is claimed:

1. An isolated humanized monoclonal antibody comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, a HCDR3, and a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3, having the polypeptide sequences of SEQ ID NO: 16, 17, 18, 19, 20, and 21, respectively.

2. The isolated humanized monoclonal antibody of claim 1 , wherein the isolated monoclonal antibody comprises a heavy chain variable domain (VH) having the polypeptide sequence of SEQ ID NO:12, and a light chain variable domain (VL) having the polypeptide sequence of SEQ ID NO:14.

3. The isolated humanized monoclonal antibody of claim 1 , further comprising a Fc portion.

4. The isolated humanized monoclonal antibody of claim 3 , comprising a heavy chain (HC) having the polypeptide sequence of SEQ ID NO:13, and a light chain (LC) having the polypeptide sequence of SEQ ID NO:15.

5. An isolated nucleic acid encoding the humanized monoclonal antibody of claim 1 .

6. A vector comprising the isolated nucleic acid of claim 5 .

7. A host cell comprising the vector of claim 6 .

8. A method of producing an isolated humanized monoclonal antibody, the method comprising culturing the host cell of claim 7 under conditions to produce the monoclonal antibody, and recovering the humanized monoclonal antibody from the cell or culture.

9. A conjugate comprising the humanized monoclonal antibody of claim 1 and at least one pharmacologically active moiety conjugated thereto.

10. The conjugate of claim 9 , wherein the pharmacologically active moiety is a therapeutic peptide.

11. The conjugate of claim 10 , wherein the therapeutic peptide is conjugated to the humanized monoclonal antibody at the cysteine residue of SEQ ID NO:18.

12. The conjugate of claim 10 , wherein the therapeutic peptide is conjugated to the humanized monoclonal antibody via a linker.

13. The conjugate of claim 12 , wherein the linker comprises a peptide linker, a hydrocarbon linker, a polyethylene glycol (PEG) linker, a polypropylene glycol (PPG) linker, a polysaccharide linker, a polyester linker, or a hybrid linker consisting of PEG and an embedded heterocycle.

14. The conjugate of claim 10 , wherein the therapeutic peptide is selected from the group consisting of oxyntomodulin, glucagon-like peptide 1 (GLP1), exendin, amylin, alpha-melanocyte stimulating hormone (MSH), cocaine- and amphetamine-regulated transcript (CART), neuropeptide Y receptor Y1 (NPY1) antagonists, neuropeptide Y receptor Y5 (NPY5) antagonists, neurotensin S, neuropeptide B, neuropeptide W, ghrelin, bombesin-like receptor 3 (BRS3), galanin, cholecystokinin (CCK), orexin, melanin-concentrating hormone (MCH), oxytocin, and stresscopin.

15. The conjugate of claim 14 , wherein the therapeutic peptide is oxyntomodulin comprising the polypeptide sequence of SEQ ID NO:24.

16. A method of producing a conjugate comprising a humanized monoclonal antibody and a therapeutic peptide, comprising reacting an electrophile, introduced onto a sidechain of the therapeutic peptide, with the sulfhydryl group of the cysteine residue of SEQ ID NO:18 of the humanized monoclonal antibody as set forth in claim 1 .

17. A pharmaceutical composition comprising the conjugate of claim 9 and a pharmaceutically acceptable carrier.

18. A method of producing a pharmaceutical composition comprising the conjugate of claim 9 , the method comprising combining the humanized monoclonal antibody with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition.

19. A method of increasing the half-life of a therapeutic peptide in a subject, the method comprising conjugating the therapeutic peptide with a humanized monoclonal antibody comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, a HCDR3, and a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3, having the polypeptide sequences of SEQ ID NO: 16, 17, 18, 19, 20, and 21, respectively, wherein the therapeutic peptide is conjugated to the humanized monoclonal antibody at the Cys residue of SEQ ID NO:18.

20. The method of claim 19 , wherein the therapeutic peptide is selected from the group consisting of oxyntomodulin, glucagon-like peptide 1 (GLP1), exendin (exenatide), amylin (pramlintide), alpha-melanocyte stimulating hormone (MSH), cocaine- and amphetamine-regulated transcript (CART), neuropeptide Y receptor Y1 (NPY1) antagonists, neuropeptide Y receptor Y5 (NPY5) antagonists, neurotensin S, neuropeptide B, neuropeptide W, ghrelin, bombesin-like receptor 3 (BRS3), galanin, cholecystokinin (CCK), orexin, melanin-concentrating hormone (MCH), oxytocin, and stresscopin.

21. The method of claim 16 , wherein the electrophile is bromoacetamide or maleimide.

22. A method of reducing food intake or treating or preventing a disease or disorder in a subject in need thereof, wherein said disease or disorder is selected from the group consisting of obesity, type II diabetes, metabolic syndrome, insulin resistance, impaired glucose tolerance, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypoglycemia due to congenital hyperinsulinism (CHI), dyslipidemia, atherosclerosis, diabetic nephropathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and renal disease, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising the conjugate of claim 14 and a pharmaceutically acceptable carrier.

23. An isolated humanized antigen-binding fragment comprising a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, a HCDR3, and a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3, having the polypeptide sequences of SEQ ID NO: 16, 17, 18, 19, 20, and 21, respectively.

24. The isolated humanized antigen-binding fragment of claim 23 , wherein the isolated monoclonal antibody comprises a heavy chain variable domain (VH) having the polypeptide sequence of SEQ ID NO:12, and a light chain variable domain (VL) having the polypeptide sequence of SEQ ID NO:14.

25. The isolated humanized antigen-binding fragment of claim 23 , further comprising a Fc portion.

26. The isolated humanized antigen-binding fragment of claim 24 , comprising a heavy chain (HC) having the polypeptide sequence of SEQ ID NO:13, and a light chain (LC) having the polypeptide sequence of SEQ ID NO:15.

27. An isolated nucleic acid encoding the humanized antigen binding fragment of claim 23 .

28. A vector comprising the isolated nucleic acid of claim 27 .

29. A host cell comprising the vector of claim 28 .

30. A conjugate comprising the humanized antigen-binding fragment of claim 23 and at least one pharmacologically active moiety conjugated thereto.

31. The conjugate of claim 30 , wherein the pharmacologically active moiety is a therapeutic peptide.

32. The conjugate of claim 31 , wherein the therapeutic peptide is conjugated to the humanized monoclonal antibody via a linker.

33. The conjugate of claim 32 , wherein the linker comprises a peptide linker, a hydrocarbon linker, a polyethylene glycol (PEG) linker, a polypropylene glycol (PPG) linker, a polysaccharide linker, a polyester linker, or a hybrid linker consisting of PEG and an embedded heterocycle.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Macielag Mark
• Patch Raymond J
• Zhang Rui
• Case Martin A
• Wall Mark J
• Zhang Yue-Mei
• Rangwala Shamina M
• Leonard James N
• Camacho Raul C
• Hunter Michael J
• D'Aquino Katharine E
• Edwards Wilson
• Swanson Ronald V
• Jian Wenying
• Chi Ellen

Classifications

• C07K2317/14

  Specific host cells or culture conditions, e.g. components, pH or temperature · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• A61K38/1709

  from mammals · CPC title

• C07K1/1072

  by covalent attachment of residues or functional groups · CPC title

• A61K38/26

  Glucagons · CPC title