Antibody-coupled cyclic peptide tyrosine tyrosine compounds as modulators of neuropeptide Y receptors

• US 10,640,544 B2
• Filed: 10/26/2017
• Issued: 05/05/2020
• Est. Priority Date: 10/27/2016
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Macielag, Mark, Patch, Raymond J, Zhang, Rui, Case, Martin A, Rangwala, Shamina M, Leonard, James N, Camacho, Raul C, Hunter, Michael J, D'Aquino, Katharine E., Edwards, Wilson, Swanson, Ronald V, Jian, Wenying, Zhang, Yue-Mei, Wall, Mark, Chi, Ellen
• Primary Examiner(s): Emch, Gregory S
• Application Number:
  US15/794,171
• Publication Number:
  US 20180117170A1
• Time in Patent Office: 922 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6845 the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
• CPC Class Codes: A61K 47/6883 Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0052 Small organic molecules oligomers, polymers, dendrimers A61K49/0054
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 1/061 : using protecting groups
• CPC Class Codes: C07K 1/1072 : by covalent attachment of residues or functional groups
• CPC Class Codes: C07K 1/12 : by hydrolysis , i.e. solvolysis in general
• CPC Class Codes: C07K 1/18 : Ion-exchange chromatography
• CPC Class Codes: C07K 14/575 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/57545 : Neuropeptide Y
• CPC Class Codes: C07K 16/00 : Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/24 : against cytokines, lymphokines or interferons
• CPC Class Codes: C07K 2317/14 : Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 5/0205 : containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof

Abstract

The present invention comprises conjugates comprising a monoclonal antibody conjugated to a cyclic PYY peptide. The invention also relates to pharmaceutical compositions and methods for use thereof. The novel conjugates are useful for preventing, treating or ameliorating diseases and disorders disclosed herein.

Claims

1. A conjugate comprising a monoclonal antibody or an antigen binding fragment thereof coupled to a cyclic PYY peptide, the monoclonal antibody or the antigen binding fragment thereof comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having the polypeptide sequences of SEQ ID NO:

141, 142, 143, 144, 145, and 146, respectively, wherein the cyclic PYY peptide is represented by Formula I or a derivative or pharmaceutically acceptable salt thereof;

2. The conjugate of claim 1, wherein the cyclic PYY peptide is a compound of Formula I or a derivative of the cyclic PYY peptide of Formula I that is modified by one or more processes selected from the group consisting amidation, lipidation, and pegylation, or a pharmaceutically acceptable salt thereof.

3. The conjugate of claim 1, wherein the cyclic PYY peptide is represented by Formula I or the derivative or pharmaceutically acceptable salt thereof, wherein:

p is 0 or 1;

m is 0, 1, 2, 3, 4, or 5;

n is 1, 2, 3, or 4;

q is 0 or 1;

provided that q is 1 only when Z₃₀ is absent;

BRIDGE is -Ph-CH₂—

S—

, -triazolyl-, —

NHC(O)CH₂S—

, —

SCH₂C(O)NH₂—

, —

(OCH₂CH₂)₂NHC(O)CH₂S, —

NHC(O)—

, or —

CH₂S—

;

Z₄ is K, A, E, S, or R;

Z₇ is A or K, wherein the amino side chain of said K is optionally substituted with

4. The conjugate of claim 1, wherein the cyclic PYY peptide is represented by Formula I or the derivative or pharmaceutically acceptable salt thereof, wherein:

p is 0 or 1;

m is 0, 1, 2, 3, or 5;

n is 1, 2, or 4;

q is 0 or 1;

provided that q may be 1 only when Z₃₀ is absent;

BRIDGE is -Ph-CH₂—

S—

, -triazolyl-, —

NHC(O)CH₂S—

, —

(OCH₂CH₂)₂NHC(O)CH₂S, —

NHC(O)—

, or —

CH₂S—

;

Z₄ is K, A, E, S, or R;

Z₇ is A or K, wherein the amino side chain of said K is substituted with

5. The conjugate of claim 1, wherein the cyclic PYY peptide is selected from the group consisting of SEQ ID NOs:

1, 73-100, and 147-156, or a pharmaceutically acceptable salt thereof.

6. The conjugate of claim 1, wherein the monoclonal antibody or the antigen binding fragment thereof is covalently linked to the cyclic PYY peptide at a lysine residue of the cyclic PYY peptide via a linker.

7. The conjugate of claim 6, wherein the linker comprises one selected from the group consisting of polyethylene glycol (PEG)8-triazolyl-CH₂CH₂CO-PEG4, a PEG chain of 2-24 PEG units, an alkyl chain containing 2-10 carbon atoms, (Gly₄Ser)_j wherein j=1-4, (AlaPro)_u wherein u=1-10, and a bond.

8. The conjugate of claim 7, wherein only one of Z₇, Z₉, Z₁₁, Z₂₂ and Z₂₃ in Formula I is lysine, and the lysine is covalently linked to an engineered cysteine residue of the monoclonal antibody or the antigen binding fragment thereof via the linker.

9. The conjugate of claim 1, wherein the isolated monoclonal antibody or the antigen binding fragment thereof comprises a heavy chain variable domain (VH) having the polypeptide sequence of SEQ ID NO:

137, and a light chain variable domain (VL) having the polypeptide sequence of SEQ ID NO;

139.

10. The conjugate of claim 9, further comprising a Fc portion.

11. The conjugate of claim 10, comprising a heavy chain (HC) having the polypeptide sequence of SEQ ID NO:

138 and a light chain (LC) having the polypeptide sequence of SEQ ID NO;

140.

12. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.

13. A method of modulating Y2 receptor activity in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of claim 12.

14. A method of reducing food intake in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of claim 12.

15. The method of claim 14, wherein the pharmaceutical composition is administered via an injection.

16. The method of claim 14, wherein the pharmaceutical composition is administered in a combination with at least one antidiabetic agent.

17. The method of claim 16, wherein said antidiabetic agent is a glucagon-like-peptide-1 receptor modulator.

18. The method of claim 16, wherein the pharmaceutical composition is administered in combination with liraglutide.

19. A kit comprising the conjugate of claim 1, further comprising liraglutide and a device for injection.

20. A method of producing a pharmaceutical composition comprising the conjugate of claim 1, comprising combining the conjugate with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition.

25. A method of producing the conjugate of claim 1, comprising reacting an electrophile, introduced onto a sidechain of the cyclic PYY peptide, with the sulfhydryl group of the cysteine residue of SEQ ID NO:

143 of the monoclonal antibody or antigen-binding fragment thereof, thereby creating a covalent linkage between the cyclic PYY peptide and the monoclonal antibody or antigen-binding fragment thereof.

26. The method of claim 25, wherein the electrophile is bromoacetamide or maleimide.

27. The method of claim 25, wherein the sidechain of the cyclic PYY peptide is a sidechain of a lysine residue of the cyclic PYY peptide.

21. A conjugate comprising a monoclonal antibody or an antigen binding fragment thereof coupled to a cyclic PYY peptide, wherein:

the monoclonal antibody or the antigen binding fragment thereof comprises a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having the polypeptide sequences of SEQ ID NO;

141, 142, 143, 144, 145, and 146, respectively, the cyclic PYY peptide comprises a polypeptide sequence selected from the group consisting of SEQ ID NOs;

1, 73-100, and 147-156, or a pharmaceutically acceptable salt thereof; and

the monoclonal antibody or antigen binding fragment thereof is conjugated to the cyclic PYY peptide at residue 7, 9, 11, 22 or 23 of the cyclic PYY peptide, directly or via a linker.

22. The conjugate of claim 21, wherein the monoclonal antibody or antigen binding fragment thereof comprises a heavy chain variable domain (VH) having the polypeptide sequence of SEQ ID NO:

137 and a light chain variable domain (VL) having the polypeptide sequence of SEQ ID NO;

139.

23. The conjugate of claim 21, wherein the monoclonal antibody or antigen binding fragment thereof comprises a heavy chain (HC) having the polypeptide sequence of SEQ ID NO:

138 and a light chain (LC) having the polypeptide sequence of SEQ ID NO;

140.

24. The conjugate of claim 21, wherein the monoclonal antibody or antigen binding fragment thereof is conjugated to the cyclic PYY peptide at lysine residue 11 of the cyclic PYY peptide.

28. A conjugate comprising a monoclonal antibody or an antigen binding fragment thereof coupled to a cyclic PYY peptide, wherein the conjugate comprises the monoclonal antibody or the antigen binding fragment thereof comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, and a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having the polypeptide sequences of SEQ ID NO:

141, 142, 143, 144, 145, and 146, respectively, and a sequence selected from the group consisting of SEQ ID NOs;

102-127 or a pharmaceutically acceptable salt thereof,

wherein mAb represents the monoclonal antibody or the antigen binding fragment thereof, and ]₂ represents that 1 or 2 of the cyclic PYY peptides is/are covalently conjugated to the mAb.