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

Patent metadata

Field	Value
Publication number	US-10640544-B2
Application number	US-201715794171-A
Country	US
Kind code	B2
Filing date	Oct 26, 2017
Priority date	Oct 27, 2016
Publication date	May 5, 2020
Grant date	May 5, 2020

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.

First claim

It is claimed:

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:

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 Z 30 is absent;
BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —SCH 2 C(O)NH—, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—;
Z 4 is K, A, E, S, or R;
Z 7 is A or K;
Z 9 is G or K;
Z 11 is D or K;
Z 22 is A or K;
Z 23 is S or K;
Z 26 is A or H;
Z 30 is L, W, absent, or K;
provided that Z 30 is absent only when q is 1;
Z 34 is

Z 35 is

wherein the derivative is the compound of Formula I that is modified by one or more processes selected from the group consisting of amidation, glycosylation, carbamylation, sulfation, phosphorylation, cyclization, lipidation, and pegylation.

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 Z 30 is absent;
BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —SCH 2 C(O)NH 2 —, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—;
Z 4 is K, A, E, S, or R;
Z 7 is A or K, wherein the amino side chain of said K is optionally substituted with

wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 9 is G or K, wherein the amino side chain of said K is optionally substituted with

wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 11 is D or K, wherein the amino side chain of said K is optionally substituted with

wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 22 is A or K, wherein the amino side chain of said K is optionally substituted with

wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 23 is S or K, wherein the amino side chain of said K is optionally substituted with

wherein i is an integer of 0 to 24, and X=Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 26 is A or H;
Z 30 is L or K, wherein the amino side chain of said K is substituted with

Z 34 is

and
Z 35 is

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 Z 30 is absent;
BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—;
Z 4 is K, A, E, S, or R;
Z 7 is A or K, wherein the amino side chain of said K is substituted with

Z 9 is G or K,
Z 11 is D or K, wherein the amino side chain of said K is substituted with

Z 22 is A or K, wherein the amino side chain of said K is substituted with

Z 23 is S or K, wherein the amino side chain of said K is substituted with

Z 26 is A or H,
Z 30 is L or K, wherein the amino side chain of said K is substituted with

Z 34 is

Z 35 is

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-CH 2 CH 2 CO-PEG4, a PEG chain of 2-24 PEG units, an alkyl chain containing 2-10 carbon atoms, (Gly 4 Ser) j wherein j=1-4, (AlaPro) u wherein u=1-10, and a bond.

8. The conjugate of claim 7 , wherein only one of Z 7 , Z 9 , Z 11 , Z 22 and Z 23 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 met

Assignees

• Janssen Pharmaceutica Nv

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

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K49/0032

  Methine dyes, e.g. cyanine dyes · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title