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

Patent metadata

Field	Value
Publication number	US-10968265-B2
Application number	US-201716344174-A
Country	US
Kind code	B2
Filing date	Oct 26, 2017
Priority date	Oct 27, 2016
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

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. a monoclonal antibody or an antigen binding fragment thereof, wherein the monoclonal antibody or antigen binding fragment thereof comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, a HCDR3, a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3, having the polypeptide sequences of SEQ ID NO:141, 142, 143, 144, 145, and 146, respectively; and
b. at least two cyclic PYY peptides,

wherein the monoclonal antibody or antigen binding fragment thereof is coupled to the at least two cyclic PYY peptides, wherein the at least two cyclic PYY peptides are 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 at least two cyclic PYY peptides are compounds of Formula I or derivatives of the cyclic PYY peptides of Formula I that are 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 at least two cyclic PYY peptides are 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 C1;
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 at least two cyclic PYY peptides are 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

 —C(O)CH 2 Br,
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 at least two cyclic PYY peptides are 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 at least two cyclic PYY peptides at a lysine residue of the at least two cyclic PYY peptides 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. A conjugate comprising:
a. a monoclonal antibody or an antigen binding fragment thereof, wherein the monoclonal antibody or antigen binding fragment thereof comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, a HCDR3, a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the polypeptide sequences of SEQ ID NOs:141, 142, 143, 144, 145, and 146, respectively; and
b. at least two cyclic PYY peptides,

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 J
• Chi Ellen

Classifications

• A61K38/00

  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 title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title