Bicyclic peptide ligands specific for caix

Patent metadata

Field	Value
Publication number	US-2022088118-A1
Application number	US-202017422932-A
Country	US
Kind code	A1
Filing date	Jan 15, 2020
Priority date	Jan 15, 2019
Publication date	Mar 24, 2022
Grant date	—

Abstract

The present invention relates to polypeptides which are covalently bound to non-aromatic molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which are high affinity binders of carbonic anhydrase IX (CAIX). The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder mediated by CAIX.

First claim

1 . A peptide ligand specific for CAIX comprising a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and a non-aromatic molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold.

2 . The peptide ligand as defined in claim 1 , wherein said loop sequences comprise 2, 3 or 7 amino acids.

3 . The peptide ligand as defined in claim 1 or claim 2 , wherein said loop sequences comprise three cysteine residues separated by two loop sequences one of which consists of 2 amino acids and the other of which consists of 7 amino acids.

4 . The peptide ligand as defined in claim 1 or claim 2 , wherein said loop sequences comprise three cysteine residues separated by two loop sequences one of which consists of 3 amino acids and the other of which consists of 7 amino acids.

5 . The peptide ligand as defined in claim 1 or claim 2 , which comprises an amino acid sequence selected from:

(SEQ ID NO: 17)

C i -X 1 -X 2 -X 3 -C ii -X 4 -W-I/A/V-D-G-W-V/I/M-X 5 -C iii ;

wherein X 1 -X 2 represent any amino acid residue, X 3 is either absent or represents any amino acid, one of X 4 and X 5 represents any amino acid and the other is absent and C i , C ii and C iii represent first, second and third cysteine residues, respectively or a pharmaceutically acceptable salt thereof.

6 . The peptide ligand as defined in claim 5 , wherein X 4 is absent and X 5 represents P or N.

7 . The peptide ligand as defined in claim 5 , wherein X 5 is absent and X 4 represents T, I, V or L.

8 . The peptide ligand as defined in claim 5 , wherein the peptide ligand of C i -X 1 -X 2 -X 3 -C ii -X 4 -W-I/A/V-D-G-W-V/I/M-X 5 -C iii (SEQ ID NO: 17) comprises an amino acid sequence selected from any one of SEQ ID NOS: 1 to 16:

(SEQ ID NO: 1)

C i TEC ii WVDGWVPC iii ;

(SEQ ID NO: 2)

C i NEC ii WVDGWVPC iii ;

(SEQ ID NO: 3)

C i SEC ii WVDGWVPC iii ;

(SEQ ID NO: 4)

C i GAC ii TWADGWVC iii ;

(SEQ ID NO: 5)

C i GDC ii IWVDGWVC iii ;

(SEQ ID NO: 8)

C i RDC ii IWVDGWVC iii ;

(SEQ ID NO: 7)

C i VDC ii VWVDGWVC iii ;

(SEQ ID NO: 8)

C i GLC ii IWVDGWVC iii ;

(SEQ ID NO: 9)

C i GRC ii TWVDGWIC iii ;

(SEQ ID NO: 10)

C i TDC ii IWVDGWMC iii ;

(SEQ ID NO: 11)

C i VEC ii WADGWVNC iii ;

(SEQ ID NO: 12)

C i HAHC ii LWVDGWVC iii ;

(SEQ ID NO: 13)

C i SSEC ii IWVDGWVC iii ;

(SEQ ID NO: 14)

C i TETC ii IWVDGWVC iii ;

(SEQ ID NO: 15)

C i ANNC ii IWVDGWVC iii ;

and

(SEQ ID NO: 16)

C i LSHC ii LWVDGWVC iii ;

wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively, or a pharmaceutically acceptable salt thereof.

9 . The peptide ligand as defined in claim 8 , wherein the peptide ligand peptide ligand of C i -X 1 -X 2 -X 3 -C ii -X 4 -W-I/A/V-D-G-W-V/I/M-X 5 -C iii (SEQ ID NO: 17) comprises an amino acid sequence selected from:
β-Ala-Sar 10 -A-(SEQ ID NO: 1) (herein referred to as 61-01-02-N025); β-Ala-Sar 10 -A-(SEQ ID NO: 2) (herein referred to as 61-01-10-N002); β-Ala-Sar 10 -A-(SEQ ID NO: 3) (herein referred to as 61-01-11-N002); A-(SEQ ID NO: 4)-A (herein referred to as 61-25-00-N001); A-(SEQ ID NO: 5)-A (herein referred to as 61-25-01-N001); A-(SEQ ID NO: 6)-A (herein referred to as 61-25-02-N001); A-(SEQ ID NO: 7)-A (herein referred to as 61-25-03-N001); A-(SEQ ID NO: 8)-A (herein referred to as 61-26-00-N001); A-(SEQ ID NO: 9)-A (herein referred to as 61-27-00-N001); A-(SEQ ID NO: 10)-A (herein referred to as 61-28-00-N001); A-(SEQ ID NO: 11)-A (herein referred to as 61-29-00-N001); A-(SEQ ID NO: 12)-A (herein referred to as 61-30-00-N001); A-(SEQ ID NO: 1

Assignees

• Bicycletx Ltd

Inventors

• Baldassarre Leonardo
• Chen Liuhong
• Lani Rachid
• Stace Catherine
• Teufel Daniel
• Walker Edward

Classifications

• A61K38/12 Primary

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• C12Y402/01001

  Carbonate dehydratase (4.2.1.1), i.e. carbonic anhydrase · CPC title

• 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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title