Heterotandem bicyclic peptide complexes

Patent metadata

Field	Value
Publication number	US-2021299210-A2
Application number	US-201916372692-A
Country	US
Kind code	A2
Filing date	Apr 2, 2019
Priority date	Apr 4, 2018
Publication date	Sep 30, 2021
Grant date	—

Abstract

The present invention relates to heterotandem bicyclic peptide complexes which comprise a first peptide ligand, which binds to a component present on an immune cell, conjugated via a linker to a second peptide ligand, which binds to a component present on a cancer cell. The invention also relates to the use of said heterotandem bicyclic peptide complexes in preventing, suppressing or treating cancer.

First claim

1 . A heterotandem bicyclic peptide complex comprising:
(a) a first peptide ligand which binds to a component present on an immune cell; conjugated via a linker to (b) a second peptide ligand which binds to a component present on a cancer cell; wherein each of said peptide ligands comprises a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and a 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 heterotandem bicyclic peptide complex as defined in claim 1 , wherein the immune cell is selected from: white blood cells; lymphocytes (e.g. T lymphocytes or T cells, B cells or natural killer cells); CD8 or CD4; CD8; dendritic cells, follicular dendritic cells and granulocytes.

3 . The heterotandem bicyclic peptide complex as defined in claim 1 , wherein the component present on an immune cell is CD137.

4 . The heterotandem bicyclic peptide complex as defined in claim 1 , wherein the first peptide ligand comprises a CD137 binding bicyclic peptide ligand.

5 . The heterotandem bicyclic peptide complex as defined in claim 4 , wherein the CD137 binding bicyclic peptide ligand comprises an amino acid sentience selected from:

(SEQ ID NO: 1)

C i IEEGQYC ii FADPY[Nle]C iii ;

(SEQ ID NO: 3)

C i [tBuAla]pE[D-Ala]PYC ii FADPY[Nle]C iii ;

(SEQ ID NO: 4)

C i IEEGQYC ii F[D-Ala]DPY[Nle]C iii ;

(SEQ ID NO: 5)

C i [tBuAla]pK[D-Ala]PYC ii FADPY[Nle]C iii ;

(SEQ ID NO: 6)

C i [tBuAla]pE[D-Lys]PYC ii FADPY[Nle]C iii ;

(SEQ ID NO: 7)

C i [tBuAla]p[K(PYA)][D-Ala]PYC ii FADPY[Nle]C iii ;

(SEQ ID NO: 8)

C i [tBuAla]pE[D-Lys(PYA)]PYC ii FADPY[Nle]C iii ;

(SEQ ID NO: 9)

C i IEE[D-Lys(PYA)]QYC ii FADPY(Nle)C iii

and

(SEQ ID NO: 10)

[dC i ][dl[dE][dE][K(PYA)][dQ][dY][dC ii ]

[dF][dA][dD][dP][dY][dNle][dC iii ];

wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively, Nle represents norleucine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid, or a pharmaceutically acceptable salt thereof.

6 . The heterotandem bicyclic peptide complex as defined in claim 5 , wherein the CD137 binding bicyclic peptide ligand comprises N- and C-terminal modifications and comprises:
Ac-A-(SEQ ID NO: 1)-Dap (hereinafter referred to as BCY7732); Ac-A-(SEQ ID NO: 1)-Dap(PYA) (hereinafter referred to as BCY7741); Ac-(SEQ ID NO: 3)-Dap (hereinafter referred to as BCY9172); Ac-(SEQ ID NO: 3)-Dap(PYA) (hereinafter referred to as BCY11014); Ac-A-(SEQ ID NO: 4)-Dap (hereinafter referred to as BCY8045); Ac-(SEQ ID NO: 5)-A (hereinafter referred to as BCY8919); Ac-(SEQ ID NO: 6)-A (hereinafter referred to as BCY8920); Ac-(SEQ ID NO: 7)-A (hereinafter referred to as BCY8927); Ac-(SEQ ID NO: 8)-A (hereinafter referred to as BCY8928); Ac-A-(SEQ ID NO: 9)-A (hereinafter referred to as BCY7744); and Ac-[dA]-(SEQ ID NO: 10)-[dA]-NH2 (hereinafter referred to as BCY11506);
wherein Ac represents an acetyl group, Dap represents diaminopropionic acid and PYA represents 4-pentynoic acid, or a pharmaceutically acceptable salt thereof.

7 . The heterotandem bicyclic peptide complex as defined in claim 1 , wherein the cancer cell is selected from an HT1080, SC-OV-3, PC3, H1376, NCI-H292, LnCap, MC38 and RKO tumor cell.

8 . The heterotandem bicyclic peptide complex as defined in claim 1 , wherein the component present on a cancer cell is EphA2.

9 . The heterotandem bicyclic peptide complex as defined in claim 1 , wherein the second peptide ligand comprises an EphA2 binding bicyclic peptide ligand.

10 . The heterotandem bicyclic peptide complex as defined in claim 9 , wherein the EphA2 binding bicyclic peptide ligand comprises an amino acid sequence selected from:

(SEQ ID NO: 2)

C i [HyP]LVNPLC ii LHP[dD]W[HArg]C iii ;

and

(SEQ ID NO: 11)

C i LWDPTPC ii ANLHL[HArg]C iii ;

wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively, HyP represents hydroxyproline, dD represents aspartic acid in D-configuration and HArg represents homoarginine, or a pharmaceutically acceptable salt thereof.

11 . The heterotandem bicyclic peptide complex as defined in claim 10 , wherein the EphA2 binding bicyclic peptide ligand comprises N-terminal modifications and comprises:
A-HArg-D-(SEQ ID NO: 2) (hereinafter referred to as BCY9594); [B-Ala]-[Sarin]-A-[HArg]-D-(SEQ ID NO: 2) (hereinafter referred to as BCY6099); [PYA]-[B-Ala]-[Sar 10 ]-A-[HArg]-D-(SEQ ID NO: 2) (hereinafter referred to as BCY6169); and [PYA]-[B-Ala]-[Sar 10 ]-VGP-(SEQ ID NO: 11) (hereinafter referred to as BCY8941);
wherein HArg represents homoarginine, PYA represents 4-pentynoic acid, Sar 10 represents 10 sarcosine units, B-Ala represents beta-alanine, or a pharmaceutically acceptable salt thereof.

12 . The heterotandem bicyclic peptide complex as defined in claim 9 which is a CD137/EphA2 complex selected from: BCY9173, BCY7985, BCY8942, BCY8943, BCY9647, BCY9648, BCY9655, BCY9656, BCY9657, BCY9658, BCY9659, BCY9758, BCY10568, BCY10570, BCY10574, BCY10575, BCY10576 and BCY10577.

13 . The heterotandem bicyclic peptide complex as defined in claim 1 , wherein the component present on a cancer cell is PD-L1.

14 . The heterotande

Assignees

• Bicycletx Ltd

Inventors

• KEEN Nicholas
• Mcdonnell Kevin
• Park Peter
• Upadhyaya Punit

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K14/47

  from mammals · CPC title

• C07K14/001 Primary

  by chemical synthesis · CPC title

• C07K14/70578

  NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151) · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title