# US 11,306,123 B2 · Heterotandem bicyclic peptide complex

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- Number: US 11,306,123 B2
- Document ID: US11306123B2
- Status: Granted
- Kind: B2
- Application number: 16/941,614
- Filed: 2020-07-29
- Published: 2021-02-11
- Granted: 2022-04-19
- Earliest claimed: 2019-07-30
- Assignees: BicycleTx Limited
- Applicants: BicycleTx Limited
- Inventors: Gemma Mudd; Punit Upadhyaya; Kevin McDonnell; Johanna Lahdenranta
- Web page: https://patentgrep.com/patent/US11306123B2

## CPC

- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- 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)}
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 47/641: {Branched, dendritic or hypercomb peptides}
- A61P 35/00: Antineoplastic agents
- C07K 11/02: cyclic, e.g. valinomycins {; Derivatives thereof}
- C07K 14/001: {by chemical synthesis}
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 14/78: Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
- 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)
- C07K 2319/00: Fusion polypeptide
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a heterotandem bicyclic peptide complex which comprises a first peptide ligand, which binds to Nectin-4, conjugated via a linker to two second peptide ligands, which bind to CD137. The invention also relates to the use of said heterotandem bicyclic peptide complex in preventing, suppressing or treating cancer.

## Claims

### Claim 1

A heterotandem bicyclic peptide complex comprising:
(a) a first peptide ligand which binds to Nectin-4 and which has the sequence CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiii (SEQ ID NO: 1); conjugated via an N-(acid-PEG3)-N-bis(PEG3-azide) linker to
(b) two second peptide ligands which bind to CD137 both of which have the sequence Ac-Ci[tBuAla]PE[D-Lys(PYA)]PYCiiFADPY[Nle]Ciii-A (SEQ ID NO: 2);
or a pharmaceutically acceptable salt thereof,
wherein each of said peptide ligands comprise a polypeptide comprising three reactive cysteine groups (Ci, Cii and Ciii), separated by two loop sequences, and a molecular scaffold which is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) and which forms covalent bonds with the reactive cysteine groups of the polypeptide such that two polypeptide loops are formed on the molecular scaffold;
wherein Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4-hydroxy-L-proline, 1Nal represents 1-naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid and Nle represents norleucine.

### Claim 2 (depends on 1)

The heterotandem bicyclic peptide complex according to claim 1 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The heterotandem bicyclic peptide complex as defined in claim 1, wherein the pharmaceutically acceptable salt is selected from the free acid or the sodium, potassium, calcium, or ammonium salt.

### Claim 4 (depends on 1)

A pharmaceutical composition which comprises the heterotandem bicyclic peptide complex of claim 1, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.

### Claim 5 (depends on 1)

A method of preventing, suppressing or treating cancer, comprising administering the heterotandem bicyclic peptide complex as defined in claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The method of claim 5, wherein the cancer is lung cancer, colon cancer, bladder cancer, or breast cancer.

### Claim 7 (depends on 1)

A method of treating cancer which comprises administration of the heterotandem bicyclic peptide complex as defined in claim 1, or a pharmaceutically acceptable salt thereof, at a dosage frequency which does not sustain plasma concentrations of said complex above the in vitro EC50 of said complex.

### Claim 8 (depends on 7)

The method of claim 7, wherein the cancer is lung cancer, colon cancer, bladder cancer, or breast cancer.

### Claim 9 (depends on 7)

The method of claim 7, wherein the dosage frequency is once per week.

### Claim 10 (depends on 7)

The method of claim 7, wherein the dosage frequency is twice per week.

### Claim 11

A heterotandem bicyclic peptide complex which is:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The heterotandem bicyclic peptide complex of claim 11, wherein the pharmaceutically acceptable salt is selected from the free acid or the sodium, potassium, calcium, or ammonium salt.

### Claim 13 (depends on 11)

A pharmaceutical composition comprising the heterotandem bicyclic peptide complex of claim 11, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients.

### Claim 14 (depends on 11)

A method of preventing, suppressing or treating cancer, comprising administering the heterotandem bicyclic peptide complex of claim 11, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein the cancer is lung cancer, colon cancer, bladder cancer, or breast cancer.

### Claim 16 (depends on 11)

A method of treating cancer which comprises administration of the heterotandem bicyclic peptide complex of claim 11, or a pharmaceutically acceptable salt thereof, at a dosage frequency which does not sustain plasma concentrations of said complex above the in vitro EC50 of said complex.

### Claim 17 (depends on 16)

The method of claim 16, wherein the cancer is lung cancer, colon cancer, bladder cancer, or breast cancer.

### Claim 18 (depends on 16)

The method of claim 16, wherein the dosage frequency is once per week.

### Claim 19 (depends on 16)

The method of claim 16, wherein the dosage frequency is twice per week.