US 11,904,020 B2
Bicyclic peptide ligands specific for TREM2
Paul Brennan, Cambridge (GB); Amy Brown, Cambridge (GB); Liuhong Chen, Cambridge (GB); John Davis, Cambridge (GB); Yuliya Demydchuk, Cambridge (GB); Donatella Di Rienzo, Cambridge (GB); Ellen Gowans, Cambridge (GB); Rama McCrory, Cambridge (GB); Emma Mead, Cambridge (GB); Emma Murphy, Cambridge (GB); Mike Rigby, Cambridge (GB); Michael Skynner, Cambridge (GB); Tom Smith, Cambridge (GB); and Steven Stanway, Cambridge (GB)
Assigned to BicycleTx Limited, Cambridge (GB)
Filed by Bicycle Tx Limited, Cambridge (GB)
Filed on Mar. 18, 2022, as Appl. No. 17/698,185.
Claims priority of application No. 2103870 (GB), filed on Mar. 19, 2021; and application No. 2114729 (GB), filed on Oct. 14, 2021.
Prior Publication US 2022/0296726 A1, Sep. 22, 2022
Int. Cl. A61K 47/64 (2017.01); A61K 47/54 (2017.01); C07K 14/00 (2006.01)
CPC A61K 47/64 (2017.08) [A61K 47/545 (2017.08); C07K 14/001 (2013.01)] 12 Claims
 
1. A peptide ligand specific for triggering receptor expressed on myeloid cells 2 (TERM2) comprising a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold, wherein the peptide ligand comprises an amino acid sequence having the following formula:
Ci-X1-X2-X3-Cii-X4-X5-X6-X7-X8-X9-Ciii  (SEQ ID NO: 43);
wherein:
X1 represents an amino acid selected from A, dA, S, T, D, and E, or a non-natural amino acid which is K(pentynoic acid) (K(PYA));
X2 represents an amino acid selected from A, dA, E, Y, S, and N, or a non-natural amino acid which is K(pentynoic acid) (K(PYA));
X3 represents an amino acid selected from A, Y and Q or a non-natural amino acid which is selected from: 2,6-dimethyl-tyrosine (2,6-DiMeTyr), 3,4-dihydroxy-phenylalanine (DOPA), and 3-fluoro-tryptophan (3FTyr);
X4 represents an amino acid selected from I and F or a non-natural amino acid selected from 4-methyl-phenylalanine (4MePhe), homophenylalanine (HPhe), 1-naphthylalanine (1Nal), 2-fluoro-phenylalanine (2FPhe), 3-fluoro-phenylalanine (3FPhe), 4-fluoro-phenylalanine (4FPhe) and 4-pyridylalanine (4Pal);
X5 represents an amino acid selected from R and W or a non-natural amino acid selected from 1-naphthylalanine (1Nal), 2-naphthylalanine (2Nal), 6-chloro-tryptophan (6ClTrp), 5-fluoro-tryptophan (5FTrp), 6-fluoro-tryptophan (6FTrp), 6-methyl-tryptophan (6MeTrp), azatryptophan (AzaTrp), methyl-tryptophan (Trp(Me)), 2-methyl-phenylalanine (2MePhe), 3-methyl-phenylalanine (3MePhe), and trichloromethyl-phenylalanine (4CF3Phe);
X6 represents an amino acid selected from P and A or a non-natural amino acid selected from N-methyl-alanine (NMeAla), aminoisobutyric acid (Aib), pipecolic acid (Pip), azetidine (Aze), Cis-hydroxyproline (Cys-HyP), and 4,4-difluoroproline (44DFP);
X7 represents an amino acid selected from L, F, and Y, or a non-natural amino acid selected from homophenylalanine (HPhe), 2-methyl-phenylalanine (2MePhe), 3-methyl-phenylalanine (3MePhe), 4-methyl-phenylalanine (4MePhe),1-naphthylalanine (1Nal), 2-naphthylalanine (2Nal), 4-fluoro-phenylalanine (4FPhe), t-butyl-alanine (tBuAla), 4,4-biphenylalanine (44BPA), 4-pyridylalanine (4Pal), and K(pentynoic acid) (K(PYA));
X8 represents an amino acid selected from W, Y, F, Q, A, dA, D, and E, or a non-natural amino acid selected from 4-fluoro-phenylalanine (4FPhe), 1-naphthylalanine (1Nal), 2-naphthylalanine (2Nal), 3-t-butyl-tyrosine (3tBuTyr), and K(pentynoic acid) (K(PYA)); and
X9 represents an amino acid selected from H, S, P, N, G, Y, Q, W, L, V, A, dA, D, E, and F, or a non-natural amino acid selected from homoarginine (HArg) and K(pentynoic acid) (K(PYA));
wherein Ci, Cii and Ciii represent first, second and third cysteine residues, respectively, or a pharmaceutically acceptable salt thereof.