Amino acid and peptide conjugates and conjugation process
Inventors
Brimble, Margaret Anne • Williams, Geoffrey Martyn • DUNBAR, Peter Roderick • Verdon, Daniel
Assignees
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Publication Number
US-11464853-B2
Publication Date
2022-10-11
Expiration Date
Abstract
The invention relates to amino acid and peptide conjugates, methods for making amino acid and peptide conjugates, conjugates produced by the methods, and pharmaceutical compositions comprising the conjugates. Methods of eliciting immune responses in a subject and methods of vaccinating a subject, uses of the conjugates for the same, and uses of the conjugates in the manufacture of medicaments for the same are also contemplated.
Core Innovation
The invention provides amino acid- or peptide conjugate compounds of formula (I), including pharmaceutically acceptable salts or solvates, with defined integer parameters m, v, w, and n and structural constraints on Z1, Z2, and substituent groups. The sum of m, v, and w is at least 3, the sum of m and w is from 0 to 7, and n is 1 or 2, with Z1 and Z2 each independently selected from defined linkage groups and with multiple R positions independently hydrogen or C1-6aliphatic.
A key structural condition requires that either A1 is a peptide comprising 8 to 220 amino acids and comprises an epitope, or R9 is A2 and A2 is a peptide comprising an epitope. A1 is defined as an amino acid, a peptide, OH, OP1, NH2, or NHP2, wherein P1 is a carboxyl protecting group and P2 is a carboxamide protecting group, and A2 is an amino acid or a peptide.
The disclosure characterizes peptide conjugate embodiments and related precursors, including epitope-containing peptides and epitope-containing amino acid sequences drawn from defined SEQ ID NO ranges, MHCI/MHCII epitopes, and EBV LMP2-derived epitopes. It also describes peptide conjugates and amino-acid conjugate precursors, including peptide conjugate 10A and peptide conjugate 10B, as well as lipid-linked moieties attached to an amino acid residue such as cysteine or an N-terminal serine as preferred embodiments.
Claims Coverage
The consolidated claim coverage centers on a compound of formula (I) with defined integer ranges and structural constraints, and it sets the scope through a peptide/epitope condition via A1 and/or R9=A2. The independent claim features four main inventive features: formula (I) constraints, Z1/Z2 linkage options, substituent and peptide definitions, and pharmaceutically acceptable salt or solvate coverage.
Formula (I) compound with constrained integer parameters
A compound of formula (I) with m and w each independently being an integer from 0 to 7 and v being an integer from 0 to 5, provided that the sum of m, v, and w is at least 3 and the sum of m and w is from 0 to 7, and with n being 1 or 2.
Z1 and Z2 substituent selection
Z1 and Z2 are each independently selected from —O—, —NR—, —S—, —S(O)—, —SO2—, —C(O)O—, —OC(O)—, —C(O)NR—, —NRC(O)—, —C(O)S—, —SC(O)—, —OC(O)O—, —NRC(O)O—, —OC(O)NR—, and —NRC(O)NR—.
Multiple group definitions with epitope-containing peptide scope
R1, R2, Rx, Ry, R4, R5, R6, and R7 are each independently hydrogen or C1-6aliphatic; R, R3, and R8 are each independently hydrogen or C1-6aliphatic; R9 is hydrogen, C1-6aliphatic, an amino protecting group, L3—C(O)—, or A2; L1 and L2 are each independently selected from C5-21aliphatic or C4-20heteroaliphatic; L3 is C1-21aliphatic or C2-20heteroaliphatic; A1 is an amino acid, a peptide, OH, OP1, NH2, or NHP2; A2 is an amino acid or a peptide; and either A1 is a peptide comprising 8 to 220 amino acids and comprises an epitope or R9 is A2 and is a peptide comprising an epitope.
Pharmaceutically acceptable salt or solvate
The compound of formula (I) is covered as a pharmaceutically acceptable salt or solvate thereof.
Overall, the claim coverage centers on a formula (I) conjugate defined by constrained integer parameters, specified Z1/Z2 linkage classes, and substituent definitions, with the epitope-containing peptide requirement expressed through either A1 as an epitope-containing peptide or R9=A2 as an epitope-containing peptide, together with pharmaceutically acceptable salts or solvates.
Stated Advantages
Reported TLR2 agonism potency: homoPam2Cys(NHAc)-SKKKK is potent to sub-nM.
Peptide cargo conjugation can diminish agonism for Pam2Cys but not for homoPam2Cys.
Enhanced CD8+ T-cell activation with homoPam2Cys conjugates, especially for longer peptide processing.
Documented Applications
TLR2 agonism use in HEK-Blue hTLR2/mTLR2 reporter assays (SEAP).
CD8+ T-cell clone antigen processing/presentation assays using activation marker CD137 and LCL antigen-presenting cells.
Synthesis and purification examples for peptide conjugates and amino-acid conjugate precursors, including peptide conjugate 10A and peptide conjugate 10B, with reporting by RP-HPLC [procedural detail omitted for safety].
Thiol-ene reactions for peptide 1 with different radical initiator/reagent conditions, with reported conversions to mono- and bis-adducts by RP-HPLC [procedural detail omitted for safety].
Example assays include TLR2 agonism comparisons for lipid/peptide constructs and peptide processing/presentation assays using a CD8+ T-cell clone.
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