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Publication Number
US-11462297-B2
Publication Date
2022-10-04
Expiration Date
Abstract
Methods and compositions related to the selective, specific disruption of multiple ligand-receptor signaling interactions, such as ligand-receptor interactions implicated in disease, are disclosed. These interactions may involve multiple cytokines in a single receptor family or multiple ligand receptor interactions from at least two distinct ligand-receptor families. The compositions may comprise polypeptides having composite sequences that comprise sequence fragments of two or more ligand binding sites. The methods and compositions may involve sequence fragments of two or more ligand binding sites that are arranged to conserve the secondary structure of each of the ligands from which the sequence fragments were taken.
Core Innovation
The invention relates to antagonist peptide or composite polypeptide compounds that selectively disrupt ligand-receptor signaling interactions. The compounds comprise composite polypeptide sequences built from sequence fragments from binding sites of γc-family cytokines, and the composite sequence preserves secondary structure to support selective antagonism.
A polyethylene glycol (PEG) unit is included with the composite polypeptide sequence. The document describes a compound represented by H-Cys(acetylamino-propyl-mPEG40k)-Gly-Ser-Gly-Gly-Ile-Lys-Glu-Phe-Leu-Gln-Arg-Phe-Ile-His-Ile-Val-Gln-Ser-Ile-Ile-Asn-Thr-Ser-NH2 (SEQ ID NO: 133).
The described strategy emphasizes combining sequence fragments from conserved binding interfaces while conserving secondary structure to control which cytokine subsets are disrupted. The partial content characterizes a γc antagonist (BNZ132-1) that inhibits a subset of γc cytokines, while non-gamma-c cytokines are not inhibited in the described examples, and cross-family and dual-antagonist constructs are also described using linkers such as PEG.
Claims Coverage
The partial content provides one independent claim, which covers a composite-polypeptide/PEG compound derived from γc-family cytokine binding-site fragments selected from IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, including a PEG unit, with an exemplary compound represented by SEQ ID NO: 133. The coverage therefore centers on composite sequences plus PEG for selective cytokine-family antagonism.
Composite polypeptide sequence from γc-family cytokine binding sites
A composite polypeptide sequence comprising sequence fragments from binding site of γc-family cytokines, where the γc-family cytokines are selected from IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.
PEG unit in the antagonist compound
A polyethylene glycol (PEG) unit included in the compound together with the composite polypeptide sequence.
Exemplary PEGylated composite structure represented by SEQ ID NO: 133
A compound represented by H-Cys(acetylamino-propyl-mPEG40k)-Gly-Ser-Gly-Gly-Ile-Lys-Glu-Phe-Leu-Gln-Arg-Phe-Ile-His-Ile-Val-Gln-Ser-Ile-Ile-Asn-Thr-Ser-NH2 (SEQ ID NO: 133).
The claim coverage in the partial content is limited to the single independent claim requiring composite polypeptide sequence fragments from binding sites of selected γc-family cytokines, inclusion of a PEG unit, and a PEGylated composite example corresponding to SEQ ID NO: 133.
Stated Advantages
Selective disruption of multiple ligand-receptor signaling interactions within γc cytokine families.
Preservation of secondary structure to support selective antagonism.
Documented Applications
The partial content describes evaluation and readouts related to cytokine antagonism using proliferation and apoptosis and signaling phosphorylation, including inhibition of a subset of γc cytokines for selective targeting examples.
Disease-relevant contexts are listed in the partial content, including HAM-TSP, celiac disease/IBD, asthma/COPD, multiple sclerosis, rheumatoid arthritis, and uveitis.
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