Peptides and methods related to ICOS signaling
Inventors
Altman, Amnon • Kong, Kok-Fai • Crotty, Shane
Assignees
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Publication Number
US-11547739-B2
Publication Date
2023-01-10
Expiration Date
Abstract
The present disclosure relates to methods and compositions useful for initiating and propagating ICOS-mediated signaling. In particular, the present disclosure provides three peptide motifs which promote ICOS binding and whose ablation leads to modulated ICOS signaling and modulated signaling mediated by TBK1, IRF4, IKKβ, or TBKBP1. The binding of these peptide motifs or the addition of such motifs as co-stimulatory agents leads to modulated immune responses, and provides new and unexpected therapies for neurodegenerative, autoimmune, metabolic, cancer inflammatory, or immunodeficiency conditions, diseases, or disorders.
Core Innovation
The patent identifies evolutionarily conserved peptide motifs in the ICOS cytoplasmic tail, including a proximal motif (IProx), a YxxM motif, and a distal motif, and states that these motifs promote ICOS binding. It further states that ablation or modification of these motifs modulates ICOS signaling.
The patent links ICOS motif-dependent binding to downstream signaling mediated by TBK1, TBKBP1 (SINTBAD), IKKβ, IRF4, and BATF, and describes a pathway in which ICOS recruits or requires TBK1 via the proximal IProx motif during combined TCR+ICOS/ICOSL stimulation. It also states that early nascent Tfh differentiation can be TBK1-independent.
The patent provides embodiments including ICOS motif peptides and modified or full-length ICOS proteins, including cytoplasmic-domain modifications, truncations, and orthologs, as well as ICOS protein fragments. It further provides nucleic acids encoding these peptides or proteins, CARs incorporating ICOS signaling domains, and nucleic acid inhibitors such as antisense, siRNA, shRNA, and miRNA.
Claims Coverage
The partial content includes three independent claims that cover methods for modulating ICOS–TBK1 interaction, and in one case the downstream interactions among TBKBP1, IKKβ, IRF4, and BATF, via modulation of ICOS–TBK1. Across the independent claims, the inventive features are grounded in contacting a cell with ICOS/TBK1-modulating peptide(s) defined by SEQ ID NOs, with cell-type limitations in some embodiments.
Modulating ICOS–TBK1 interaction with an ICOS/TBK1 peptide agonist or antagonist
A method of modulating the interaction between ICOS and TBK1 in a cell selected from a T-cell, a B-cell, or a Tfh cell comprising contacting the cell with an agonist or antagonist of ICOS-mediated or TBK1-mediated immune signaling wherein the agonist or antagonist is a peptide consisting of any one of SEQ ID NOs 24 or 25.
Modulating TBKBP1–IKKβ–IRF4–BATF via ICOS–TBK1 interaction using SEQ ID NO 24
A method of modulating the interaction between TBKBP1, IKKβ and IRF4 and BATF in a cell by modulating the interaction between ICOS and TBK1 comprising contacting the cell with a peptide consisting of SEQ ID NO 24.
Modulating ICOS–TBK1 interaction with SEQ ID NO 24
A method of modulating the interaction between ICOS and TBK1 in a cell comprising contacting the cell with a peptide consisting SEQ ID NO 24.
Overall, the independent claims cover contacting immune cells with peptide agonists or antagonists that modulate the ICOS–TBK1 interaction, including a specific embodiment using SEQ ID NO 24 to also modulate interactions among TBKBP1, IKKβ, IRF4, and BATF.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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