pHLIP®-mediated intracellular delivery of immuno-stimulatory compounds
Inventors
Reshetnyak, Yana K. • Andreev, Oleg A. • Engelman, Donald M. • Moshnikova, Anna • Deacon, John
Assignees
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Publication Number
US-12397060-B2
Publication Date
2025-08-26
Expiration Date
Abstract
The invention features a composition comprising an immuno-stimulatory compound and a pHLIP® peptide, e.g., an immunostimulatory compound that comprises a cyclic purine dinucleotide, which binds to a stimulator of interferon genes (STING) such as a cGAMP cyclic compound inside a cell.
Core Innovation
The invention relates to immuno-stimulatory cargo delivery mediated by a pH low insertion peptide (pHLIP) peptide for cytosolic delivery in the tumor microenvironment. The cargo is an immuno-stimulatory compound (ISC) selected as cyclic dinucleotides (CDN) or cyclic purine dinucleotides, including cyclic purine dinucleotides that bind to stimulator of interferon genes (STING), and includes cGAMP, 3′,5′-cyclic diadenylic acid (c-di-AMP), and cyclic diguanylate (c-di-GMP). The disclosed concept addresses the need for intracellular localization because the polar/cationic cyclic dinucleotides are described as poorly diffusing passively across cell membranes.
The invention further discloses low-pH–triggered membrane insertion of pHLIP and its use to deliver the ISC to cytosol. It is described as enabling STING-pathway engagement by delivering STING agonists to tumor cells and acidic tumor-associated macrophages. The disclosure includes embodiments where the cargo is connected using optional cleavable or self-immolative linkers so that the cargo can be released in a non-modified form.
In addition, the disclosure provides optional polarity modulators to optimize LogP for delivery, and supports constructs with multiple pHLIP peptides, including PEG-linked multi-pHLIP architectures. Numerous pHLIP sequence variants are described, including Var3 and cysteine/lysine/azido functionalized forms for conjugation. The disclosed targeting rationale is directed toward acidic tumor tissue versus healthy tissue to reduce systemic autoimmune/off-target inflammation, and embodiments include therapeutic use and diagnostic imaging using pHLIP-linker-cargo conjugates.
Claims Coverage
Two independent claims are identified: a composition claim and a method claim. The claims cover pHLIP-mediated delivery of specified STING-related immuno-stimulatory cyclic compounds and defined pHLIP/construct architectures, and include an anti-tumor immune response augmentation method with administration and performance constraints tied to pHLIP presence.
Immuno-stimulatory compound composition with pH low insertion peptide
A composition comprising an immuno-stimulatory compound (ISC) and a pH low insertion peptide (pHLIP) peptide, wherein said ISC is selected from cyclic dinucleotide (CDN), cyclic purine dinucleotide, cyclic purine dinucleotide which binds to stimulator of interferon genes (STING), cGAMP, 3′,5′-cyclic diadenylic acid (c-di-AMP), and cyclic diguanylate (c-di-GMP).
Augmenting an anti-tumor immune response using pHLIP and an immuno-stimulatory compound
A method of augmenting an anti-tumor immune response, comprising administering to a subject a composition comprising an immuno-stimulatory compound and a pHLIP peptide, wherein said immuno-stimulatory compound is selected from cyclic dinucleotide (CDN), cyclic purine dinucleotide, cyclic purine dinucleotide which binds to stimulator of interferon genes (STING), cGAMP, 3′,5′-cyclic diadenylic acid (c-di-AMP), and cyclic diguanylate (c-di-GMP).
Overall claim coverage centers on pairing a pHLIP peptide with STING-related cyclic dinucleotide and cyclic purine dinucleotide immuno-stimulatory compounds, including cGAMP, c-di-AMP, and c-di-GMP, in a composition, and administering that composition to augment an anti-tumor immune response. Dependent limitations describe peptide-ISC architectures, cleavable or self-immolative linkers, polarity modulation, multi-pHLIP configurations, administration route, and enhanced biological effect in the presence of pHLIP.
Stated Advantages
Augments an anti-tumor immune response.
Targets the immuno-stimulatory compound preferentially to diseased tissue compared to healthy tissue, thereby minimizing damage to healthy tissue.
Reduces systemic autoimmune/off-target inflammation.
Delivers an immuno-stimulatory compound with a biological effect at least 20% greater than that delivered in the absence of pHLIP.
Documented Applications
Therapeutic anti-tumor immune response augmentation by administering a composition comprising an immuno-stimulatory compound and a pHLIP peptide to a subject.
Diagnostic imaging via pHLIP-linker-cargo conjugates.
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