Compositions and conjugates comprising an interleukin and polypeptides that specifically bind TGF-beta
Inventors
Galipeau, Jacques • Ng, Spencer
Assignees
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Publication Number
US-12577323-B2
Publication Date
2026-03-17
Expiration Date
Abstract
This disclosure relates to compositions and conjugates comprising an interleukin, e.g., IL-15 and a polypeptide that specifically binds TGF-beta. Typically the polypeptide that specifically binds TGF-beta is a type II TGF-beta receptor. In certain embodiments, the type II TGF-beta receptor is a human isoform, fragment or variant thereof. Uses for treating or preventing cancer and infectious diseases are contemplated.
Core Innovation
The invention concerns a conjugate comprising a polypeptide fragment of a type II TGF-beta receptor that specifically binds TGF-beta, a polypeptide fragment of a sushi domain of the IL-15 receptor alpha chain that specifically binds IL-15, and a polypeptide fragment of IL-15. The conjugate has greater than 90% sequence identity to SEQ ID NO: 21, and in some embodiments is exemplified by FIST-15, where a TGF-beta ligand-trapping type II receptor fragment is linked with IL-15 and the IL-15Ralpha sushi domain.
The disclosed FIST-15 neutralizes TGF-beta/Smad signaling while activating STAT phosphorylation. The resulting activity includes enhanced NK and CD8+ T-cell proliferation and cytokine production, together with protection against TGF-beta inhibition.
The document reports anti-tumor activity in melanoma models, including reduced tumor establishment and improved survival, and provides mechanistic evidence implicating NK cells. In vitro and in vivo results are described in the melanoma context, with additional mention of B16-F0 melanoma and B16-FIST15 outcomes and related model support.
Claims Coverage
The provided claim set includes one independent claim defining a specific IL-15/TGF-beta receptor type II and IL-15Ralpha sushi domain conjugate with a sequence-identity threshold, and dependent claims covering four additional inventive features.
Type II TGF-beta receptor fragment, IL-15Ralpha sushi domain fragment, and IL-15 conjugate with >90% identity
A conjugate comprising a polypeptide fragment of type II TGF-beta receptor that specifically binds TGF-beta; a polypeptide fragment of a sushi domain of the IL-15 receptor alpha chain that specifically binds IL-15; and a polypeptide fragment of IL-15, wherein the conjugate has greater than 90% sequence identity to SEQ ID NO: 21.
Encoding polynucleotide for the conjugate
A polynucleotide that encodes a conjugate as defined in the independent conjugate claim.
Vector comprising the polynucleotide
A vector that comprises the polynucleotide recited for encoding the conjugate.
Expression system including the vector
An expression system that includes the vector recited for encoding the conjugate.
Cancer treatment by administering an effective amount of the conjugate
A method for treating cancer by administering to a subject in need thereof an effective amount of a composition containing the conjugate as defined in the independent conjugate claim.
Combination therapy with checkpoint inhibitors and/or immunostimulatory cytokines/antibodies
The method further administers the conjugate together with one or more checkpoint inhibitors, immunostimulatory cytokines, and/or antibody agents including anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CD40, anti-IL-7, or anti-IL-6.
Protection centers on a conjugate that links a TGF-beta-binding type II receptor fragment with IL-15 and an IL-15Ralpha sushi domain fragment with >90% sequence identity, and extends to nucleic acids, vectors, expression systems, and cancer treatment including combination therapy with defined checkpoint inhibitors and immunostimulatory cytokines/antibodies.
Stated Advantages
Neutralizes TGF-beta/Smad signaling while activating STAT phosphorylation.
Enhances NK and CD8+ T-cell proliferation and cytokine production.
Protects against TGF-beta inhibition.
Provides in vitro and in vivo anti-tumor activity in melanoma models, including reduced tumor establishment and improved survival.
Documented Applications
Cancer treatment by administering a composition containing the IL-15/TGF-beta receptor type II and IL-15Ralpha sushi domain conjugate to a subject in need thereof.
Combination cancer therapy by administering the conjugate together with checkpoint inhibitors and/or immunostimulatory cytokines/antibody agents including anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CD40, anti-IL-7, or anti-IL-6.
Melanoma model anti-tumor activity in the context of B16-F0 melanoma and outcomes including reduced tumor establishment and improved survival.
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