Antibody-ALK5 inhibitor conjugates and their uses
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Publication Number
US-11583593-B2
Publication Date
2023-02-21
Expiration Date
Abstract
The present disclosure relates to antibody-drug conjugates comprising ALK5 inhibitors and their uses.
Core Innovation
The invention relates to a composition comprising an ALK5 inhibitor covalently attached to a protease-sensitive linker. The disclosure describes antibody-drug conjugates that include an antibody, an ALK5 inhibitor drug moiety, and a linker, with representative formulas of the form Ab-(L-D)p and drug loading parameter p.
The linker architecture includes stretcher units, spacer units, and amino acid units, and the protease-sensitive linker includes protease-cleavable amino acid sequences such as Val-Cit and valine-citrulline variants. The disclosure also includes cleavable versus non-cleavable linker options, linker spacer architectures, and representative protease-sensitive linker/spacer components integrated with an ALK5 inhibitor drug moiety.
The document further describes derivatization of ALK5 inhibitor candidates to provide attachment handles for linker coupling, including introduction of a free NH or NH2 handle for linker attachment. It also describes targeting of T cells with an intact antibody or fragment that binds a T-cell surface molecule, positioning the conjugate for modulation of TGF-β signaling-related suppression mechanisms in cancer.
Claims Coverage
The independent claim defines a composition where an ALK5 inhibitor is covalently attached to a protease-sensitive linker. It is narrowed by dependent claims specifying the protease-sensitive linker as a dipeptide, tripeptide, tetrapeptide, or pentapeptide, and by a valine-citrulline example.
Covalently attached ALK5 inhibitor to a protease-sensitive linker
A composition comprising an ALK5 inhibitor covalently attached to a protease-sensitive linker.
Protease-sensitive linker with defined peptide length
The protease-sensitive linker includes a dipeptide, tripeptide, tetrapeptide, or pentapeptide.
Valine-citrulline protease-sensitive linker
The protease-sensitive linker is made from a valine-citrulline dipeptide.
Overall, the claim set covers an ALK5 inhibitor drug moiety covalently linked via a protease-sensitive linker, with additional limitations on peptide length and a specific valine-citrulline example.
Stated Advantages
Restores CD4+/CD8+ T-cell function.
Reduces Treg-mediated suppression.
Minimizes host toxicity.
Documented Applications
Treating cancer by restoring T-cell function while reducing Treg-mediated suppression to minimize host toxicity.
In vitro evaluation in TGF-β/ALK5 signaling assays, including HEK293T SMAD luciferase reporter assays and primary mouse CD4+ T-cell proliferation assays.
Cancer indications are described, including pancreatic cancer, glioblastoma, prostate cancer, hepatocellular carcinoma, melanoma, breast cancer, NSCLC, bladder cancer, and renal cancer.
Combination regimens are described that include a checkpoint inhibitor (ipilimumab/nivolumab/pembrolizumab).
BRAF mutation is referenced in the context of cancer indication/combination regimens.
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