Compositions and methods for treatment of cancer
Inventors
Assignees
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Publication Number
US-10508143-B1
Publication Date
2019-12-17
Expiration Date
Abstract
Compositions, e.g., compositions comprising cellular therapeutics and/or protein therapeutics, and methods of using such compositions for treating cancer are described.
Core Innovation
The invention relates to a T-cell comprising a constitutive expression construct encoding a secreted fusion protein. The secreted fusion protein comprises an antibody, or an antigen-binding fragment thereof, that binds a tumor antigen, and an extracellular domain of CD19, or a fragment thereof, that includes an epitope recognized by the FMC63 anti-CD19 antibody.
The disclosed construct architecture also includes inducible expression constructs activated by antigen binding to an antigen-binding receptor comprising an antigen-binding domain, a transmembrane domain, and a cytoplasmic signaling domain that triggers promoter-driven expression of a secreted or surface-tethered fusion or effector protein. The document further describes inducible toxin expression constructs, control via inducible promoters, and a tandem kill switch using a caspase-9/rimiducid safety switch.
Additional embodiments describe targeting tumor heterogeneity and the tumor microenvironment by secreting or locally presenting secondary antigen targets, expressing relevant enzymes, and using fusion proteins with cleavable linkers to enable exposure or functional activation in tumor-associated contexts. The disclosure also includes broad component options such as constitutive promoters, inducible promoters, signaling domains derived from RTKs or JAK/STAT pathway receptors, cytokines such as IL-21 and IL-15, toxins, scaffold proteins, and Fc-based constructs.
Claims Coverage
The independent claim coverage centers on one inventive concept: a T-cell with a constitutive expression construct encoding a secreted fusion protein that combines tumor antigen binding with an extracellular CD19 domain containing an FMC63-recognized epitope. Dependent claims further refine the tumor antigen choices, the antibody or antigen-binding fragment formats, and the T-cell as a CAR-T cell.
Secreted fusion protein with tumor antigen binder and CD19 FMC63 epitope
A T-cell comprising a constitutive expression construct encoding a secreted fusion protein comprising an antibody, or antigen-binding fragment thereof, that binds a tumor antigen; and an extracellular domain of CD19, or a fragment thereof, that includes an epitope recognized by the FMC63 anti-CD19 antibody.
Specified tumor antigen targets for the binder
The T-cell wherein the tumor antigen is HER-2/neu, c-met, EGFR, Ga733\EpCAM, CD20, ROR1, or BCMA.
Antigen-binding fragment format selection
The T-cell wherein the antigen-binding fragment is an Fab, scFv, Fv, or VHH.
CAR-T cell limitation
The T-cell wherein the T-cell is a CAR-T cell.
The claims are directed to a constitutive expression construct encoding a secreted fusion protein that includes a tumor-antigen binder and an extracellular CD19 domain carrying an FMC63-recognized epitope, with dependent refinements specifying tumor antigen targets, antigen-binding fragment formats, and a CAR-T cell limitation.
Stated Advantages
Supports antigen-gating and redirects additional CAR-Ts by secreting or locally presenting secondary antigen targets to mitigate tumor heterogeneity.
Documented Applications
Cancer adoptive cell therapy using immune cells engineered with constitutive and/or inducible expression constructs.
Combination with additional cellular therapeutics and protein therapeutics including antibody/ADC/radioimmunotherapy.
Antigen binding triggering inducible toxin expression to kill tumor cells.
Targeting tumor microenvironment degradation by expressing relevant enzymes.
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