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Publication Number
US-11377480-B2
Publication Date
2022-07-05
Expiration Date
Abstract
The disclosure provides inducible caspase polypeptides, compositions comprising inducible caspase polypeptides and sequences encoding the same, cells modified to express the polypeptides and compositions of the disclosure, as well as methods of making and methods of using same for adoptive cell therapy.
Core Innovation
The disclosure describes an inducible proapoptotic/caspase polypeptide built from a ligand-binding region, an artificial linker, and a proapoptotic caspase payload. The ligand-binding region is described in the context of chemical-inducible dimerization, including FKBP12 and an F36V embodiment, and the caspase payload is truncated caspase-9. An inducible caspase polypeptide embodiment is provided as SEQ ID NO: 9.
The invention further defines construct architecture constraints and sequence embodiment considerations. The document emphasizes avoiding non-human sequences and includes sequence embodiments with constraints that relate to non-human elements being limited to a restriction site. The construct is described with components such as a linker (GS/GGGGS) and self-cleaving peptide options, including T2A and variants such as T2A (SEQ ID NO: 11), as part of polypeptide design options.
The disclosure also describes delivery and expression vehicle architectures for producing inducible caspase polypeptides. It describes transposons and vectors, including viral vector and nanoparticle vector options, and transposases such as piggyBac/Super piggyBac, Sleeping Beauty/SB100X, Helitron/Helraiser, and Tol2, including transposase mRNA. Apoptosis is selectively triggered by administering an induction agent, including AP1903 (Rimiducid) and AP20187, with potential reversibility via inhibition/competitive monomer.
Claims Coverage
The provided independent claim covers one inventive feature: the exact amino-acid identity of the inducible caspase polypeptide defined by SEQ ID NO: 9.
Inducible caspase polypeptide defined by SEQ ID NO: 9
An inducible caspase polypeptide comprising the amino acid sequence of SEQ ID NO: 9.
The claimed subject matter is specifically directed to an inducible caspase polypeptide having the amino-acid sequence of SEQ ID NO: 9.
Stated Advantages
The safety switch provides inducible apoptosis upon exposure to AP1903 (Rimiducid).
Apoptosis is selectively triggered by administering an induction agent, including AP1903 (Rimiducid) and AP20187, with potential reversibility via inhibition/competitive monomer.
Documented Applications
An integrated piggyBac iC9 safety switch in human Pan T-Cells, with inducible apoptosis upon exposure to AP1903 (Rimiducid).
In vivo efficacy assessment in NSG mice against P-BCMA-101 using the iC9 switch.
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