Chimeric antigen receptors and methods of use
Inventors
ORENTAS, Rimas • Schneider, Dina • Dropulic , Boro
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11905515-B2
Publication Date
2024-02-20
Expiration Date
Abstract
Chimeric antigen receptors containing tumor necrosis factor receptor superfamily member transmembrane domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.
Core Innovation
The patent discloses an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR) comprising at least one extracellular antigen binding domain, at least one transmembrane tumor necrosis factor receptor superfamily (TNFRSF) domain, and at least one intracellular signaling domain. The disclosed CAR component architecture includes an extracellular antigen-binding domain, a linker/spacer domain, a TNFRSF transmembrane region, and intracellular signaling domains such as 4-1BB (CD137) and CD3z (CD247).
The encoded CAR comprises the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 10, or SEQ ID NO: 36. The CAR designs specify a transmembrane domain derived from TNFRSF members, including TNFRSF16 or TNFRSF19, and identify nucleic acid/protein sequence identifiers for key CAR elements, including vectors and host cells described as T cells.
CARs with a TNFRSF19-derived transmembrane domain, including TNFRSF19/TNFRSF19-linker CARs, exhibit high CAR surface expression and unexpectedly strong cytolytic activity and cytokine induction in vitro. In vivo, these TNFRSF19-transmembrane CARs provide superior control of established disseminated Raji leukemia in NSG mice, including donor-to-donor repetition, while a TNFRSF16-derived CAR construct can be highly expressed yet shows little or no in vitro activity and poor in vivo tumor control.
Claims Coverage
The consolidated claim content includes one independent claim directed to an isolated nucleic acid molecule encoding a CAR with a TNFRSF transmembrane domain and defined intracellular signaling, and the CAR amino acid sequence is limited to specified SEQ ID NOs.
Isolated nucleic acid encoding a CAR with defined TNFRSF transmembrane and intracellular signaling
An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR) comprising at least one extracellular antigen binding domain, at least one transmembrane tumor necrosis factor receptor superfamily (TNFRSF) domain, and at least one intracellular signaling domain.
CAR amino acid sequence matching specified SEQ ID NOs
The encoded CAR comprises the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 10, or SEQ ID NO: 36.
Overall, the claim coverage centers on isolated nucleic acids encoding CARs with an extracellular antigen binding domain, a TNFRSF transmembrane domain, and an intracellular signaling domain, with the CAR amino acid sequence restricted to SEQ ID NO: 8, SEQ ID NO: 10, or SEQ ID NO: 36.
Stated Advantages
High CAR surface expression.
Unexpectedly strong cytolytic activity and cytokine induction in vitro for TNFRSF19-derived CARs.
Superior control of established disseminated Raji leukemia in NSG mice for TNFRSF19-derived CARs.
Donor-to-donor repetition of the superior in vivo control.
Ability to fine-tune CAR function by transmembrane/linker selection, contrasted by comparatively poor performance of a TNFRSF16-derived construct.
Documented Applications
Cancer treatment/prevention using CAR T cells and related compositions/kits described in the patent content.
Control of established disseminated Raji leukemia in NSG mice using CAR constructs, including donor-to-donor repetition.
Interested in licensing this patent?