T-cells expressing anti-LIV1 chimeric antigen receptor
Inventors
Terrett, Jonathan Alexander • Sagert, Jason
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12304968-B2
Publication Date
2025-05-20
Expiration Date
Abstract
Provided herein, in some embodiments, are methods and compositions (e.g., cell compositions) for the treatment of cancer, such as LIV1+ malignancies.
Core Innovation
The invention relates to engineered T cells comprising a nucleic acid encoding a chimeric antigen receptor (CAR), where the CAR is defined by one of the nucleotide sequences of SEQ ID NOs: 49, 51, 104, and 108. The disclosed CAR nucleic acids and encoded CARs include scFv elements comprising VH and VL regions with CDRs, linkers arranged between the VH and VL regions, and defined CAR component sequence layouts.
The disclosed CAR constructs further include a transmembrane region, a co-stimulatory domain, and CD3ζ as a signaling component. The architectures include a CD8 signal peptide combined with a VL-linker-VH arrangement, followed by transmembrane and a co-stimulatory domain (CD28 or 41BB), and then CD3ζ.
The invention also relates to engineered T cells for treating LIV1+ cancers, including engineered allogeneic/edited T cells with LIV1-binding CAR constructs. The described engineered cell systems include TRAC disruption with CAR insertion and optional β2M knockout/disruption, and are described with CRISPR/Cas9, gRNAs, donor templates and homology arms, and delivery using AAV6.
Claims Coverage
The independent claim covers engineered T cells where the CAR is encoded by one of a specified set of nucleotide sequences (SEQ ID NOs: 49, 51, 104, and 108). The inventive features include CAR sequence-defined variants, CAR expression level constraints for a cell population, an anti-LIV1 scFv sequence requirement, TRAC disruption, CAR insertion into disrupted TRAC, and selection of CD28 or 4-1BB co-stimulatory domain.
Nucleic-acid encoded CAR defined by selected SEQ ID NOs
An engineered T cell comprising a nucleic acid encoding a chimeric antigen receptor (CAR) encoded by the nucleotide sequence of any one of SEQ ID NOs: 49, 51, 104, and 108.
Cell population CAR expression threshold
An engineered T cell population has a specified minimum CAR expression level, with at least 15% or at least 50% of the cells expressing the CAR.
Anti-LIV1 scFv of SEQ ID NO: 83 in the CAR
The engineered T cell has a CAR that includes an anti-LIV1 scFv defined by the amino acid sequence SEQ ID NO: 83.
Disrupted TRAC gene
The engineered T cell further includes a disrupted T cell receptor alpha chain constant region (TRAC) gene.
CAR insertion into disrupted TRAC gene
The engineered T cell is defined by inserting nucleic acid encoding a CAR into a disrupted TRAC gene.
CAR includes CD28 or 4-1BB co-stimulatory domain
The engineered T cell includes a CAR further comprising either a CD28 co-stimulatory domain or a 4-1BB co-stimulatory domain.
The claim coverage centers on engineered T cells defined by specific CAR-nucleic acid SEQ ID options, with additional constraints including CAR expression thresholds, an anti-LIV1 scFv sequence requirement, TRAC disruption with CAR insertion, and CD28 or 4-1BB co-stimulatory domain components.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating LIV1+ cancers using engineered T cells comprising LIV1-binding CAR constructs.
In vitro cytotoxicity against LIV1+ A498 and ZR-75-1 target cells.
Allogeneic transplantation with graft-versus-host disease mitigation considerations.
Interested in licensing this patent?