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Publication Number
US-10646558-B2
Publication Date
2020-05-12
Expiration Date
Abstract
The invention provides improved compositions for adoptive T cell therapies for B cell related conditions.
Core Innovation
The invention relates to chimeric antigen receptor (CAR) constructs defined by specific amino acid and polynucleotide sequences, where the CAR comprises the amino acid sequence set forth in SEQ ID NO: 9 encoded by the polynucleotide sequence set forth in SEQ ID NO: 10. The disclosed CAR constructs target BCMA, including anti-BCMA CAR variants and a murine anti-BCMA antibody or antigen-binding fragment, including an scFv.
The CAR extracellular and signaling architecture includes defined hinge/spacer, transmembrane, and intracellular signaling components. The intracellular signaling includes CD3ζ as the primary signaling domain, and co-stimulatory domains including CD28, 4-1BB (CD137), and/or OX40 (CD134), while the extracellular components are described using hinge/spacer elements such as IgG1/IgG4 hinge or CH2/CH3.
The invention also provides vectors and polynucleotides encoding the exemplary CAR, with retroviral/lentiviral architectures that include optional self-inactivating LTRs (SIN-LTR). The polynucleotide constructs are described with heterologous promoters and defined polyadenylation signals, and include retroviral vector elements such as packaging and export components. In addition, the engineered immune effector cells are described as T lymphocytes or NK cells.
Claims Coverage
The independent claim recites a CAR defined by a specific amino acid sequence and the corresponding encoding polynucleotide. The claim coverage also includes dependent limitations related to retroviral vector architecture, promoter and polyadenylation sequence selection, self-inactivating LTR configuration, and restriction of the immune effector cell type to T lymphocytes or NK cells.
Sequence-defined BCMA CAR
A chimeric antigen receptor (CAR) comprising the amino acid sequence set forth in SEQ ID NO: 9 encoded by the polynucleotide sequence set forth in SEQ ID NO: 10.
Retroviral vector architecture with defined elements
A retroviral vector includes a left (5′) retroviral LTR, Ψ packaging signal, cPPT/FLAP, a retroviral export element, a promoter operably linked to the CAR-encoding polynucleotide, and a right (3′) retroviral LTR.
Heterologous promoter selection among named viral promoters
A heterologous promoter selected from a CMV promoter, an RSV promoter, or an SV40 promoter.
Polyadenylation sequence selection among named signals
The polyadenylation sequence is either a bovine growth hormone polyadenylation or a rabbit β-globin polyadenylation sequence.
Self-inactivating LTR
The 3′ LTR is a self-inactivating (SIN) LTR.
Immune effector cell restricted to T lymphocyte or NK cell
The immune effector cell is selected from a T lymphocyte and a natural killer (NK) cell.
Overall, the claim coverage centers on a BCMA CAR specified by SEQ ID NO: 9 and SEQ ID NO: 10, with additional inventive aspects in dependent claims focused on retroviral vector components including SIN-LTR, promoter and polyadenylation selections, and narrowing the immune effector cell type to T lymphocytes or NK cells.
Stated Advantages
Enriches proliferative, less-differentiated T cells to improve persistence.
Supports in vivo persistence and memory differentiation using IL-2 together with a PI3K inhibitor.
Reduced exhaustion/differentiation marker profiles are described as an outcome of PI3K inhibitor modulation.
Avoid cytokine storm.
Spare humoral immunity.
Documented Applications
Therapeutic methods for treating B cell malignancies using BCMA-targeting CAR immune effector cells, including CAR T cell therapy.
Multiple myeloma treatment and non-Hodgkin lymphoma-related tumor control evaluation in mouse tumor models.
Treatment of B-cell malignancies using BCMA-targeting CAR T cell therapies.
Treatment of autoimmune B-cell conditions using BCMA-targeting engineered immune effector cells.
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