Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10639358-B2
Publication Date
2020-05-05
Expiration Date
Abstract
The invention provides improved compositions for adoptive T cell therapies for B cell related conditions.
Core Innovation
The invention provides a chimeric antigen receptor (CAR) encoded by the polynucleotide sequence set forth in SEQ ID NO: 10. The CAR comprises an antigen-binding domain and a CAR intracellular signaling architecture, with murine anti-BCMA antibody(-fragment) binding domains, specified CDRs, and SEQ ID NOs for variable light chain and variable heavy chain components.
The CAR architecture includes a hinge or spacer region and a transmembrane domain, together with co-stimulatory and primary signaling domains, including CD28, CD134 (OX40), CD137 (4-1BB), and CD3. The disclosure also describes polynucleotides encoding the BCMA CAR and CAR-associated vector systems, including retroviral and lentiviral vectors with regulatory and expression elements.
Immune effector cell compositions are described in which immune effector cells express the BCMA CAR. The immune effector cells are T lymphocytes or natural killer (NK) cells, and the disclosure includes manufacturing or manipulation concepts involving PI3K pathway inhibition, including ZSTK474, to increase proliferative or “young” T-cell marker expression and improve persistence and anti-tumor activity.
Claims Coverage
The independent claim is directed to a CAR defined by its polynucleotide sequence (SEQ ID NO: 10). The provided material additionally identifies dependent inventive features centered on vector and nucleic acid expression/processing elements for that CAR-encoding polynucleotide, and immune effector cell compositions limited to T lymphocytes or NK cells. Across the claim coverage, there are six inventive features.
Car encoded by the polynucleotide sequence set forth in SEQ ID NO: 10
A chimeric antigen receptor (CAR) wherein the CAR is encoded by the polynucleotide sequence set forth in SEQ ID NO: 10.
Retroviral vector with specified retroviral regulatory elements and signals
A retroviral vector including specified retroviral regulatory elements and signals, along with a promoter driving a polynucleotide encoding a CAR.
Heterologous promoter selected from CMV, RSV, or SV40
A vector wherein the heterologous promoter is selected from a cytomegalovirus (CMV) promoter, a Rous Sarcoma Virus (RSV) promoter, or a Simian Virus 40 (SV40) promoter.
Heterologous polyadenylation sequence is bovine growth hormone or rabbit β-globin
A vector wherein a heterologous polyadenylation sequence is selected from a bovine growth hormone polyadenylation signal or a rabbit β-globin polyadenylation sequence.
Self-inactivating (SIN) 3′ LTR configuration
A vector wherein the 3′ LTR is a self-inactivating (SIN) LTR.
Immune effector cell selected as T lymphocyte or NK cell
An immune effector cell that is selected as either a T lymphocyte or a natural killer (NK) cell.
Coverage is primarily established by a BCMA CAR encoded by the polynucleotide sequence set forth in SEQ ID NO: 10, and narrowed through vector embodiments specifying promoter selection, polyadenylation signal alternatives, and LTR configurations, with further narrowing to immune effector cells expressing the CAR that are limited to T lymphocytes or NK cells.
Stated Advantages
Enriches for developmentally potent or “young” T cells marked by increased CD62L, CCR7, CD28, CD27, CD122, CD127, CD197, and CD38 and decreased differentiation markers such as CD57, PD-1, CTLA4, TIM3, and LAG3.
PI3K pathway inhibition is described as increasing proliferative or “young” T-cell marker expression and improving persistence and anti-tumor activity.
ZSTK474-treated CAR T cells show reduced tonic cytokine/inflammatory/apoptosis activity and increased potency.
Documented Applications
Treating B-cell malignancies including multiple myeloma and non-Hodgkin lymphoma using anti-BCMA CAR T cells.
Treating B-cell related conditions.
CAR T-cell manufacturing use case aimed at enriching developmentally potent or “young” T cells via PI3K pathway modulation, including PI3K inhibitors such as ZSTK474.
Tumor control in xenograft models.
Comparative evaluation of anti-BCMA CARs (anti-BCMA02 versus anti-BCMA10) for differential tonic cytokine/inflammatory/apoptosis behavior and testing involving ZSTK474-treated CAR T cells.
Interested in licensing this patent?