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Publication Number
US-10383929-B2
Publication Date
2019-08-20
Expiration Date
Abstract
The invention provides improved compositions for adoptive T cell therapies for B cell related conditions.
Core Innovation
The invention relates to improved BCMA-targeting chimeric antigen receptor (CAR) therapies for B-cell conditions. It provides a polynucleotide encoding a CAR comprising a sequence set forth in SEQ ID NO: 10, where the CAR includes a murine anti-BCMA antibody-derived antigen-binding component and defined extracellular and intracellular signaling components.
The CAR architecture includes a hinge/spacer region, a transmembrane domain, co-stimulatory signaling domains such as CD28, CD134, and CD137, and primary signaling based on TCRζ. Genetically modified T or NK effector cells are described as carrying the BCMA CAR, and the description further specifies scFv variants and light-chain and heavy-chain regions through CDRs and corresponding SEQ ID NOs.
The description also includes PI3K-pathway modulation during activation and expansion to maintain proliferation and increase memory or less-differentiated phenotypic markers, including CD62L, CD127, and CD197, with reduced CD38. Immune effector manufacturing is further described with PI3K/Akt/mTOR pathway modulators, anti-BCMA CAR-encoding vectors, sorting, heterogeneous or multi-vector CAR expression, artificial APCs, CD3/CD28 and co-stimulatory molecules, isolated T cells or CD34+ progenitor cells, and cryopreservation.
Claims Coverage
The claims content identifies one independent claim covering a specific CAR-encoding polynucleotide sequence (SEQ ID NO: 10). The dependent claim set further specifies vector architecture and regulatory elements, and it narrows the immune effector cell type to T lymphocytes or natural killer (NK) cells, for a total of six inventive-feature areas.
Sequence-defined CAR polynucleotide encoding
A polynucleotide encoding a chimeric antigen receptor (CAR) comprising the polynucleotide sequence set forth in SEQ ID NO: 10.
Retroviral regulatory elements with CAR-linked promoter
A viral vector includes retroviral regulatory and functional elements with a promoter operably linked to polynucleotide encoding the CAR, including left (5′) and right (3′) retroviral LTRs, a Psi (Ω) packaging signal, a cPPT/FLAP, and a retroviral export element.
Named polyadenylation sequence alternatives
A vector including a polyadenylation sequence that is either a bovine growth hormone polyadenylation sequence or a rabbit β-globin polyadenylation sequence.
Selected heterologous promoter choices
A vector including a heterologous promoter that is a cytomegalovirus (CMV) promoter, a Rous Sarcoma Virus (RSV) promoter, or a Simian Virus 40 (SV40) promoter.
Self-inactivating 3′ LTR modification
The vector is characterized by having a 3′ LTR that is a self-inactivating (SIN) LTR.
Immune effector cell selected as T lymphocyte or NK cell
An immune effector cell selected to be either a T lymphocyte or a natural killer (NK) cell.
Overall, the claim coverage centers on a CAR polynucleotide defined by SEQ ID NO: 10, and it is narrowed through dependent limitations specifying viral vector architecture and regulatory element choices and through selection of immune effector cells as T lymphocytes or NK cells.
Stated Advantages
Maintains proliferation.
Increases memory or less-differentiated phenotypic markers.
Reduces or decreases CD38 while increasing CD62L, CD127, and CD197.
Documented Applications
Therapeutic use for B-cell malignancies including multiple myeloma and non-Hodgkin’s lymphoma (NHL).
Therapeutic use for autoimmune/inflammatory B-cell-associated diseases including systemic lupus erythematosus, rheumatoid arthritis, immune thrombocytopenic purpura (ITP), myasthenia gravis, and autoimmune hemolytic anemia.
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