Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12029784-B2
Publication Date
2024-07-09
Expiration Date
Abstract
The invention provides improved compositions for adoptive T cell therapies for B cell related conditions.
Core Innovation
The disclosure provides improved BCMA-targeting chimeric antigen receptor (CAR) architectures for adoptive T-cell therapy and improved adoptive immunotherapy by manufacturing and selecting human immune effector cells that express a CAR. The CAR targets BCMA (CD269/TNFRSF17), also referred to as B cell maturation antigen, and is defined by the amino acid sequence set forth in SEQ ID NO: 9.
The document further describes CAR polynucleotides and encoding constructs, including CAR amino acid sequences and CAR polynucleotide sequences set forth by SEQ ID NOs. It includes expression and delivery systems for the CAR, including episomal and viral vector systems, with viral examples including retroviral and lentiviral vectors and a lentiviral vector configuration with defined left and right LTR elements, a CMV promoter, Psi packaging signal, cPPT/FLAP, RRE, an MND promoter, a self-inactivating LTR, and a heterologous polyadenylation sequence.
A central aspect of the improved manufacturing and selection is conducting CAR T cell manufacture in the presence of PI3K-pathway modulators/inhibitors to enrich developmentally potent or younger phenotypes. The document links this approach to PI3K/Akt/mTOR pathway modulation, reports associated cell surface marker changes with decreased exhaustion/differentiation markers, and describes manufacturing and storage approaches such as cryopreservation and culture approaches involving PI3K-pathway inhibition.
The disclosure addresses therapeutic use and associated treatment context for B-cell conditions, including B cell malignancy such as multiple myeloma and non-Hodgkin’s lymphoma, as well as autoimmune B-cell disorders. It also addresses immune effector cells, including genetically modified T cells and NK cells, and includes described benefits related to efficacy and safety such as reduced cytokine storm risk and cytokine release effects.
Claims Coverage
The partial content provides five independent claims. Across these independent claims, the main inventive features include administering human immune effector cells expressing a CAR defined by SEQ ID NO: 9 for B cell malignancy treatment, using pharmaceutical compositions with specified excipients, employing CAR expression via vector-based constructs including lentiviral vectors with defined LTR/regulatory elements, and treating multiple myeloma with CAR-expressing immune effector cells.
Treating a B cell malignancy using SEQ ID NO: 9 CAR immune effector cells
A method of treating a B cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells that express a chimeric antigen receptor (CAR) comprising the amino acid sequence set forth in SEQ ID NO: 9.
Treating a B cell malignancy using a composition with pharmaceutically acceptable excipient and SEQ ID NO: 9 CAR immune effector cells
A method of treating a B cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a pharmaceutically acceptable excipient and human immune effector cells that express a chimeric antigen receptor (CAR) consisting of the amino acid sequence set forth in SEQ ID NO: 9.
Treating a B cell malignancy using a vector encoding a SEQ ID NO: 9 CAR
A method of treating a B cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising a vector comprising a polynucleotide that expresses a CAR consisting of the amino acid sequence set forth in SEQ ID NO: 9.
Treating a B cell malignancy using lentiviral vector LTR/regulatory-element CAR construct in immune effector cells
A method of treating a B cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a physiologically acceptable excipient and human immune effector cells; wherein the immune effector cells comprise a lentiviral vector; wherein the lentiviral vector comprises a left (5′) lentiviral LTR wherein the promoter of the 5′ LTR is replaced with a CMV promoter; a Psi (Ψ) packaging signal; a cPPT/FLAP; a Rev response element (RRE); a myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter operably linked to a polynucleotide encoding a CAR consisting of the amino acid sequence set forth in SEQ ID NO: 9; a right (3′) lentiviral self-inactivating (SIN) LTR; and a heterologous polyadenylation sequence.
Treating multiple myeloma using SEQ ID NO: 9 CAR immune effector cells
A method of treating multiple myeloma (MM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells that express a chimeric antigen receptor (CAR) consisting of the amino acid sequence set forth in SEQ ID NO: 9.
Overall, the independent claims cover treating B cell malignancies and multiple myeloma by administering therapeutically effective amounts of human immune effector cells expressing a CAR defined by SEQ ID NO: 9, including embodiments using compositions with pharmaceutically acceptable or physiologically acceptable excipients and vector-based CAR expression, including lentiviral vectors with defined LTR and regulatory components.
Stated Advantages
Enrichment for developmentally potent or younger phenotypes by manufacturing in the presence of PI3K-pathway modulators/inhibitors, associated with increased CD62L, CCR7, CD28, CD27, CD122, CD127, CD197, and CD38 and decreased exhaustion/differentiation markers including PD-1, CTLA4, TIM3, LAG3, CD57, CD244, and CD160.
Improved therapeutic efficacy support in B cell malignancies using constructs and PI3K-pathway modulation, based on reported marker expression changes and therapeutic performance in lymphoma/myeloma mouse models.
Differences between anti-BCMA02 and anti-BCMA10 CAR performance are associated with tonic cytokine/inflammation and apoptosis and reduced tumor control reported for anti-BCMA10.
Reduced cytokine storm risk.
Improved efficacy/safety is supported by the disclosure rationale and described cytokine release effects.
Documented Applications
Treatment of a B cell malignancy in a subject, including multiple myeloma and non-Hodgkin lymphoma, using CAR-expressing human immune effector cells defined by SEQ ID NO: 9.
Treatment of multiple myeloma (MM) in a subject using CAR-expressing human immune effector cells defined by SEQ ID NO: 9.
Use of PI3K-pathway inhibition/modulation during CAR T cell manufacturing to enrich developmentally potent/younger T cell phenotypes for adoptive immunotherapy in B cell malignancies.
Evaluation in lymphoma/myeloma mouse models, including NSG and models associated with RPMI-8226 and Daudi.
Therapeutic targeting of autoimmune B-cell disorders (e.g., SLE, rheumatoid arthritis, ITP, myasthenia gravis, autoimmune hemolytic anemia).
Interested in licensing this patent?