Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10624960-B2
Publication Date
2020-04-21
Expiration Date
Abstract
The invention provides improved compositions for adoptive T cell therapies for B cell related conditions.
Core Innovation
The disclosure relates to CAR-modified immune effector cells, including BCMA-targeting CAR-based adoptive T cell therapies and lentiviral CAR expression. The CAR constructs include murine anti-BCMA binding domains and anti-BCMA CARs, including humanized anti-BCMA02 and anti-BCMA10 CARs, with extracellular architecture coupled to hinge/spacer and transmembrane options and intracellular signaling domains including CD3ζ and co-stimulatory domains such as CD28, CD137 (4-1BB), and OX40 (CD134).
The disclosure describes a lentiviral vector architecture in which the promoter of the 5′ lentiviral LTR is replaced with a CMV promoter, while the construct includes a Ψ packaging signal, a cPPT/FLAP, and a Rev response element (RRE). It further includes an MND promoter operably linked to a CAR-encoding polynucleotide sequence set forth in SEQ ID NO: 10, a right (3′) lentiviral self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence, with vector embodiments delivered using lentiviral or retroviral vectors.
The disclosure frames the use of these CAR constructs in immune effector cells including T lymphocytes and NK cells for targeting BCMA+ malignancies and B-cell malignancies, including multiple myeloma and NHL. It further emphasizes manufacturing and enrichment toward developmentally potent and less differentiated T cells by using modulators of the PI3K pathway, including PI3K inhibitors, and associates the approach with cryopreservation of CAR-expressing cells and therapeutic use in the context of CAR T cell manufacturing.
Claims Coverage
The claims coverage centers on a specifically configured lentiviral vector with a CMV promoter-replaced 5′ LTR, Ψ packaging signal, cPPT/FLAP, RRE, an MND promoter driving a CAR polynucleotide set forth in SEQ ID NO: 10, a 3′ SIN LTR, and a heterologous polyadenylation sequence. The independent and dependent claims further extend the vector to an immune effector cell and to a composition that includes a physiologically acceptable excipient, while also specifying permitted lentivirus types and polyadenylation signals.
CMV promoter-replaced 5′ LTR with defined transfer elements
A lentiviral vector comprising a left (5′) lentiviral LTR wherein the promoter of the 5′ LTR is replaced with a CMV promoter, including a Ψ packaging signal, a cPPT/FLAP, and a Rev response element (RRE).
MND promoter-driven CAR polynucleotide set forth in SEQ ID NO: 10
A myeloproliferative sarcoma virus enhancer with a negative control region deleted and a dl587rev primer-binding site substituted (MND) promoter operably linked to a polynucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the polynucleotide sequence is set forth in SEQ ID NO: 10.
Self-inactivating 3′ LTR and heterologous polyadenylation
A right (3′) lentiviral self-inactivating (SIN) LTR and a heterologous polyadenylation sequence in the lentiviral vector.
Choice of lentivirus type for the lentiviral vector
The lentiviral vector is selected from the group consisting essentially of HIV-1, HIV-2, VMV, CAEV, EIAV, FIV, BIV, and SIV.
Alternative heterologous polyadenylation signal options
The heterologous polyadenylation sequence is either a bovine growth hormone polyadenylation signal or a rabbit β-globin polyadenylation sequence.
Immune effector cell comprising the lentiviral vector
An immune effector cell comprising the lentiviral vector.
Immune effector cell limited to T lymphocytes or NK cells
The immune effector cell is selected from the group consisting of a T lymphocyte and a natural killer (NK) cell.
Composition including the immune effector cell and a physiologically acceptable excipient
A composition comprising the immune effector cell and a physiologically acceptable excipient.
Overall, the claim coverage focuses on a defined CAR-encoding lentiviral vector architecture and its extension to immune effector cell and composition embodiments. The claims also retain dependent refinements concerning vector components, lentivirus type, and polyadenylation sequence options.
Stated Advantages
Improved persistence/anti-tumor efficacy in BCMA+ malignancies.
Reduced cytokine storm risk.
Improved expansion/persistence.
Manufacturing reproducibility.
Developmentally potent and less differentiated T cells.
Reduction of differentiation and exhaustion markers.
Differences in functional outcomes, including inferior tumor control for one CAR variant.
Effects of ZSTK474/IL-2 treatment on phenotype and antitumor efficacy.
Documented Applications
Adoptive T cell therapies targeting BCMA using CAR-based constructs.
Treatment of BCMA+ malignancies including multiple myeloma and NHL.
Adoptive immunotherapy for B-cell malignancies, including multiple myeloma.
CAR T cell manufacturing.
Therapeutic use in the context of CAR T cell manufacturing.
Interested in licensing this patent?