Compositions for treating cancer
Inventors
Friedman, Kevin M. • Perkins, Molly R. • Dobson, Connor S. • SAZINSKY, Stephen L. • Contrastano, Shannon G. • Thompson Beura, Emily • Ahonen, Cory • Avery, Andrew
Assignees
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Publication Number
US-12403194-B2
Publication Date
2025-09-02
Expiration Date
Abstract
The present disclosure provides compositions and methods comprising recombinant particles suitable for specifically delivering one or more chimeric antigen receptors to immune effector cells in vivo.
Core Innovation
The invention relates to recombinant lentiviral particles and recombinant lentiviral vectors for in vivo CAR delivery for treating cancer. The particles include a viral envelope combining a VSIV-G envelope glycoprotein or a mutated viral envelope glycoprotein with specified amino-acid substitutions or sequences and a non-viral membrane-bound tropism polypeptide comprising an anti-CD3ε scFv and a human CD8α hinge and transmembrane domain.
The recombinant lentiviral vector encodes an anti-BCMA chimeric antigen receptor (CAR) and includes defined promoter and regulatory architectures. In one embodiment, an MND U3 promoter or an EF1α promoter is operably linked to a polynucleotide encoding a signal peptide and an anti-BCMA CAR comprising specified heavy and light chain CDR amino-acid sequences, or a specified CAR amino-acid sequence, together with a CD8α hinge and transmembrane domain, a CD137 costimulatory domain, and a CD3ζ primary signaling domain.
Across the embodiments, the invention defines specific sequence constraints for envelope components, tropism polypeptides, and CAR-related elements using amino-acid substitutions or SEQ ID NOs. The vector further includes defined lentiviral elements such as 5′ and 3′ LTR regions, Ψ packaging signal, cPPT/FLAP, RRE, optional WPRE, polyadenylation signal, and poly(A) tail, and the disclosure includes treatment context for multiple myeloma and related patient conditions.
Claims Coverage
The independent claims focus on recombinant lentiviral particles that combine engineered viral envelope targeting to CD3 with an anti-BCMA CAR expression cassette in a lentiviral vector. Across the independent claims, the inventive coverage is built from a modified viral envelope glycoprotein, a non-viral membrane-bound anti-CD3ε tropism polypeptide fused to a human CD8α hinge and transmembrane domain, promoter-regulated anti-BCMA CAR expression, and lentiviral vector regulatory/processing elements. Three independent claims are presented.
VSIV-G substituted envelope with anti-CD3ε tropism and anti-BCMA CAR vector
A recombinant lentiviral particle comprising a viral envelope comprising a vesicular stomatitis Indiana virus envelope glycoprotein (VSIV-G) comprising amino acid substitutions selected from K47A and R354A; K47A and R354Q; K47Q and R354A; and K47Q and R354Q; and a non-viral membrane-bound tropism polypeptide comprising an anti-CD3ε scFv and a human CD8α hinge and transmembrane domain; and a recombinant lentiviral vector comprising an MND U3 promoter or an EF1α promoter operably linked to a polynucleotide encoding a signal peptide and an anti-BCMA chimeric antigen receptor comprising specified heavy chain and light chain CDR amino acid sequences, a CD8α hinge and transmembrane domain, a CD137 costimulatory domain, and a CD3ζ primary signaling domain.
Mutated viral envelope sequence with defined LTR/packaging elements and anti-BCMA CAR
A recombinant lentiviral particle comprising a viral envelope comprising a mutated viral envelope glycoprotein comprising the amino acid sequence of any one of SEQ ID NOs: 332, 333, 334, and 335 and a non-viral membrane-bound tropism polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 324, 325, 326, 327, 328, 329, 330, and 331; and a recombinant lentiviral vector comprising a 5′ LTR comprising R and U5 regions, a Ψ packaging signal, a cPPT/FLAP, a rev response element (RRE), a polynucleotide encoding an MND promoter or an EF1α promoter operably linked to a polynucleotide encoding a signal peptide and an anti-BCMA chimeric antigen receptor comprising the amino acid sequence of SEQ ID NO: 270; optionally a WPRE; a 3′ LTR comprising U3 and R regions; a polyadenylation signal; and a poly(A) tail.
SEQ ID-defined mutated envelope and tropism with EF1α-driven anti-BCMA CAR
A recombinant lentiviral particle comprising a viral envelope comprising a mutated viral envelope glycoprotein comprising the amino acid sequence of SEQ ID NO: 335 and a non-viral membrane-bound tropism polypeptide comprising the amino acid sequence of SEQ ID NO: 324; and a recombinant lentiviral vector comprising a 5′ LTR comprising R and U5 regions, a Ψ packaging signal, a cPPT/FLAP, a rev response element (RRE), a polynucleotide encoding an EF1α promoter operably linked to a polynucleotide encoding a signal peptide and an anti-BCMA CAR comprising the amino acid sequence of SEQ ID NO: 270; optionally a WPRE; a 3′ LTR comprising U3 and R regions; a polyadenylation signal; and a poly(A) tail.
Across the independent claims, the core claim coverage is a recombinant lentiviral particle that pairs a modified viral envelope glycoprotein with a non-viral membrane-bound tropism polypeptide targeting CD3ε or specified mutated/tropism sequence pairs, and that includes a lentiviral vector encoding an anti-BCMA CAR with defined promoter/regulatory and signaling elements such as CD137 costimulatory and CD3ζ primary signaling domains.
Stated Advantages
Enables in vivo CD3-driven anti-BCMA CAR delivery to immune effector cells.
Provides anti-BCMA CAR expression and function as assessed in provided in vitro and in vivo results.
Provides anti-tumor efficacy in multiple myeloma mouse models.
Assesses off-target transduction.
The disclosed strategy is directed to immune effector cells via a tropism polypeptide that targets CD3ε while expressing an anti-BCMA CAR with costimulatory and primary signaling domains.
Documented Applications
In vivo transduction of CD3-expressing immune cells, including immune effector cells such as T cells and NK cells, for anti-BCMA CAR delivery.
Treatment for multiple myeloma, including use with pharmaceutical formulations and related embodiments described in the document.
Off-target transduction assessment and evaluation of anti-BCMA CAR expression/function in vitro and in vivo.
In vivo evaluation in NSG mouse models using bioluminescence imaging in the context of multiple myeloma.
In vivo CAR delivery for treating cancer.
Treatment and prevention of multiple myeloma and related patient conditions.
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