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Publication Number
US-11299549-B2
Publication Date
2022-04-12
Expiration Date
Abstract
The present invention is directed to a humanized BCMA single-chain variable fragment (scFv), comprising VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. This humanized BCMA-CAR-T cells have specific killing activity against BCMA-positive tumor cells.
Core Innovation
The disclosed invention relates to a humanized anti-BCMA single-chain variable fragment (scFv) defined by a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 5. The scFv is incorporated into an anti-BCMA chimeric antigen receptor (CAR) architecture.
The anti-BCMA CAR is described as a CAR fusion protein including an scFv linked to a transmembrane domain, one or more co-stimulatory domains, and an activating domain. The document further describes domain options for the transmembrane, co-stimulatory, and activating components, including examples such as CD8 transmembrane, CD28 or 4-1BB co-stimulation, and CD3-zeta (CD3ζ) as an activating domain.
The disclosed approach uses immune cells expressing the humanized BCMA-CAR, including humanized BCMA-CAR-T cells, to specifically kill BCMA-positive tumor cells while sparing BCMA-negative controls. The document reports cytokine (IFN-γ) secretion, reduced RPMI8226 xenograft tumor growth in NSG mice, and limited in vivo toxicity described as no body weight decrease. Corresponding CAR components and an example lentiviral CAR construct design are described, together with sequence listings for a humanized BCMA-CAR protein (e.g., SEQ ID NO: 17).
Claims Coverage
The independent claims define two inventive features centered on an anti-BCMA CAR whose scFv is specified by SEQ ID NO: 3 (VH) and SEQ ID NO: 5 (VL) and whose CAR includes a transmembrane domain, a co-stimulatory domain, and an activating domain, with an excipient included.
Humanized anti-BCMA scFv with specified VH and VL sequences
An anti-BCMA chimeric antigen receptor (CAR) having an anti-BCMA single-chain variable fragment (scFv) comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 5.
CAR architecture with transmembrane, co-stimulatory, and activating domains
A CAR that further comprises a transmembrane domain, a co-stimulatory domain, and an activating domain, with the CAR including an excipient in the therapeutic agent or method.
Therapeutic agent includes immune cells expressing the specified anti-BCMA CAR
A therapeutic agent for inhibiting growth of BCMA-positive tumors, the agent comprising immune cells expressing an anti-BCMA chimeric antigen receptor (CAR) with the specified anti-BCMA scFv (SEQ ID NO: 3 and SEQ ID NO: 5) and including a transmembrane domain, a co-stimulatory domain, and an activating domain, and further comprising an excipient.
Administration of immune cells to inhibit growth of BCMA-positive tumors
A method of inhibiting growth of a BCMA-positive tumor, the method comprising administering to a patient an effective number of immune cells expressing an anti-BCMA chimeric antigen receptor (CAR) having an anti-BCMA single-chain variable fragment (scFv) comprising SEQ ID NO: 3 (VH) and SEQ ID NO: 5 (VL), and further comprising a transmembrane domain, a co-stimulatory domain, and an activating domain, and further comprising an excipient.
Overall, the claim set is centered on immune cells expressing an anti-BCMA CAR built from a humanized anti-BCMA scFv defined by SEQ ID NO: 3 (VH) and SEQ ID NO: 5 (VL), combined with a CAR architecture comprising a transmembrane domain, a co-stimulatory domain, and an activating domain, together with an excipient.
Stated Advantages
Specifically killing BCMA-positive tumor cells while sparing BCMA-negative controls.
Cytokine (IFN-γ) secretion.
Reduced RPMI8226 xenograft tumor growth in NSG mice.
Limited in vivo toxicity, described as no body weight decrease.
Documented Applications
Therapeutic use as a therapeutic agent for inhibiting growth of BCMA-positive tumors by administering immune cells expressing the specified anti-BCMA CAR.
Treatment context demonstrating killing of BCMA-positive tumor cells including CHO-BCMA and RPMI8226, while sparing BCMA-negative controls.
NSG mouse xenograft context reporting reduced RPMI8226 tumor growth and cytokine (IFN-γ) secretion.
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