Chimeric antigen receptors
Inventors
Bondanza, Attilio • Casucci, Monica • Bonini, Maria Chiara
Assignees
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Publication Number
US-11299529-B2
Publication Date
2022-04-12
Expiration Date
Abstract
A chimeric antigen receptor (CAR) comprising an extracellular spacer which comprises at least part of the extracellular domain of human low affinity nerve growth factor (LNGFR) or a derivative thereof.
Core Innovation
The invention provides chimeric antigen receptor (CAR) constructs that include an extracellular spacer derived from human low affinity nerve growth factor receptor (LNGFR). Instead of using an IgG1 CH2CH3/Fc spacer, the CAR uses at least part of the extracellular domain of LNGFR for facilitating immunoselection and identification of cells transduced with the CAR.
In particular, the extracellular spacer comprises the first three TNFR-Cys domains of LNGFR. The disclosed spacer may be extended to comprise additional LNGFR extracellular elements, including sequence-level edits within a TNFR-Cys domain, together with a suitable architecture for placement between the targeting domain and a transmembrane domain.
The CAR architecture further comprises an antigen-specific targeting domain, a transmembrane domain, and an intracellular signaling domain. The antigen-specific targeting domain targets isoform 6 of CD44 (CD44v6), CD19, and/or CEA, and the constructs include variants in which the targeting format, transmembrane domain composition, costimulatory domain selection, and intracellular signaling domain are specified to support CAR functionality.
Claims Coverage
The document contains two independent CAR claims. Each independent claim requires four core structural components: antigen targeting, an LNGFR-derived extracellular spacer for immunoselection, a transmembrane domain, and an intracellular signaling domain.
LNGFR extracellular spacer-based immunoselection CAR for CD44v6, CD19, and CEA
A chimeric antigen receptor (CAR) comprising an antigen-specific targeting domain which targets an antigen selected from isoform 6 of CD44 (CD44v6), CD19, and CEA; an extracellular spacer which comprises at least part of the extracellular domain of human low affinity nerve growth factor receptor (LNGFR) suitable for facilitating immunoselection and identification of cells transduced with the CAR, wherein the extracellular spacer comprises the first three TNFR-Cys domains of LNGFR; a transmembrane domain; and an intracellular signaling domain.
Tumour antigen targeting CAR with LNGFR extracellular spacer for immunoselection
A chimeric antigen receptor (CAR) comprising an antigen-specific targeting means for targeting a tumour antigen selected from CD44v6, CD19, CEA, and combinations thereof; an extracellular spacer which comprises at least part of the extracellular domain of human low affinity nerve growth factor receptor (LNGFR) suitable for facilitating immunoselection and identification of cells transduced with the CAR, wherein the extracellular spacer comprises the first three TNFR-Cys domains of LNGFR; a transmembrane domain; and an intracellular signalling domain.
Across both independent claims, the central inventive coverage is the use of an LNGFR-derived extracellular spacer, specifically comprising the first three TNFR-Cys domains, positioned within a CAR that includes an antigen-specific targeting domain, a transmembrane domain, and an intracellular signaling domain.
Stated Advantages
Facilitating immunoselection and identification of cells transduced with the CAR.
Avoiding FcγR-mediated off-target activation and soluble NGF signaling (as stated in the provided description chunk).
Improving T-cell persistence and antitumor efficacy in vitro and in mouse xenograft models (as stated in the provided description chunk).
Facilitating cell tracking (as stated in the provided description chunk).
Documented Applications
Therapeutic use of CARs targeting CD44v6, CD19, and/or CEA, including in in vitro and mouse xenograft models (as stated in the provided description chunk).
Polynucleotide/vector/cell/pharmaceutical compositions comprising the CARs, and therapeutic use of those compositions (as stated in the provided description chunk).
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