Chimeric antigen receptor for tumor targeting
Inventors
Valamehr, Bahram • Lee, Tom Tong • Hosking, Martin • Yamamoto, Susumu • Maeda, Tatsuo
Assignees
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Publication Number
US-12122846-B2
Publication Date
2024-10-22
Expiration Date
Abstract
Provided are chimeric antigen receptors (CAR) specific to a selected tumor antigen. Also provided are structure designs and function profiles of provided CAR candidates.
Core Innovation
The invention describes a chimeric antigen receptor (CAR) that recognizes a HER2 antigen. The CAR comprises an ectodomain with an antigen binding domain including a heavy chain variable (VH) domain and a light chain variable (VL) domain, a transmembrane domain, and an endodomain comprising at least one signaling domain. The VH domain includes H-CDR1, H-CDR2, and H-CDR3, and the VL domain includes L-CDR1, L-CDR2, and L-CDR3, each comprising specified SEQ ID NOs.
The signaling domain is configured to respond specifically to binding of the CAR to a HER2 antigen expressed on a cancer cell, thereby generating a cancer antigen specific response. The document further defines structural options for the CAR signaling architecture, including immune receptor cytoplasmic domains or portions thereof and formats where two different signaling domains are formed by fused cytoplasmic domains.
The document also defines spacer/hinge composition and length categories, including IgG4 spacers and CD28/CD8/CH3/CH2/CH3 spacer types, with defined short, medium, and long ranges. It further states that sequence identity constraints are provided for the HER2-binding components, including optional scFv arrangements and linkers, and includes optional humanized antibody options.
From the described background problem, there is a need to improve tumor selectivity and manage on-target off-tumor effects associated with HER2-targeting CARs. The document presents experimental evidence that CasMab214- and CasMab250-derived HER2 CARs show improved tumor selectivity compared to a 4D5/Herceptin-based CAR, and that CasMab250 shows least on-target off-tumor effects.
Claims Coverage
The document provides one independent claim defining a HER2-targeting CAR with specified VH and VL CDR sequences, a transmembrane domain, and an endodomain that generates a cancer antigen specific response. Dependent claims in the provided set primarily refine this independent claim by adding identity thresholds, specifying signaling-domain options and fused architectures, constraining spacer/hinge structure, and limiting HER2 responsiveness on non-cancer cells. The inventive features below summarize the main inventive elements for the independent claim and major refinements tied to dependent claims.
HER2-targeting CAR with specified VH and VL CDRs for cancer antigen specific response
A CAR comprising an ectodomain with an antigen binding domain recognizing a HER2 antigen, where the antigen binding domain comprises a VH domain including H-CDR1, H-CDR2, and H-CDR3 with specified SEQ ID NOs and a VL domain including L-CDR1, L-CDR2, and L-CDR3 with specified SEQ ID NOs; a transmembrane domain; and an endodomain comprising at least one signaling domain configured to respond specifically to CAR binding to HER2 expressed on a cancer cell, thereby generating a cancer antigen specific response.
Overall, the claim coverage centers on a HER2-specific CAR defined by VH and VL CDR sequences, coupled to a signaling endodomain producing a cancer antigen specific response upon HER2 binding. Dependent refinements further restrict identity for antigen-binding and signaling components, define fused endodomain signaling architectures, constrain spacer/hinge composition and length categories, and specify reduced responsiveness to HER2 on non-cancer cells.
Stated Advantages
Improved tumor selectivity versus a 4D5/Herceptin-based CAR.
Reduced on-target off-tumor effects, with CasMab250 described as showing least on-target off-tumor effects.
Spacer length and signaling configuration are described as affecting cytokine (IFNγ) production and cytolysis against HER2+ tumor versus non-tumorigenic HER2+ normal cell lines.
Documented Applications
HER2-targeting CAR design and evaluation for cancer cells, including assessment of tumor selectivity and on-target off-tumor effects using HER2+ tumor versus non-tumorigenic HER2+ normal cell lines.
Use in CAR constructs that are evaluated using cytokine (IFNγ) production and cytolysis readouts, including Jurkat activation via an NFκB reporter and cytotoxicity analysis described as using xCELLigence™ RTCA.
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