The remarkable efficacy of anti-CD19 chimeric antigen receptor (CAR) -T cell therapy in patients with leukemia and lymphoma has led to unprecedented response rates, demonstrating the clinical importance of genetically modified T cells as immunotherapy. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies and challenges remain in managing cytokine-related toxicity.
As a leading cell therapeutics provider, Creative Biolabs has established a novel CellRapeutics™ antibody-TCR (AbTCR) technology platform for the next generation of cell-based therapy. By combining the Fab domain of the antibody with the gamma and delta chains of TCR as effector domains, we demonstrated that AbTCR activates a cytotoxic T cell response similar to conventional CD3ζ-CAR, but with less cytokine release. Therefore, this revolutionary combination product holds huge potential and is expected to become an alternative therapy for cancer treatment.
Classical TCR versus CAR
T cells are defined by TCR molecules present on the surface of their cells. TCR promotes tumor immune surveillance by enabling T cells to recognize abnormal cells and triggering a series of signal events that lead to T cell activation and subsequent cancer cell lysis. In most T cells, TCR consists of alpha and beta chains, while in 1-5% of T cells, TCR consists of gamma (γ) and delta (δ) chains. Antigen-mediated activation of the αβ chains (or γδ chains) induces downstream signaling.
The chimeric antigen receptor borrows the hypervariable portion of a tumor-specific antibody and combines it into a single-chain hypervariable fragment (scFv) to confer CAR specificity. The design of CAR includes single-chain variable fragments with antigen-binding affinity fused to the spacer and transmembrane domains. Effector functions are conferred through the TCR CD3ζ domain, and the addition of a (2nd generation) or 2nd (3rd generation) co-stimulatory domain can drive signal activation and amplification of various effector signal cascades.
To date, effective single-chain designs have proven clinical efficacy as the foundation of most CAR-T therapies. However, the direct fusion of antigen recognition and cell activation domains produces a synthetic activation signal that may differ from the cell activation signal transmitted from the endogenous TCR-CD3 complex.
Fig.1 Structure of TCRs and CARs.
AbTCR Design and Construction
Based on our AbTCR platform, we designed and characterized a two-chain AbTCR. Considering there were technical hurdles with the mispairing with the T-cell ’s endogenous α and β TCR chains, our AbTCR platform avoids mismatches by using the transmembrane and intracellular domains of γδTCR. More specifically, our synthetic AbTCR fuses the antigen-binding domain of an antibody with the signal domain of γδTCR. Similar to exogenously expressed TCR in TCR-T cells, our AbTCR engages endogenous CD3 complexes to initiate T cell activation. Since the γδTCR chain does not bind to TCR in αβT cells, AbTCR avoids the pairing errors of traditional αβTCR-based synthetic receptors. In addition, AbTCR's Fab antigen-binding domain can be used to target peptide-MHC complexes or cell surface antigens by using TCR-mimetic antibodies or conventional antibodies, respectively. Overall, the AbTCR design combines the antigen-binding utility of an antibody with an endogenous TCR activation pathway.
Fig.2 Schematic of antibody-TCR (AbTCR) platform compared to classical TCR and CAR platform.
One-stop AbTCR Development Services
Empowered by our high qualified groups and advanced technologies, Creative Biolabs provides one-stop AbTCR development services:
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