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Author: Sophia
Introduction: Ligand-induced receptor dimerization or oligomerization is a broad mechanism to ensure communication specificity, protect receptor activation, and promote signal transduction across cell membrane expansion. However, cell surface antigen-induced multimerization (referred to herein as AIM) has not been consciously used in chimeric antigen receptor (CAR) engineering to enrich T cell-based **. We co-developed Ciltacabtagene Autoleucel (Cilta-CEL), whose CAR binds two B-cell maturation antigen (BCMA)-targeted nanobodies, for multiple myeloma.
On December 8, the team of Academician Chen Saijuan from Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, National Research Center for Translational Medicine, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, and Professor Chen Xiaohong from Shanghai Public Health Clinical Center jointly published an article entitled "Antigen-induced Chimeric Antigen" in the journal "Signal Transduction and Targeted Therapy". receptor multimerization amplifies on-tumor cytotoxicity".Studies elucidate a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of the BCMA-nanobody complex revealed atomic details of antigen-antibody heteropolymerization, while analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA juxtaposition and CAR juxtaposition in solution. BCMA-induced nanoantibody CAR multimerization enhances cytotoxicity to myeloma-derived cells while enhancing immune synapse formation and cytotoxicity-mediated cytokine release. Our findings provide a framework for considering the AIM approach when designing the next generation of cars.
Background:
B-cell maturation antigen (BCMA) is a member of the TNF receptor superfamily (Figure 1A, left). Therefore, the binding of TNF-like trimer ligands (proliferation-inducing ligand (APRIL) and B cell activation factor (BAFF)) can induce trimerization and activation of BCMA, promoting B cell proliferation and survival. BCMA is preferentially expressed on mature B lymphocytes and is markedly elevated in multiple myeloma (MM) cells, along with soluble April and BAFF in MM patients. Therefore, BCMA is a hot target for MM** development. MM is a common hematologic malignancy, the criteria for which include proteasome inhibitors, immunomodulatory drugs, antibodies, steroids, chemotherapy, and autologous hematopoietic stem cell transplantation, but almost impossible**. Clinical options for more recent *** or refractory MM (RRMM) include BCMA-directed CAR T** and bispecific T cell engagers.
We co-developed the Ciltacabtagene Autoleucel (Cilta-CEL), which relies on a CAR guided by two BCMA-targeted nanobodies (hereafter referred to as nanobody tandem) to **mm (Figure 1A, right). Nanobodies, including the VHH (Heavy Chain Variable Region of Heavy Chain Antibodies Only) variant used in Cilta-cel, are single immunoglobulin-folded antibodies with 120 residues per antibody. CILTA-CEL is the first nanobody-based CAR-T** approved by the U.S. Food and Drug Administration (FDA). Due to the encouraging clinical results of the rrmm, CILTA-CEL is in the process of receiving regulatory approval globally. In this study,:We set out to describe the structural and functional mechanisms involved in cilta-cel tandem BCMA in myeloma-targeted CAR activation and T cytotoxicity to guide future CAR design.
Research Progress
As far as we know,Our data characterize cilta-cel as the first structural example of cell surface antigen-induced CAR multimerization in T cell-based cancer immunity** (Figure 7). Balancing on- and extratumoral cytotoxicity by engineering T cells is a delicate behavior for CARS targeting non-mutated cancer-associated antigens, and antigen-induced multimerization may be a comprehensive way to alter the balance. The CD19 paradigm and the recent success of BCMA with CAR T** B-cell carcinoma are centered on high levels of these antigens on cancer cells relative to normal tissues (confined to B-cell lineages). The targeted, extratumoral toxicity of CAR T**, including cilta-cel, to these B cells can be mitigated by immunoglobulin substitution**. ThisCell surface antigens have been shown to be challenging for solid tumor recognition, so CAR must distinguish between targeted solid tumor cells with high antigen densities, amplifying the T cell response when engaged, and cells with lower antigen levels. Notably, multiple BCMA molecules are required to induce cilta-cel nanobody tandem-mediated multimerization, which implies a relatively high antigen density. In addition, solid tumors have a more complex structure and microenvironment than hematologic malignancies such as multiple myeloma (MM). Cytotoxicity, as well as immunosynaptic and cytotoxicity-mediated cytokine release, assays for the direct application of cytotoxic T cell activity to hematologic malignancies, resulting in successful **mm, e.g., cilta-cel**mm.
BCMA-induced model of nanobody CAR multimerization.
Conclusions of the study
Taken together, our findings suggest that antigen-induced polymerization (AIM) is a potential approach for designing future CARs:In the absence of antigen and in the presence of antigen, stoichiometric assay experiments can be integrated into the current pipeline to aid in the selection of antibodies that are otherwise similar in respect. AIM should be considered in conjunction with the characteristics of the antibody, such as affinity and kinetics, as well as other areas in the modular CAR architecture that are relevant to its target antigen and disease, to provide optimized clinical benefit. We anticipate that for solid tumors, a different CAR T regimen will be required due to the need for a tighter antigen window, necessitating stratification of patients based on cancer-associated antigen levels.
References: Note: This article aims to introduce the progress of medical research and cannot be used as a reference for ** scheme. If you need health guidance, please visit a regular hospital.
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