8HXR

Nanobody2 in complex with human BCMA ECD

Summary for 8HXR

• Entry DOI: 10.2210/pdb8hxr/pdb
• Descriptor: Nanobody2, Tumor necrosis factor receptor superfamily member 17 (3 entities in total)
• Functional Keywords: complex, nanobody, immune system
• Biological source: Vicugna pacos; More
• Total number of polymer chains: 4
• Total formula weight: 39072.06

Authors

Sun, Y.,Zhang, B. (deposition date: 2023-01-05, release date: 2024-01-03, Last modification date: 2024-11-13)

Primary citation

Sun, Y.,Yang, X.N.,Yang, S.S.,Lyu, Y.Z.,Zhang, B.,Liu, K.W.,Li, N.,Cui, J.C.,Huang, G.X.,Liu, C.L.,Xu, J.,Mi, J.Q.,Chen, Z.,Fan, X.H.,Chen, S.J.,Chen, S.
Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.
Signal Transduct Target Ther, 8:445-445, 2023

PubMed Abstract: Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

PubMed: 38062078
DOI: 10.1038/s41392-023-01686-z

Experimental method

X-RAY DIFFRACTION (2.7 Å)