Deep Learning-based Modeling Enhances Efficacy of Natural Ligand CAR Binders Targeting CD70
Year: 2026
Type: preprint
Abstract: CD70 is well-recognized as a promising “pan-cancer” chimeric antigen receptor (CAR) T-cell target. Prior work has shown that a “natural ligand” (NL)-based CAR targeting CD70, employing its physiological interaction partner CD27, may have therapeutic advantages over antibody- based CARs. Yet while antibody-based CARs are routinely optimized by affinity maturation of their scFv, whether the binding sequence of an NL CAR can be engineered to improve its function remains unexplored. Here, we combined deep learning with physics-based modeling to redesign residues at the CD27:CD70 interface, identifying a CD27 variant, “N88A”, which enhances the efficacy of CD70-targeting CAR T-cells across models of acute myeloid leukemia, multiple myeloma, and renal cell carcinoma. Biophysical approaches, including molecular dynamics simulations, support a mechanism of increased binder conformational freedom underlying potency enhancement. Our work presents CD27 N88A CAR T-cells as a promising new therapeutic option and proposes that computational modeling could be applied to enhance efficacy of other NL-based immunotherapies.
Authors: Amrik S Kang, Radhika Dalal, Mingcheng Li, Anupam Anand Ojha, Sujata Walunj, Caitlin E Cornell, Ruyan Rahnama, Abhilash Barpanda, Sanjana Prudhvi, Trishna S Patel, Mark Aspinall-O’Dea, Beth Walker, Clare Adams, Veronica Steri, Paul Phojanakong, Juan Antonio Camara Serrano, Hua Li, Yan Zeng, Jose Rivera, Daniel A Fletcher, Benjamin J Huang, Sonya M Hanson, Pilar Cossio, Tanja Kortemme, Justin Eyquem, Arun P Wiita
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, Simons Foundation, Silicon Valley Community Foundation, Multiple Myeloma Research Foundation, Alexander and Margaret Stewart Trust, Parker Institute for Cancer Immunotherapy, Flatiron Health, National Institutes of Health, University of California, San Francisco, Hyundai Hope On Wheels, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
Awards: G1348001003, G2342450115, G839201715
OpenAlex ID: W7212160685