Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer

  • Cancer Cell. 2025 Oct 13;43(10):1902-1916.e9. doi: 10.1016/j.ccell.2025.07.013.
Juan C Osorio  1 ,  David A Knorr  2 ,  Polina Weitzenfeld  3 ,  Lucas Blanchard  3 ,  Ning Yao  4 ,  Maria Baez  3 ,  Carlo Sevilla  2 ,  Meghan DiLillo  3 ,  Jahan Rahman  5 ,  Ved P Sharma  5 ,  Jacqueline Bromberg  6 ,  Michael A Postow  6 ,  Charlotte Ariyan  7 ,  Mark E Robson  6 ,  Jeffrey V Ravetch  8
Affiliations
  • 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10065, USA. Electronic address: [email protected].
  • 2. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10065, USA.
  • 3. Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10065, USA.
  • 4. Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10065, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5. Bio-Imaging Resource Center, Rockefeller University, New York, NY 10065, USA.
  • 6. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 8. Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10065, USA. Electronic address: [email protected].
PMID: 40816292 DOI: 10.1016/j.ccell.2025.07.013
Abstract

CD40 agonism enhances antitumor immunity but is limited by systemic toxicity and poor efficacy. Here, we present a phase 1 study (NCT04059588) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced binding to the inhibitory receptor FcγRIIB. Among 12 metastatic Cancer patients, 2141-V11 was well tolerated without dose-limiting toxicities. Six patients experienced tumor reduction, including two complete responses in Melanoma and Breast Cancer. 2141-V11 induced regression in injected and non-injected lesions, correlating with systemic CD8+ T cell activation and mature tertiary lymphoid structures (TLSs) in complete responders. In CD40/FcγRs humanized mice bearing orthotopic Tumors, i.t. 2141-V11 promoted de novo TLS formation, facilitating i.t. CD8+ T cell effector responses independent of lymph node priming. The resulting local immune responses by 2141-V11 mediated abscopal antitumor effects and sustained immune memory. These findings demonstrate that i.t. 2141-V11 is safe and promotes immune-privileged tumor microenvironments that promote systemic and durable antitumor immunity.

Keywords
CD40; Fc receptor; FcγRIIB; antibody engineering; cancer immunotherapy; clinical trial; complete response; dendritic cell; tertiary lymphoid structures.
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