2025-08-14 ロックフェラー大学
Histology image of a patient whose metastatic cancer went into complete remission after receiving a new immunotherapy treatment (Ravetch lab)
<関連情報>
- https://www.rockefeller.edu/news/38120-immunotherapy-drug-eliminates-aggressive-cancers-in-clinical-trial/
- https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00319-8
- https://www.pnas.org/doi/10.1073/pnas.1810566115
Fc最適化CD40アゴニスト抗体は、転移性がんにおいて三次リンパ組織構造の形成と全身性抗腫瘍免疫を誘導する Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer
Juan C. Osorio ∙ David A. Knorr ∙ Polina Weitzenfeld ∙ … ∙ Charlotte Ariyan ∙ Mark E. Robson ∙ Jeffrey V. Ravetch
Cancer Cell Published:August 14, 2025
DOI:https://doi.org/10.1016/j.ccell.2025.07.013
Highlights
- First-in-human phase 1 study of Fc-enhanced CD40 agonistic antibody (2141-V11)
- Intratumoral 2141-V11 is safe and induces local and systemic antitumor responses
- 2141-V11 induces tertiary lymphoid structures formation in mouse and human tumors
- 2141-V11 intratumoral activity is independent of lymph node immune egress
Summary
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.
Fc改変抗CD40抗体の毒性は、腫瘍内投与により消失し、持続的な抗腫瘍免疫を引き起こす Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity
David A. Knorr, Rony Dahan, and Jeffrey V. Ravetch
Proceedings of the National Academy of Sciences Published:October 8, 2018
DOI:https://doi.org/10.1073/pnas.1810566115
Significance
Antibodies blocking inhibitory checkpoints on T cells have been a major advance in cancer treatment. However, agonistic antibodies have had less success due to toxicity concerns. Harnessing the knowledge that agonistic antibodies require the inhibitory Fc receptor (FcR), we engineered a CD40 antibody with improved in vivo activity. Because current models fail to recapitulate important dose-limiting toxicities in patients, we developed a mouse model carrying human CD40 and FcRs. This model mirrors human toxicities and allowed for the development of an in situ vaccination approach leading to durable tumor control. These results support the rational design of immune modulating antibodies as well as stress the importance, and possible reconsiderations needed, for optimal preclinical models allowing parallel efficacy and toxicity analyses.
Abstract
Immune stimulation has emerged as a promising approach to the treatment of neoplastic diseases. Currently approved therapeutics, such as anti-CTLA4 and anti-PD1, are primarily aimed at blocking inhibitory signaling by immune cells. An alternative and potentially synergistic approach would involve activation of immune pathways by agonism of stimulatory receptors, such as CD40. Agonistic antibodies, while promising in principle, have encountered significant barriers in clinical trials limited by the systemic toxicity of such approaches. Using a mouse model humanized for both Fc receptors and CD40, we previously demonstrated enhanced antitumor activity with an Fc-modified antibody. We now demonstrate that this model recapitulates the platelet and hepatic toxicities seen with anti-CD40 antibodies in patients, providing a predictive measure of the dose-limiting activity of this approach. We further show that such toxicity can be circumvented and durable systemic antitumor immunity achieved by intratumoral delivery of an Fc-engineered anti-CD40 agonistic antibody.
