Using mice lacking cDC1s, Salomon and Rotem et al. showed that CD40 agonist antibodies must engage cDC1s to mediate antitumor activity, whereas macrophages, platelets, and monocytes, but not cDC1s, mediate toxicity. BsAbs created with enhanced FcγRIIB binding that coupled variable domains specific for CD11c, DEC-205, or CLEC9A with that of the anti-human CD40 Ab Selicrelumab were shown to preferentially activate CD40+ DCs. In a mouse model humanized for CD40 and FcγRs that recapitulates both antitumor and toxicity responses of human CD40 mAbs, bsAbs had an improved safety profile and potent antitumor activity, and synergized with anti-PD-1.
Contributed by Paula Hochman
ABSTRACT: Therapeutic use of agonistic anti-CD40 antibodies is a potentially powerful approach for activation of the immune response to eradicate tumors. However, the translation of this approach to clinical practice has been substantially restricted due to the severe dose-limiting toxicities observed in multiple clinical trials. Here, we demonstrate that conventional type_1 dendritic cells are essential for triggering antitumor immunity but not the toxicity of CD40 agonists, while macrophages, platelets and monocytes lead to toxic events. Therefore, we designed bispecific antibodies that target CD40 activation preferentially to dendritic cells, by coupling the CD40 agonist arm with CD11c-, DEC-205- or CLEC9A-targeting arms. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody while triggering potent antitumor activity. We suggest such cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of anti-CD40, and of additional types of agonistic antibodies used for cancer immunotherapy.
Author Info: (1) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Immuno
Author Info: (1) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (4) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (7) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (8) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. rony.dahan@weizmann.ac.il.
