Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement

Abstract

Summary While engagement of the inhibitory Fcγ-Receptor (FcγR) IIB is an absolute requirement for in vivo antitumor activity of agonistic mouse anti-CD40 monoclonal antibodies (mAbs), a similar requirement for human mAbs has been disputed. By using a mouse model humanized for its FcγRs and CD40, we revealed that FcγRIIB-engagement is essential for the activity of the human CD40 mAbs, while engagement of the activating FcγRIIA inhibits this activity. By engineering Fc variants with selective enhanced binding to FcγRIIB, but not to FcγRIIA, significantly improved antitumor immunity was observed. These findings highlight the necessity of optimizing the Fc domain for this class of therapeutic antibodies by using appropriate pre-clinical models that accurately reflect the unique affinities and cellular expression of human FcγR.

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

“…Recent work has shown that engineering CP-870,893 with an IgG1 Fc domain, to enhance binding to FcγRIIB, can improve the potency of CP-870,893 as measured by its ability to invoke antigen-specific T cell immunity in a novel humanized mouse model [31]. FcγRIIB is the only inhibitory Fc receptor and variations in the gene encoding this protein have long been associated with susceptibility to autoimmune disease [32].…”

“…While FcγRIIB polymorphisms are known [32], whether these variations will have therapeutic implications for the translation of IgG1-modified CD40 agonists is presently unclear. In addition, the enhanced potency of IgG1 CD40 agonists seen in murine models is associated with an increased capacity to produce transient thrombocytopenia[31]. Reducing the dose of the Fc-modified CD40 agonist, though, was found to diminish the level of thrombocytopenia while still maintaining improved agonist activity compared to the IgG2 isotype [31].…”

Inhibitory IgG Receptor-Expressing Cells: The Must-Have Accessory for Anti-CD40 Immunomodulatory mAb Efficacy

“…This discrepancy might rely on the expression pattern of hFcgRIIB versus activating hFcgRs in vivo compared to cell lines, in conjunction with the superior capping abilities of the FcgRIIB1 isoform (Figure 1). Interestingly, the use by Dahan and colleagues (Dahan et al, 2016) of similar mutants of two other anti-CD40 mAbs binding different hCD40 epitopes (CD40.1 and CD40.2 clones) indicated that the FcgR-independent agonistic activity of anti-CD40 mAbs is not related to the ability of the mAbs to compete with CD40 ligand (CD40L) binding, as previously suggested (Richman and Vonderheide, 2014).…”

“…In this issue of Cancer Cell, Dahan and colleagues (Dahan et al, 2016) describe an elegant pre-clinical model to study the mechanism underlying the agonistic effect of anti-human CD40 mAbs. They used transgenic mice that expressed both human CD40 and human FcgRs: hFcgRI, hFcgRIIAH 131 variant (the only hFcgR to markedly bind IgG2; Bruhns et al, 2009), hFcgRIIB, hFcgRIIIA (F 158 variant), and hFcgRIIIB.…”

CIMT 2016: Mechanisms of efficacy in cancer immunotherapy — Report on the 14th Annual Meeting of the Association for Cancer Immunotherapy May 10–12 2016, Mainz, Germany

“…Dahan described the development of a mouse model fully humanized for its FcγRs and CD40. Using this model, they were able to appropriately assess the activity of human CD40 agonistic Abs by considering both its Fab- and Fc-mediated mechanisms 43 . They discovered that the antitumor activity of the human IgG, including the IgG2 subclass, depends on FcγRIIB-engagement.…”