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Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective Fc?R Engagement.

ABSTRACT: While engagement of the inhibitory Fc?-receptor (Fc?R) 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 Fc?Rs and CD40, we revealed that Fc?RIIB engagement is essential for the activity of human CD40 mAbs, while engagement of the activating Fc?RIIA inhibits this activity. By engineering Fc variants with selective enhanced binding to Fc?RIIB, but not to Fc?RIIA, 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 preclinical models that accurately reflect the unique affinities and cellular expression of human Fc?R.

SUBMITTER: Dahan R

PROVIDER: S-EPMC4975533 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Dahan Rony R Barnhart Bryan C BC Li Fubin F Yamniuk Aaron P AP Korman Alan J AJ Ravetch Jeffrey V JV

Cancer cell 20160602 6

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 human CD40 mAbs, while engagement of the activating FcγRIIA inhibits this activity. By engineering Fc variants with selective enhanced binding ...[more]

PMID: 27265505

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Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies.

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Project description:Despite the clinical success of checkpoints inhibitors, a significant gap still exists in our understanding of their in vivo mechanism of action, thus limiting the rational development of next generation agents. Amongst these, anti-CTLA-4 antibodies were originally developed to block inhibitory signals into activated effector T cells. However, several recent studies have demonstrated that depletion of regulatory T cells expressing high levels of CTLA-4 is critical to anti-CTLA-4 anti-tumor activity. Whereas the mechanism of action remains controversial, the emerging data support clinical development of new antibodies with enhanced killing activity. Here, using single-cell RNA sequencing in in vivo and in vitro mouse models, we sought to dissect the impact of anti-CTLA-4 blocking, Treg depleting, and FcR engaging activity on the immune responses within tumors. We observed a rapid remodeling of the innate immune landscape as early as 24-hours post-treatment. Immune remodeling was driven mainly by FcγR-engagement, and not by Treg depletion or CTLA-4 blockade, and included reduction of suppressive macrophages and activation of type-I interferon signaling. Our findings indicate that FcγR engagement and innate immune remodeling are involved in successful anti-CTLA-4 treatment, supporting further development of optimized immunotherapy agents with these features.

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2021-12-12 | GSE184009 | GEO

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Agonistic anti-CD40 induces thyrocyte proliferation and promotes thyroid autoimmunity by increasing CD40 expression on thyroid epithelial cells.

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| S-EPMC3622184 | biostudies-literature

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