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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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