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

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.

虽然抑制性Fcγ受体（FcγR）IIB的结合对于激动性小鼠抗CD40单克隆抗体（mAbs）的体内抗肿瘤活性是绝对必要的，但对于人源单克隆抗体是否有类似要求一直存在争议。通过使用其FcγR和CD40人源化的小鼠模型，我们发现FcγRIIB的结合对于人源CD40单克隆抗体的活性至关重要，而激活型FcγRIIA的结合会抑制这种活性。通过改造Fc变体，使其选择性地增强与FcγRIIB的结合，而不与FcγRIIA结合，观察到抗肿瘤免疫显著提高。这些发现强调了通过使用能准确反映人FcγR独特亲和力和细胞表达的合适临床前模型来优化此类治疗性抗体Fc结构域的必要性。