Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane. In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists. Thus, the membrane distal CRD1 provides a region of choice for selecting CD40 agonists while CRD2-4 provides antagonistic epitopes.

中文翻译：

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表位特异性和同种型之间的复杂相互作用决定了抗人CD40抗体的生物学活性。

促进或抑制受体功能的抗CD40单克隆抗体（mAb）有望作为癌症和自身免疫的治疗剂。但是，缺乏管理其各种功能范围的规则。在这里，我们确定了9个hCD40 mAb的特征，这些hCD40 mAb参与了整个CD40细胞外区域中表现为不同同种型的表位。当超交联时，所有mAb形式都是强激动剂。然而，只有那些结合膜远端富半胱氨酸结构域1（CRD1）的分子才具有与生理学Fcγ受体交联或作为人类免疫球蛋白G2同型的激动活性。当表位靠近膜时，激动活性降低。另外，所有结合CRD2-4的mAb都阻断CD40配体相互作用，并且是有效的拮抗剂。因此，