Abstract
SummaryMonoclonal antibody (mAb) drugs that stimulate antitumor immunity are transforming cancer treatment but require optimization for maximum clinical impact. Here, we show that, unlike other immunoglobulin isotypes, human IgG2 (h2) imparts FcγR-independent agonistic activity to immune-stimulatory mAbs such as anti-CD40, -4-1BB, and -CD28. Activity is provided by a subfraction of h2, h2B, that is structurally constrained due its unique arrangement of hinge region disulfide bonds. Agonistic activity can be transferred from h2 to h1 by swapping their hinge and CH1 domains, and substitution of key hinge and CH1 cysteines generates homogenous h2 variants with distinct agonistic properties. This provides the exciting opportunity to engineer clinical reagents with defined therapeutic activity regardless of FcγR expression levels in the local microenvironment.
Highlights
Monoclonal antibodies that modulate immune responses are proving highly effective in cancer treatment, with increasing evidence that such responses can be harnessed to provide durable eradication of tumors (Hodi et al, 2010; Sliwkowski and Mellman, 2013; Topalian et al, 2012; Wolchok et al, 2013)
Promising clinical data are emerging with immunostimulatory Monoclonal antibody (mAb) that bind agonistically to the costimulatory receptor CD40 on antigen-presenting cells (APCs) (Beatty et al, 2011, 2013; Vonderheide and Glennie, 2013) with agents against a number of other costimulatory targets, such as 4-1BB (CD137), OX40 (CD134), and glucocorticoid-induced tumor necrosis factor receptorrelated protein (GITR), in clinical development (Moran et al, 2013)
Human immunoglobulin G (IgG) Isotypes and Anti-CD40 Activity To examine the effect of human constant regions on agonistic activity, we used the anti-human CD40 mAb ChiLob 7/4 (Chowdhury et al, 2014), currently in phase 1 clinical trial in cancer patients
Summary
Monoclonal antibodies (mAbs) that modulate immune responses are proving highly effective in cancer treatment, with increasing evidence that such responses can be harnessed to provide durable eradication of tumors (Hodi et al, 2010; Sliwkowski and Mellman, 2013; Topalian et al, 2012; Wolchok et al, 2013). Promising clinical data are emerging with immunostimulatory mAbs that bind agonistically to the costimulatory receptor CD40 on antigen-presenting cells (APCs) (Beatty et al, 2011, 2013; Vonderheide and Glennie, 2013) with agents against a number of other costimulatory targets, such as 4-1BB (CD137), OX40 (CD134), and glucocorticoid-induced tumor necrosis factor receptorrelated protein (GITR), in clinical development (Moran et al, 2013) These agonistic agents have the potential to enhance therapeutic efficacy of other anticancer mAbs, such as those directed against CD20 or epidermal growth factor receptor (EGFR). Only a minority of patients show durable responses to immunomodulatory agents, and a detailed understanding of Significance
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have