Paper

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Mockridge, Ian, Martennson, Linda, Griffiths, Jordana, Smith, Hannah L, Penfold, Chris, English, Vikki, Cragg, Mark S, Hussain, Khiyam, French, Ruth R, Al-Shamkhani, Aymen, Teige, Ingrid, Tutt, Alison L, Cox, Kerry, Kim, Jinny, Chan, Claude Ht, Semmrich, Monika, Inzhelevskaya, Tatyana, Sanders, Theodore, Frendeus, Bjorn, Glennie, Martin J, Willoughby, Jane E

2020

Overview

Previous data suggests that anti-OX40 mAb can elicit anti-tumour effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. The contributions of these different effector mechanisms has not previously been systematically evaluated, particularly for mAb directed to human OX40. Therefore, we generated a novel human OX40 knock-in (KI) mouse to evaluate a panel of anti-hOX40 mAb and show that their activities relate directly to two key properties: 1) isotype; with mIgG1 mAb evoking receptor agonism and CD8+ T cell expansion and mIgG2a mAb evoking deletion of Treg and; 2) epitope; with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumour models by engaging these different mechanisms. These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T cell expansion or Treg depletion might be preferable according to the composition of different tumours. Competing Interest Statement MSC is a retained consultant for BioInvent International and has performed educational and advisory roles for Baxalta and Boehringer Ingleheim. He has received research funding from Roche, Gilead, Bioinvent International and GSK. BF, IT, LM and MS are employees of Bioinvent International.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: CD8 antigen / Epitopes / Immunology / Isotypes / Lymphocytes T / Monoclonal antibodies / Tumor necrosis factor / Tumors