Abstract 4538: A safe and potent agonist ADG106 targeting a unique epitope of CD137 with novel mechanism of actions

Abstract

Abstract Antagonist antibodies targeting immune checkpoint co-inhibitory receptor such as PD-1/PD-L1 have achieved great clinical success in cancer immunotherapy. However, agonistic antibodies targeting the co-stimulatory T cell receptors in the TNFR superfamily, and CD137 in particular, has suffered significant setback due to either dose-dependent severe liver toxicity by Urelumab, or modest clinical anti-tumor activity by Utomilumab. ADG106, a safe and potent antibody targeting a unique epitope of CD137, is shown to hold the great promise to achieve much better efficacy and safety profile for immunotherapy in preclinical and phase 1 studies. ADG106, a fully human agonistic anti-CD137 IgG4 mAb, binds to a unique and conserved epitope with multiple cross-species reactivity, and overlaps with CD137 ligand binding site. This unique antibody acts in a novel mechanism with the following attributes: 1) it agonizes CD137 in a natural ligand-like fashion; 2) it blocks ligand to disable its reverse signaling; 3) it exhibits strong but specific Fc receptor mediated crosslinking in comparison with Utomilumab. ADG106 shows robust dose-dependent single agent anti-tumor activity in multiple syngeneic mouse tumor models and induces durable antigen-specific memory immunity that protects animals from the same re-challenged tumor cells. Consistent with the preclinical observations, ongoing phase I trial shows that the same antibody, ADG106, is well-tolerated in cancer patients in dose escalation from 0.03 to 3 mg/kg; and it also shows single agent activity on circulating T cell activation and clonal expansion in anti-tumor activity. Furthermore, ADG106 has also induced complete remission of the liver metastatic lesion in a lymphoma patient at 1mg/kg dose. Preclinical studies demonstrate that ADG106 enhances activation and inflammatory cytokine release of primed T cells alone or together with other immunomodulatory agents in vitro, as well as exhibits synergistic in vivo anti-tumor activity in combination with variety of other cancer therapies, including checkpoint inhibitors, chemotherapies and targeted agents. Mechanistic analyses suggest that ADG106 stimulates tumor infiltration and expansion of CD4+ and CD8+ T cells, thereby promoting the antitumor responses. These findings support that ADG106-boosted immune response could offer an effective but alternative solution for cancer immunotherapy in single and combination therapies, especially for non-responders to current PD-1/PD-L1 based immunotherapies. Citation Format: Guizhong Liu, Felix Du, Xiaohong She, Yi Zhu, Anthony W. Tolcher, Peter Luo. A safe and potent agonist ADG106 targeting a unique epitope of CD137 with novel mechanism of actions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4538.