Abstract A207: Utilizing human OX40 knock-in mice (HuGEMMTM) to assess antitumor efficacy of OX40-agonistic antibodies

Abstract

Abstract OX40 is a costimulatory molecule of TNF receptor family, primarily expressed on activated effector T cells and regulatory T cells. Engagement of OX40 by ligand leads to dramatic expansion, effector function, cytokine production, and survival of T cells. Several OX40-agonistic antibodies are in early stages of clinical development and some have shown promising antitumor immunity and improved tumor-free survival in the patients compared with standard-of-care therapies. Preclinical studies using surrogate OX40-agonistic antibodies have also shown robust tumor growth inhibition (TGI) efficacies, especially when combined with other checkpoint inhibitors like PD1 and CTLA-4 antibodies. However, we are lacking reliable preclinical models to assess the efficacy of human therapeutic antibodies. To address this need, we created a human OX40 knock-in GEMM (OX40 HuGEMM), where the entire 2.5 Kb mouse OX40 coding region is replaced by human OX40. We confirmed the expression of human OX40 in the 95% of activated T cells from the homozygous knock-in mice, while the mouse OX40 is completely eliminated. In the heterozygous knock-in mice, 58% of activated T cells express both mouse and human OX40. We then used both heterozygous and homozygous knock-in mice for efficacy studies of OX40 antibodies. In the heterozygous knock-in mice bearing MC38 syngeneic tumors, human and mouse OX40 antibody monotherapies led to 49% and 20% TGI, respectively, while their combination with PD1 antibody was synergistically effective, resulting in ~90% TGI with multiple complete tumor regressions. When we grafted the homozygous knock-in mice with B16F10 syngeneic tumors, single 5 mg/kg dose of an investigational human OX40 antibody led to 47% TGI. Tumor-killing efficacy of OX40 antibody is also correlated with significantly increased tumor infiltrated T cells and NK cells. Taken together, our OX40 HuGEMM provides an urgently needed tool for testing in vivo efficacy of human OX40 therapeutics, both as a single agent and as various combination strategies with other treatment modalities. Citation Format: Xuesong Huang, Lei Zheng, Wenyi Ouyang, Mingkun Zhang, Annie Xiaoyu An, Jing Zhao, Xiang Gao, Jean Pierre Wery, Qian Shi. Utilizing human OX40 knock-in mice (HuGEMMTM) to assess antitumor efficacy of OX40-agonistic antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A207.