Abstract 1883: Mechanism of action and biomarker strategy for HFB200301, an anti-TNFR2 agonist antibody for the treatment of cancer

Abstract

Despite the success of immune check point inhibition, identification of other pathways capable of modulating the immune response against the tumor remains challenging. T-cell co-stimulation has been investigated with limited clinical success so far due in part to the fine tuning required for agonist antibodies against those co-stimulatory receptors and to the lack of biomarkers to facilitate the selection of patients likely to benefit from T-cell co-stimulation. TNFR2 belongs to the TNFR family of costimulatory molecules, and its expression on tumor infiltrating lymphocytes across a wide range of tumors make it an attractive target for T-cell co-stimulation. Recently, we identified HFB200301, an anti-TNFR2 antibody with Fc-independent agonist activity that does not block TNFR2 interaction with TNFα. HFB200301 activates CD4+, CD8+ T cells, and NK cells in vitro. In vivo, HFB200301 demonstrated potent single agent anti-tumor activity in syngeneic tumor models and can further increase the antitumor activity in combination with PD-1 blockade. To understand the immunological basis for the anti-tumor efficacy of HFB200301, we investigated the pharmacodynamic effects of HFB200301 in syngeneic mouse tumor models, including immuno-phenotyping and receptor occupancy of tumor infiltrating cells. In hTNFR2 knock-in mice bearing MC38 tumors, HFB200301 induces expansion of CD4+ and CD8+ T cells, and NK cells in the tumor micro-environment without affecting regulatory T cell numbers. We also demonstrate that the anti-tumor efficacy of HFB200301 is correlated with receptor occupancy and circulating soluble TNFR2 in a dose-dependent manner in this model. To discover predictive biomarkers of response to HFB200301, we used primary tumor samples and our proprietary Drug Intelligent Science (DIS™) single-cell platform to establish an immune-related signature. Single-cell RNA sequencing and clonotype barcoding of ex-vivo tumor cultures treated with HFB200301 were used to identify unique T cell profiles with a T cell centric gene panel. These unique T cell profiles may help identifying patients more likely to respond to HFB200301 treatment. In summary, HFB200301 exhibits a unique mechanism of action mainly relying on its agonistic activity on several effector cell types in tumor micro-environment that we expect will benefit a patient population selected with a unique biomarker signature. HFB200301 is currently in preclinical development and a biomarker-driven Phase 1 clinical study is projected for 2021. Citation Format: Shuo Wei, Ross Fulton, Yun-Yueh Lu, Qian Zhang, He Zhou, Andreas Raue, Mingjie Chen, Wenhua Xu, Xing Cai, Juliana Crivello, Zachary Duda, Zhiyuan Wang, Rebecca Silver, Alexandra Staskus, Charina Ortega, Sami Ellouze, Carine George, Sophie Foulon, Dean Lee, Monika Manne, Nicola Beltraminelli, Jinping Gan, Francisco Adrian, Liang Schweizer, Jennifer Watkins-Yoon. Mechanism of action and biomarker strategy for HFB200301, an anti-TNFR2 agonist antibody for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1883.

Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives

“…Using human TNFR2 knock-in mouse models, it was suggested that HFB200301 could stimulate anti-tumor responses through expansion of effector T cells and NK cells without depleting the Tregs. The agonistic ability of the antibody was found to be independent of FcγR mediated cross-linking ( 146 ). Although much of the data is not yet mature, with peer review lacking for most of the pre-clinical studies, the potential of TNFR2 targeting antibodies in oncology are exciting and the initial results from clinical trials are eagerly awaited by the immuno-oncology community.…”

Therapeutic potential of TNFR2 agonists: a mechanistic perspective

“…This effect of TNFR2 agonism has shown to be pathological-relevant, as TNFR2 is expressed by tumor-infiltrating Tcon cells ( 89 , 91 – 93 ) and proinflammatory subsets of CD4 Tcon cells ( 94 , 95 ), suggesting that TNFR2 agonists could induce the activation of TNFR2 signal in Tcon cells in tumor and inflammatory diseases. In the mouse tumor model, it was reported that TNFR2 agonistic antibodies induced the expansion of CD4 + Tcon cells without affecting the Treg number in vivo ( 58 ). Therefore, Tcon cells are also a potential target of TNFR2 agonists albeit with relatively lower TNFR2 expression.…”

“…The antitumor effect of TNFR2-targetingantibody (Y9) can be impaired by the depletion of NK cells, suggesting that TNFR2 agonists may also target the NK cells to elicit antitumor immune responses ( 54 ). Now several TNFR2-stimulating antibodies in clinical development have been reported to enhance NK cell activation ( 58 , 73 ). However, the mechanism that how TNFR2 agonism affects tumor-infiltrating NK cells remains to be investigated.…”

“…Both humanized TNFR2 antagonists and agonists have been developed for the treatment of tumors ( 19 , 110 ), based on the notion that antagonistic antibodies may eliminate the immunosuppressive Tregs, while antibodies that trigger TNFR2 signaling may activate CD8 CTLs and NK cells ( 54 , 56 – 58 , 72 ). Despite the assumptions are opposite, the results of the studies appear to support that TNFR2 antagonistic antibodies inhibit the tumor infiltration of Tregs and consequently enhance the antitumor immune responses ( 111 – 119 ), while antibodies that trigger the TNFR2 signal in vitro also elicited antitumor immune responses ( 54 , 56 – 58 , 72 ). It was shown that TNFR2 activation promotes the differentiation and the production of effector cytokine by CD8 T cells ( 96 , 120 ).…”

Targeting TNFR2 in Cancer: All Roads Lead to Rome

“…HFB200301 is a first-in-class agonistic anti-TNFR2 agonist antibody that binds potently and selectively to TNFR2, which demonstrates potent antitumor activity alone and in combination with anti-PD-1. HFB200301 activates CD4+, CD8+ T cells, and NK cells in vitro and induces expansion of CD4+ and CD8+ T cells and NK cells in the TME without affecting regulatory T cells numbers in vivo ( 64 ). Another TNFR2 agonist antibody is MM-401, which shows T-cell co-stimulation and robust antitumor activity and immune memory in a mouse.…”