Background BT7480 is a novel, synthetic Bicycle tumor-targeted immune cell agonist^® (Bicycle TICA^®) comprising 3 bicyclic peptides, 1 targeting Nectin-4 and 2 targeting CD137. Nectin-4 and CD137 are overexpressed in many cancers; CD137 is also expressed on activated immune cells. Simultaneous binding of Nectin-4 and CD137 induces complete tumor regression and resistance to tumor re-challenge in preclinical models.¹ A phase 1/2 study (NCT05163041) is evaluating BT7480 ± nivolumab in patients with Nectin-4 associated advanced solid tumors. Here we present a comprehensive clinical biomarker analysis of patients treated with BT7480 monotherapy, to explore the immune effects downstream of CD137 agonism and to assess the translation of preclinical pharmacodynamics to patients.

Methods Adult patients with advanced solid tumors associated with Nectin-4 expression and refractory to or ineligible for standard therapy were included in this 3+3 monotherapy dose escalation study. Biomarker analyses were primarily exploratory endpoints; receptor occupancy status was a secondary endpoint. Tumor samples were collected at baseline for analysis of target molecules by immunohistochemistry and multiplex immunofluorescence. Peripheral blood samples were collected pre-and post-dose to assess CD137 receptor occupancy by flow cytometry. Immune-related pharmacodynamic (PD) markers were assessed by Olink, NanoString, and flow cytometry assays.

Results As of April 29, 2024, 40 patients had received BT7480 monotherapy (0.002–3.5 mg/kg weekly IV). At baseline, >75% of patients (n=33 evaluable) had tumors that were Nectin-4+; >60% (n=30 evaluable) were both Nectin-4+ and CD137+, including non-small cell lung, bladder, head and neck, and cervical cancers. CD137 receptors in the blood were fully occupied by BT7480 at doses ≥0.15 mg/kg. NanoString analysis of circulating immune cells demonstrated that administration of BT7480 led to immune cell reprogramming, promoting the expression of immune activation genes and the downregulation of immunosuppressive genes. Furthermore, transient and robust induction of soluble CD137, CXCL9, and CD4 T-cell activation markers in patient blood samples were observed within the first 2 cycles (8 weeks), with maximal PD signal observed following BT7480 doses of 1.3–3.5 mg/kg.

Conclusions Clinical biomarker findings in this study were consistent with preclinical observations. Collectively, these data indicate that BT7480 is a pharmacologically active CD137 agonist that induces innate and adaptive immune activation. These data support the continued development of BT7480 in patients with Nectin-4 associated solid tumors, with the potential for future clinical use in combination with checkpoint inhibitors.

Acknowledgements This study was sponsored by BicycleTx Ltd. Writing assistance was provided by Tamara Fink, PhD, and Rebecca L. Crepeau, PhD, of Fishawack Communications Ltd, part of Avalere Health, funded by BicycleTx Ltd.

Trial Registration NCT05163041

Reference

1. Hurov K, Lahdenranta J, Upadhyaya P, et al. BT7480, a novel fully synthetic bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™) induces localized CD137 agonism. J Immunother Cancer 2021;9:e002883.

Ethics Approval The protocol was approved by the independent ethics committees and institutional review boards of the participating centers.