BT7480

PK and PD analyses will be performed to support dose escalation decisions and to further the understanding of safety and clinical activity signals as a result of treatment with BT7480. This study is actively recruiting.

The first molecule of this class, BT7480, a Nectin-4-dependent CD137 (4-1BB) agonist, entered clinical trials in 2021 in patients with solid tumors associated with Nectin-4 expression...The kinetics and extent of the immune microenvironment modulation differentiated BT7455 from both a checkpoint inhibitor (anti-mouse PD-1) as well as an anti-CD137 agonist antibody (urelumab analogue)...Cancer Res 2020; 80:5300 4Xiao, et al. J Hematol Oncol 2020; 13:114.

1 The first molecule of this class, BT7480, a Nectin-4-dependent CD137 (4-1BB) agonist, entered clinical trials in 2021 in patients with solid tumors associated with Nectin-4 expression...The kinetics and extent of the immune microenvironment modulation differentiated BT7455 from both a checkpoint inhibitor (anti-mouse PD-1) as well as an anti-CD137 agonist antibody (Urelumab analogue)...Conclusions BT7455 is a highly potent EphA2 expression-dependent CD137 agonist with optimal target binding, pharmacologic, and pharmacokinetic properties that enable intermittent dosing for curative effect through modulation of the tumor immune microenvironment in syngeneic mouse models. BT7455 is currently being evaluated in IND-enabling safety studies.

Cohorts 1 and 2 have been completed without DLT. Enrollment in cohort 3 began in January 2022.

The optimized method and dose-dependent detection of CD137+ cells and RO by BT7480 was further verified in unstimulated lung cancer patient whole blood samples (n=5). Results from this study represent the first report of a clinic-ready CD137 RO assay and the first flow cytometry assay using fluorescently labelled Bicycle® reagents and demonstrate the utility of the Bicycle® CD137 RO assay to monitor target engagement in the BT7480 first-in-human clinical trial.

P1/2, N=200, Recruiting, BicycleTx Limited

A subset of CD137+ cells (32.7%) were found to be deeply tumor penetrant and within close proximity of Nectin-4+ tumor cells across all indications tested. Conclusions Results from this study support prioritization of indications for BT7480 clinical development and the utility of the MultiOmyx™ assay to monitor Nectin-4 and CD137 expression and to demonstrate proof-of-mechanism for the BT7480 FIH clinical trial expected to start in 2H-2021.

This is distinct from the reported clinical behavior of checkpoint inhibitors. In summary, BT7480 is a novel Nectin-4/CD137 TICA that represents a new generation of chemically synthetic tumor antigen targeted CD137 agonists and the compound is currently in preclinical development.

Akin to our findings with transcriptional profiling of the tumor response to BT7480, BCY11864 activity was shown not to be limited to T cells but also included other CD137 positive cell populations such as myeloid and NK cells. We hypothesize that tumor targeted CD137 agonism may lead to initial myeloid cell response that enhances the cytotoxic T cell recruitment and activation in the tumor tissue.

Further dose-range finding and safety analysis in NHPs is currently ongoing. BT7480 represents a new generation of chemically synthetic tumor antigen targeted 4-1BB agonists.