Title: Exploratory development of BT7401 a CD137 agonist multivalent bicyclic peptide for a FIH clinical trial
Funder: Cancer Research UK

Abstract: Background: Checkpoint inhibitors, e.g. anti-PD-1, remove brakes on exhausted anti-tumor responding T cells and have been successful in specific tumor types. A major unmet need in immuno-oncology is to prevent or rescue checkpoint failures. CD137 fills a complementary role to checkpoint inhibitors as it activates both cytotoxic T-cells and natural killer (NK) cells, innate lymphocytes that participate in immunologic cancer surveillance. Bicycles represent a differentiated approach to target these anti-tumor cells that may confer several advantages over existing modalities due to the multivalent and pharmacokinetic characteristics of Bicycles. Our Bicycle candidates are designed to circumvent the limitations of monoclonal antibody therapies, such as liver effects and limited efficacy, and to better enable combination therapy. We have identified potent Bicycle activators of CD137 - a receptor that activates T-cells and NK cells. Our multimeric CD137 candidates offer a completely different pharmacologic approach, that does not include reactive Fc domains and provides intermittent CD137 receptor stimulation that better replicates natural targeting while achieving substantial and lasting changes in memory and effector CD8+T-cells and other lymphocyte and monocyte populations in primate studies. Lead compound BCY8945 increases tumor infiltrating cytotoxic T-cells and anti-tumor activity in syngeneic and humanized mouse models. Only minor transient elevations in liver function tests were observed in primates, unlike the dose limiting effects seen in the clinic with CD137 antibodies. Aims: Partner with Cancer Research UK to: 1) employ the strong translational capabilities in the CR-UK network to complete preclinical research, including e.g. establishing an assay to set a phase 1 starting dose and to enable various biomarker approaches 2) produce drug substance and patient vials for enabling toxicology, safety, and Phase 1/2a first-in-human (FIH) studies 3) oversee necessary toxicology and safety studies and file with MHRA to initiate FIH trials 4) complete FIH studies to define a regulatory pathway for full development in the UK and globally Methods: Cancer Research UK (with Bicycle Therapeutics assistance as requested) will determine appropriate studies and resources to conduct each development phase How the results of this research will be used: FIH studies are essential to establish the initial safety, PK, dosing and proof-of-concept of a Bicycle-enabled approach to CD137 as an anti-cancer strategy. This study would enable full development options for the lead CD137 Bicycle candidate. In addition, the collaboration would leverage the expertise and resources of Cancer Research UK to characterize the CD137 mechanism and enable additional immune-oncology candidates.

Lay abstract: Background: Checkpoint inhibitors, e.g. anti-PD-1, remove brakes on exhausted anti-tumor responding T cells and have been successful in specific tumor types. A major unmet need in immuno-oncology is to prevent or rescue checkpoint failures. CD137 fills a complementary role to checkpoint inhibitors as it activates both cytotoxic T-cells and natural killer (NK) cells, innate lymphocytes that participate in immunologic cancer surveillance. Bicycles represent a differentiated approach to target these anti-tumor cells that may confer several advantages over existing modalities due to the multivalent and pharmacokinetic characteristics of Bicycles. Our Bicycle candidates are designed to circumvent the limitations of monoclonal antibody therapies, such as liver effects and limited efficacy, and to better enable combination therapy. We have identified potent Bicycle activators of CD137 - a receptor that activates T-cells and NK cells. Our multimeric CD137 candidates offer a completely different pharmacologic approach, that does not include reactive Fc domains and provides intermittent CD137 receptor stimulation that better replicates natural targeting while achieving substantial and lasting changes in memory and effector CD8+T-cells and other lymphocyte and monocyte populations in primate studies. Lead compound BCY8945 increases tumor infiltrating cytotoxic T-cells and anti-tumor activity in syngeneic and humanized mouse models. Only minor transient elevations in liver function tests were observed in primates, unlike the dose limiting effects seen in the clinic with CD137 antibodies. Aims: Partner with Cancer Research UK to: 1) employ the strong translational capabilities in the CR-UK network to complete preclinical research, including e.g. establishing an assay to set a phase 1 starting dose and to enable various biomarker approaches 2) produce drug substance and patient vials for enabling toxicology, safety, and Phase 1/2a first-in-human (FIH) studies 3) oversee necessary toxicology and safety studies and file with MHRA to initiate FIH trials 4) complete FIH studies to define a regulatory pathway for full development in the UK and globally Methods: Cancer Research UK (with Bicycle Therapeutics assistance as requested) will determine appropriate studies and resources to conduct each development phase How the results of this research will be used: FIH studies are essential to establish the initial safety, PK, dosing and proof-of-concept of a Bicycle-enabled approach to CD137 as an anti-cancer strategy. This study would enable full development options for the lead CD137 Bicycle candidate. In addition, the collaboration would leverage the expertise and resources of Cancer Research UK to characterize the CD137 mechanism and enable additional immune-oncology candidates.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS