Programs

Immuno-Oncology

Introduction

Exploring the potential for Bicycles to activate the body’s immune response in ways not possible with existing treatments, and improve patient outcomes in cancer.

Strategies that activate T and NK (“natural killer”) cells, which form part of the body’s normal immune response, have been observed to improve patient outcomes in cancer. We believe Bicycles, as synthetic small molecules, potentially represent a paradigm shift in targeting these cell types as they may confer several advantages over existing modalities – namely their small size, modularity for conjugation and favorable pharmacokinetics. The modular nature of Bicycles allows us to rapidly generate agonists of immune cell receptors, for example CD137, and to direct these agonists by coupling them to tumor cell antigen targeting Bicycles. These Bicycle® immune cell agonists are designed to better enable combination therapy and may circumvent many of the limitations of existing antibody and biologic therapies, such as liver and gastrointestinal toxicities.

We have identified potent Bicycle agonists of multiple tumor necrosis factor (or TNFR family) receptors, including CD137 – a receptor that activates T cells, and other immune cell types, to better enable combination therapy.

In preclinical studies, we have linked these TNFR binding Bicycles to a range of tumor antigen targeting Bicycles to construct Bicycle tumor-targeted immune cell agonizing molecules. We have observed these Bicycle TICA™ molecules agonize the CD137 receptor only in the vicinity of cells that express the associated tumor antigen, effectively converting the tumor cell into the equivalent of an antigen presenting cell.

Bicycle is advancing two novel candidates: BT7480, a Nectin-4/CD137 Bicycle TICA; and BT7455, an EphA2/CD137 Bicycle TICA. BT7480 entered the clinic in November 2021 and BT7455 is progressing through preclinical development. Bicycle also has a strategic collaboration with Genentech to potentially discover, develop and commercialize novel Bicycle-based immuno-oncology treatments.

BT7480

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BT7480 (Nectin-4/CD137 Bicycle TICA™)

In preclinical models, Nectin-4/CD137 Bicycle® TICAs have shown powerful anti-tumor activity

BT7480 is a novel, fully synthetic Bicycle tumor-targeted immune cell agonist® (Bicycle TICA™) that contains three Bicycles. One targets Nectin-4, a cell adhesion molecule from the Nectin and Nectin-like family shown to be overexpressed on the surface of tumor cells. The others bind to and agonize CD137, a member of the TNFR family involved in the activation of several immune cell types, including T cells and NK cells.

In preclinical models, Nectin-4/CD137 Bicycle TICAs have shown powerful anti-tumor activity, enabled by potent and tumor antigen dependent CD137 agonism.

BT7480 is currently being evaluated in a Company-sponsored Phase I/II clinical trial, with plans to evaluate BT7480 in combination with nivolumab.

Bicycle strategy

We have engineered our novel and proprietary Bicycle® TICAs with features that may in the future overcome the limitations of other immuno-oncology approaches, such as hepatoxicity, long half-life and immunogenicity. These beneficial characteristics may induce robust CD137-mediated and tumor-localized efficacy in a manner that introduces immunogenic memory. The modular nature of the Bicycle technology allows us to quickly generate fully synthetic Bicycles that link immune-agonizing molecules to a tumor target, which could pave the way for a future of next-generation non-biologic immune cell engaging immunotherapies.

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BT7455

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BT7455 (EphA2/CD137 Bicycle TICA™)

In preclinical models, BT7455 exhibits highly potent EphA2-dependent stimulation of CD137 and robust in vivo anti-tumor activity.

BT7455 is a novel, fully synthetic EphA2/CD137 targeting Bicycle TICA™. EphA2 (or Ephrin type-A receptor 2) is a member of the Ephrin superfamily of receptor tyrosine kinases; and CD137 is a member of the TNFR family involved in the activation of several immune cell types, including T cells and NK cells.

In preclinical models, BT7455 exhibits highly potent EphA2-dependent stimulation of CD137 and robust in vivo anti-tumor activity against EphA2 expressing tumors.

Bicycle strategy

We have engineered our novel and proprietary Bicycle TICAs with features that may in future overcome the limitations of other immuno-oncology approaches, such as hepatoxicity, long half-life and immunogenicity. These beneficial characteristics may induce robust CD137-mediated and tumor-localized efficacy in a manner that introduces immunogenic memory. The modular nature of Bicycle technology allows us to quickly generate fully synthetic Bicycles that link immune-agonizing molecules to a tumor target, which could pave the way for a future of next-generation non-biologic immune cell engaging immunotherapies.

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BT7401

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BT7401 (Systemic CD137 Agonist)

Cancer Research UK’s Centre for Drug Development is funding and sponsoring development of BT7401 through to a Phase I/IIa clinical study.

BT7401 is a novel, fully synthetic, multivalent, agonistic Bicycle® built from multiple CD137 monomeric Bicycles connected by stable linkers through a central hinge.

Existing antibody approaches to agonize CD137 have demonstrated robust and durable anti-tumor effects in patients, but treatments have been limited by severe hepatotoxicity observed in clinical trials.

BT7401 has shown significant pharmacologic activity in preclinical models and no hepatotoxicity was seen in early preclinical toxicology studies. These findings indicate BT7401 may offer an improved therapeutic index when compared to antibody-based approaches.

Cancer Research UK’s Centre for Drug Development is funding and sponsoring development of BT7401, which is currently in pre-clinical development, through to a Phase I/IIa clinical study. This collaboration aims to further characterize the clinical activity and therapeutic potential of BT7401.

Bicycle strategy

Therapies that activate cytotoxic T cells, a type of cell used in a body’s immune response, have been observed to improve outcomes in cancer. However, prolonged immune activation can have adverse consequences and may lead to T cell exhaustion or anergy. This extended immune activation has often been observed with long half-life antibodies and biologics, some of which are used clinically. We believe the highly differentiated properties of Bicycles may allow us to develop molecules with better-tailored pharmacokinetic and pharmacodynamic profiles, avoiding the deficiencies of existing therapies.

CD137 agonism is a well-validated mechanism in immuno-oncology that could yield expanded options for patients who need rescue from checkpoint inhibitor failure or who cannot be treated with that class of therapies. BT7401 represents a unique, fully synthetic approach to CD137 agonism that could in future offer improved safety and anti-tumor activity over antibody-based approaches.

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IO Programs

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Immuno-Oncology

Introduction

BT7480 (Nectin-4/CD137 Bicycle TICA™)

BT7455 (EphA2/CD137 Bicycle TICA™)

BT7401 (Systemic CD137 Agonist)

Undisclosed IO Programs

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