Approach

An entirely new class of therapies

Based on groundbreaking work conceived in the laboratory of Sir Greg Winter with the help of Professor Christian Heinis, we are pioneering the development of bicyclic peptides, or Bicycles^® – a novel class of versatile, chemically synthesized medicines. Bicycles are fully synthetic short peptides constrained to form two loops which stabilize their structural geometry. This constraint is designed to confer high affinity and selectivity, and the relatively large surface area presented by the molecule allows targets to be drugged that have historically been intractable to non-biological approaches. Bicycles represent a unique therapeutic class, combining the pharmacological properties normally associated with a biologic with the manufacturing and pharmacokinetic advantages of a small molecule, yet with no signs of immunogenicity observed to date.

To achieve a therapeutic effect while minimizing undesired effects on other proteins and physiological functions, drugs must bind to target proteins with high affinity and selectivity. We have designed our molecules to be highly constrained by linking a chemical connector compound, also known as a scaffold, to particular amino acids in the peptide chain. The resulting cyclized molecule, which we refer to as a Bicycle, is locked in the preferred state to bind to the target proteins. Their small size and exquisite tumor targeting are designed to deliver rapid tumor penetration and retention, while clearance rates and routes can be tuned to minimize exposure of healthy tissue and bystander toxicities.

Key properties of Bicycles

Short peptides consisting of nine to 15 amino acids
No immunogenicity observed to date
Chemically synthesized
Versatility for multimerization and conjugation
Low molecular weight (1.5-2kDa), delivering attractive PK and rapid tissue penetration
Classified as small molecules by regulatory agencies
Large molecular footprint allowing protein-protein interactions to be targeted
Scalable and controllable manufacturing using established methodologies
Renal elimination, minimizing potentially deleterious bystander cell interactions in liver and gut

Watch a video on how our approach works

A modular platform

Bicycles are highly versatile, allowing rapid assembly into more complex molecules.

Bicycles can be used to generate more complex molecules

Simple Bicycles: Bicycles can be used to modulate single targets as stand-alone therapeutics.

Tandems: Bicycles can be linked together as bi-specifics, which simultaneously bind to two different proteins to deliver dual pharmacology.

Trimers: Bicycles can be linked as multimeric Bicycles to bring together multi-subunit receptors or to deliver combinatorial pharmacology.

Tetramers: Bicycles can be further elaborated into tetravalent or higher valency multimeric Bicycles to deliver more complex pharmacology.

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Drug Conjugates: Our Bicycle conjugates are tripartite molecules that use a Bicycle to recognize and bind to a specific tumor antigen, a selectively cleavable linker only cleaved by enzymes within the tumor microenvironment and a small molecule payload. The linker and coupling chemistry hold the payload inert until the conjugate is localized in the tumor microenvironment, delivering payloads into solid tumors with extensive tissue penetration, a short duration of systemic exposure and liver-sparing rapid renal elimination. These properties limit the body’s exposure to payload to minimize any damage to normal tissue.

A unique screening platform

Our novel, proprietary phage display screening platform combines biology with chemistry. We use synthetic biology to display a substantial diversity (quadrillions) of linear peptides on the surface of engineered bacteriophage (phage) and chemistry to transform them into Bicycles. Phage can be harnessed to identify Bicycles by splicing DNA into the phage genome so that linear peptides encoding Bicycles are presented on the phage surface. Our founder Sir Greg Winter, a pioneer in phage display, applied this technology, adding a cyclization step that forms Bicycles from these linear peptides. As a result, we can rapidly select phage that bind to a chosen biological target and use evolution-driven, informed selection to derive optimum molecules.

Our proprietary Bicycle Screening Process

Our screening platform can be deployed to screen either soluble proteins or cell-based targets. In addition to being resource-efficient and rapid, the process uniquely uses an integral on-phage binding assay that informs structure activity relationships. We can incorporate a broad range of small molecule scaffolds into Bicycles to increase diversity and confer differentiated physicochemical and structural properties.

This screening process self-selects for Bicycles that are amenable to attachment – commonly referred to as conjugation – to other molecular payloads such as cytotoxins, innate immune activators or other Bicycles. Bicycles can be linked together with synthetic ease to create complex molecules with combinatorial pharmacology. Alternatively, Bicycles in the form of multimers can also be used as standalone therapeutics, including those that we are exploring in our T-cell modulator program. We believe that the flexibility of our Bicycles and our powerful screening platform allow new therapeutics to be rapidly conceived and reduced to practice to potentially serve diverse therapeutic applications across a wide range of indications.

Bicycles can be readily identified to drug a wide spectrum of targets and target classes, including many that have so far been undruggable with small molecules, such as protein-protein interactions.

A breadth of therapeutic opportunities

To leverage the broad applicability of Bicycles, we have entered into several collaborations outside of our internal focus in oncology. These strategic partnerships, each with collaborators that have deep therapeutic expertise, are based on the broad applicability of the proprietary Bicycle platform and its ability to address a wide variety of targets. These partnerships enhance our ability to bring this important class of medicines to patients with debilitating diseases besides cancer.

Learn more about our oncology pipeline and our activities beyond oncology.

our pipeline

beyond oncology