New modalities: Innovations in peptides as biotherapeutics 

What advantages can peptides as a drug modality offer over traditional small molecules or biologics?

At Bicycle Therapeutics we like to say that peptides sit in the ‘goldilocks zone’ between biologics and small molecules, because they embody advantageous properties of both. Features of biologics that are generally considered superior over small molecules include very high binding affinity and slow off rate, as well as exquisite selectivity. Peptides can also possess these attributes and, like biologics, are compatible with evolution-driven display technologies such as phage or DNA display, meaning that identification of novel binders can be miniaturised and facile.

On the other hand, due to their low molecular weight, small molecules benefit from efficient tissue penetration, ensuing that the drug can get to where it needs to be. Peptides share this positive feature of small molecules. In addition, like small molecules, peptides are chemically synthesised and amenable to medicinal chemistry optimisation, meaning that desirable drug-like properties can be designed in. Something unique to peptides is their rapid renal clearance, which can be beneficial when delivering toxic payloads, in the case of targeted cancer therapy, as it limits the exposure of healthy tissue to a damaging payload. If a longer half life is required to achieve a different pharmacology, this can also be engineered in.

What sort of biological targets are amenable to targeting with peptides or peptide drug conjugates?

Extracellular targets are the most accessible to peptides, given that most peptidic compounds are not passively cell permeable. Although this provides a vast pool of biologically important targets, many different approaches to widen the target space by accessing intracellular targets have been explored. For example, engineering the peptides themselves to be cell permeable by taking inspiration from the very few naturally occurring cell permeable peptides such as cyclosporin. Other approaches include appending vectors to allow delivery into cells, such as highly charged cell permeating peptides, or moieties that can hitch a ride on transporters.

Tell me a bit about your research in the field of peptides and peptide drug conjugates

I have been working as a medicinal chemist at Bicycle Therapeutics for almost 9 years, mostly focusing on the application of Bicycle® peptides in cancer therapy. In many of the approaches we have explored, the Bicycle peptide is used as a targeting vector to deliver cargo selectively to tumours and destroy them. This work involves engineering the Bicycle peptide to have the desired properties, such as high affinity for the target and good in vivo stability, and then matching this up with the right conjugate format and payload. I have worked on programs developing Bicycle Toxin Conjugates (BTC®), Bicycle tumour-targeted immune cell agonists (Bicycle TICA™), and Bicycle Radio Conjugates (BRC™), amongst others. I have had the privilege of seeing some of these compounds progress to clinical trials and bring us closer to our goal of having a positive impact on patients.

How did you get started in researching peptides or peptide drug conjugates

I became very interested in bioconjugation, biorthogonal chemistry and methods of peptide screening and modification during my PhD, which was focused on identification of peptide tool compounds to elucidate biological mechanisms. Ultimately I knew I wanted to pursue a career in drug discovery, and moving into the field of peptide drug conjugates seemed like a really neat way to combine all of these scientific interests and satisfy my desire to get new medicines to patients.

Where do you see the most exciting advances being made in the next 20 years in your field?

Peptides are showing incredible promise as ligands for targeted radiopharmaceuticals and are being touted as the superior modality for this approach. This exciting field has recently gained clinical and commercial validation and following a large volume of investment and collaboration deals in this space recently, I would expect to see a wave of new peptide-based radiopharmaceutical drugs beyond those targeting PSMA and SSTR making their way into the clinic and beyond in the next 20 years.

In addition, advancements are being made towards enabling cell permeability and oral delivery of peptides, which may open up the target space and allow novel approaches for peptide based therapeutics.

What do you most enjoy about your work?

I really enjoy the innovative aspect of my work, pioneering the development of Bicycle molecules as a novel modality and being able to explore this in many applications. I also love working in a very cross functional environment with so many talented and motivated people who ultimately all have one goal in common –  to help patients not just live longer, but live well. That is very inspiring for me.

What are you excited about sharing with the attendees in the New modalities: Innovations in peptides as biotherapeutics symposium in April?

I am very excited to talk about our radiopharmaceutical programs and showcase why we believe that Bicycle molecules are an ideal modality for this approach and importantly, how Bicycle Therapeutics can contribute to growth of the field by developing radiopharmaceutical ligands to novel targets. Currently marketed radiophamaceuticals are based on peptidic antigen binding delivery systems, but the number of natural peptidic ligands is limited. The Bicycle platform is able to create new peptidic ligands to targets that lack these endogenous start points and so lend themselves well to next generation radiopharmaceutical approaches.

What would you tell your younger self now about starting out in research?

I would say don’t be scared to share abstract or unpolished thoughts and ideas – talking to colleagues and benefitting from their insights and experience is so important and can often be the stimulus that clarifies a hypothesis or steers you in a better direction. I realised that many of the pieces of work that I am most proud of were born from ‘crazy’ ideas that were refined into something of value through collaborative thinking. Just throw all of the spaghetti at the wall and see which pieces stick!