Our DARPin Approach to Radiopharmaceuticals
Radiopharmaceuticals have recently captured broad attention. Their potential to deliver potent radiation locally and with high specificity to cancer cells, while sparing healthy tissue, addresses a high unmet medical need of people with cancer.
The balancing act of designing a successful radiopharmaceutical
Radiopharmaceuticals consist of a radioactive payload attached to a delivery vector which can target specific proteins overexpressed on cancer cells. While a seemingly simple construct, development attempts often must make trade-offs between efficacy and safety, and the number of cancers druggable by the respective vector modality. Large antibody-based vectors are highly specific and display good tumor uptake, yet their long circulation time in blood can potentially damage bone marrow. Low molecular weight ligands are quickly eliminated from the body and show good tumor uptake and penetration. However, they often have insufficient tumor selectivity and can only be generated against a limited number of targets. Small protein-based vectors allow high affinity and selective targeting, but kidney toxicity related to their renal clearance and reabsorption often limits efficacious dosing.
Why are we excited about Radio-DARPins?
DARPins (designed ankyrin repeat proteins) are an engineered protein drug class with unique properties, derived from natural human binding proteins. They can be designed to bind to a broad range of targets with high affinity and specificity. With their small size, high stability, robustness and short systemic half-life, DARPins are ideal candidates for targeted radiotherapy, potentially allowing us to overcome the limitations seen with other vectors. Our DARPin platform allows us to reliably and quickly generate highly tailored candidates, as demonstrated with so far 7 DARPin molecules entering clinical development for different oncology and non-oncology indications in the past years.
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What have we achieved so far?
A dedicated Radio-DARPin research team focuses on engineering advancements of our platform to address the key challenges of targeted radiotherapy. Through surface engineering of the highly stable DARPin backbone, we successfully reduced the renal reabsorption of Radio-DARPins, leading to an increased excretion in the urine and strongly reduced accumulation of radioactivity in the kidneys. In addition, our expertise in DARPin half-life modulation allowed us to further optimize their circulation in blood and achieve increased uptake across different targeted tumors while keeping blood levels low. This work has validated our Radio-DARPin approach and is paving our way to the clinic. Building on 20 years of DARPin leadership and experience in preclinical and clinical development, we are convinced that most of our Radio-DARPin research achievements are transferable from one target to another.
New partners, first targets… what’s next?
In addition to our standing Radio-DARPin collaboration with Novartis, we are excited about our recently announced co-development agreement with Orano Med. Orano Med brings a wealth of expertise in targeted alpha therapy and masters the production and supply of 212Pb, an alpha emission precursor. DLL3, a known lung cancer target with low expression in healthy tissues, is our first disclosed target among several planned 212Pb-based Radio-DARPin therapies. We aim to share more details in 2024 including novel data and our plans to the clinic. If you would like to know more about Radio-DARPins, please visit our website or feel free to message me directly!
Regulatory & clinical writing solutions for biotech | Director, Operations & Strategy at Morula Health
1moThanks for sharing Daniel Steiner. We are starting to do a lot of work in this space, writing protocols and CTD modules for radiopharmaceuticals. It's fascinating to learn about the innovative approaches, and how radiopharmaceuticals are being development for diagnostic and therapeutic purposes. Good luck with your Radio-DARPin development! 😀
VP Partnering & Alliances bei Molecular Partners
5moVery cool summary of the DARPin RadioTherapeutic uniqueness … Thanks Dani and team!