On June 11, 2024 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics and Orano Med, a clinical stage radiopharmaceutical company developing targeted alpha therapies with lead-212 (212Pb), reported the debut of their lead Radio-DARPin therapy (RDT) candidate MP0712, targeting DLL3, in an oral presentation (Press release, Molecular Partners, JUN 11, 2024, View Source [SID1234644228]). The data presented today provide strong support for MP0712’s clinical development in small-cell lung cancer (SCLC) and other DLL3+ neuroendocrine tumors. MP0712 features 212Pb as a potent therapeutic payload. The data were presented today at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2024 Annual Meeting taking place June 8-11 in Toronto, Canada.

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"Three years ago, we started our venture into the radiotherapy space. We have made tremendous progress with our Radio-DARPins and are proud to present MP0712, our first RDT development candidate targeting DLL3 delivering and 212Pb to kill the tumor, in partnership with Orano Med," said Patrick Amstutz, Ph.D., Molecular Partners’ Chief Executive Officer. "We have made key learnings how to reduce kidney accumulation and increase tumor uptake. We are now exploiting the long-known DARPin advantages to a full pipeline of candidates addressing high medical need. Kudos to both the Orano Med and Molecular Partners team for advancing the science to make this happen."

"We are extremely excited with the first preclinical results of the MP0712 program, which confirm the potential of the combination between Molecular Partners’ targeting technology and 212Pb, an isotope perfectly suited for targeted alpha therapy. We eagerly anticipate advancing the drug’s development and initiating clinical trials to provide solutions for patients with unmet medical needs," said Julien Dodet, CEO of Orano Med.

MP0712 is the first high-affinity DLL3-targeting RDT combining the advantages of DARPins as small protein-based delivery vectors and the short-lived alpha particle-emitting radioisotope 212Pb. DLL3 is expressed in >85% of SCLC patients and in other neuroendocrine tumors, while its expression in healthy tissues is low, making it a priority target for radiopharmaceutical therapy. SCLC is an aggressive form of lung cancer, with a poor five-year survival prognosis and a high unmet need for patients.

The preclinical package presented at SNMMI includes in vivo data demonstrating strong and homogeneous tumor uptake of 212Pb-DLL3 RDT, as well as significant and durable inhibition of tumor growth at clinically-relevant doses. The safety results seen across the tested dosing levels in mice suggest a favorable safety profile and potential for clinical use. 212Pb-DLL3 RDT candidates were engineered by tuning their biophysical properties to achieve an optimal safety/antitumor activity profile in vivo. The selected lead candidate, MP0712, demonstrated a promising biodistribution profile in mouse xenograft tumor models, with close to 60% of injected dose detectable in the tumor and encouraging tumor to kidney ratios over two. The replicable DARPin learnings from the development of MP0712, as well as additional platform improvements, are being taken forward to the broader RDT portfolio.

The intrinsic properties of DARPins, such as small size, high affinity and selectivity, and a broad range of potential targets, make them ideal vector candidates for radiopharmaceutical therapeutics. Historically, small protein-based vectors faced challenges with kidney accumulation and toxicity, as well as suboptimal tumor uptake. Molecular Partners has evolved its RDT platform to address these limitations with its half-life extension technologies and surface engineering approaches, while preserving the advantages of the small protein format. In addition, Molecular Partners’ DARPin candidates have been clinically validated with over 2500 patients treated worldwide and multiple DARPin mechanisms have been demonstrated as biologically active in for different indications, contributing to validation of the drug class and Molecular Partners as leader in the field of DARPin engineering and development.

Details of the presentation summarizing the MP0712 preclinical data at the SNMMI 2024 Annual Meeting can be found below. The presentation will be made available on Molecular Partners’ website after the presentation.

Presentation Title: Lead-212 Radio-DARPin Therapeutic (RDT) targeting delta-like ligand 3 (DLL3) shows promising preclinical antitumor efficacy and tolerability in small cell lung cancer (SCLC)
Session: IS09 Integrated Session: Radionuclides (CMIIT/RPSC);
Timing: 11 June 2024; 8:00–9:15 am EDT