This technology introduces a legumain-cleavable antibody drug complex (ADC) that delivers topoisomerase inhibitors directly into tumor cells using a short, polar linker design. The platform employs low-potency Top1i derivatives that maintain strong in vivo efficacy while potentially improving safety, offering a balanced approach to stability, tumor specificity, and therapeutic index in next-generation targeted oncology therapeutics.
Background: Current antibody-drug conjugates face challenges in achieving selective tumor release while maintaining systemic stability, often resulting in premature drug activation, off-target toxicity, and reduced therapeutic impact. Topoisomerase inhibitors, though widely used, also exhibit solubility and polarity limitations when conjugated, lowering performance and complicating formulation. These issues highlight the need for improved linker systems and controlled enzymatic release strategies that enhance tumor specificity, pharmacokinetic behavior, and overall therapeutic index without compromising safety or manufacturability.
Technology Overview: This invention uses a legumain-cleavable AsnAsn peptide linker that exploits tumor-associated legumain to release exatecan derivatives within lysosomes. The short, polar linker architecture improves biophysical properties and supports efficient intracellular delivery. In vitro evaluations demonstrate activity across multiple cancer models, and in vivo studies show potent antitumor activity with a pharmacokinetic profile similar to the naked antibody. The released exatecan derivatives exhibit dramatically reduced potency as free payloads, suggesting improved tolerability and safety when compared to traditional exatecan-based ADCs, while maintaining robust therapeutic activity.
Advantages: • Enables precise intracellular release through legumain-dependent cleavage • Improves pharmaceutical properties with a short polar linker architecture • Decreased potency of the Top1i (compared to exatecan) offers potential of improved safety • Supports novel IP protection through the AsnAsn linker motif • Validated on 4 different solid-tumor antibody platforms • Facilitates efficient and scalable manufacturing through streamlined linker chemistry
Applications: • Targeted oncology therapeutics • Platform licensing for ADC development
Intellectual Property Summary: • United States 63/520,946 Publication 9/7/2023 Status: Filed • United States PCT/US2024/043170 8/21/2024 Status: Filed • WO 2025/042953 PCT Publication 2/2/2025 Status: Filed • Journal publication: https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c02681
Stage of Development: Prototype – in vitro, in vivo mouse/rat, and PK validation.
Licensing Status: This technology is available for licensing.
Licensing Potential: Suitable for biopharmaceutical companies developing next-generation ADC platforms seeking improved safety, tumor selectivity, and manufacturability.
Additional Information: Information available upon request.
Inventors: L. Nathan Tumey, Nicholas Bianchi, Victor Ojo