This technology introduces a legumain-cleavable antibody drug complex that delivers a topoisomerase inhibitor directly into tumor cells. Its short, polar linker design enables controlled intracellular release, improving targeting precision and therapeutic potential. In contrast to other related technologies, this invention employs low-potency Top1i inhibitors that retain superb in vivo efficacy while potentially improving safety and tolerability.
Background: Current antibody-drug conjugates struggle to balance systemic stability with tumor-specific release, often leading to premature drug activation, off-target toxicity, and limited efficacy. Topoisomerase inhibitors, while potent, also pose solubility and polarity challenges upon conjugation, further limiting their performance. These issues underscore the need for improved linker architectures and release mechanisms that enhance tumor specificity, pharmacokinetics, and therapeutic index.
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 enhances the biophysical properties of the conjugate, supporting efficient intracellular delivery. In vitro evaluations demonstrate activity across multiple cancer models, while in vivo studies demonstrate potent antitumor activity, and have a similar pharmacokinetic profile to naked antibody. The released exatecan derivatives exhibit dramatically reduced potency as free payloads, thus suggesting higher tolerability and improved safety as compared to traditional exatecan-based ADCs.
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 • 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: Targeted oncology therapeutics and platform licensing for ADC development.
Additional Information: Information available upon request.
Inventors: L. Nathan Tumey, Nicholas Bianchi, Victor Ojo
Alternate NCS Title: Targeted Legumain-Cleavable Top1i ADC Platform