Abstract 1314: A novel small molecule drug conjugate -avb3 integrin antagonist linked to a cytotoxic camptothecin derivative- for the treatment of multiple cancer types
Authors: Lerchen Hans-Georg , Stelte-Ludwig Beatrix , Kopitz Charlotte , Heroult Melanie , Zubov Dmitry , Willuda Joerg , Schlange Thomas , Kahnert Antje , Izumi Raquel , Hamdy Ahmed 
Published: July 2021

To improve tumor selectivity of cytotoxic agents we designed small molecule drug conjugates leveraging two independent mechanisms of targeted delivery by utilizing an integrin binder for tumor homing and release of the active drug by proteases present in tumor stroma. Integrins are transmembrane receptors that mediate cell-extracellular matrix and cell-cell interaction. αvβ3 integrins in the tumor microenvironment are involved in critical events for tumor progression, cytotoxic therapy resistance and metastasis including angiogenesis, matrix remodeling and the recruitment of immune and inflammatory cells. Proteases in tumor stoma such as neutrophil elastase also contribute to cancer progression by enhancing tumor evasion and metastasis. The expectation is that small molecule drug conjugates could have better efficacy for solid tumors than antibody drug conjugates due to better tissue penetration. Following this rationale the small molecule drug conjugate is composed of a peptidomimetic αvβ3 integrin antagonist linked to a cytotoxic camptothecin derivative via a linker susceptible to cleavage by neutrophil elastase. Imaging studies with the αvβ3 antagonist conjugated with an IR-800 dye demonstrated efficient tumor targeting to 786-0 renal adenocarcinoma tumors, as compared with a weakly binding epimer used as a control conjugate. The targeted conjugate is highly stable in rat plasma and shows strong cytotoxic activity only in the presence of neutrophil elastase. The payload displays high cellular permeability and in contrast to SN38, the active metabolite of irinotecan, it is not a substrate of efflux transporters. The conjugate is highly efficacious in vivo effecting tumor regressions in SW480 (colon cancer), MX1 (breast cancer) and NCI-H69 (lung cancer) xenograft models with T/C ratios of 0.1, 0.03 and 0.06 (p&lt;0.05 each, compared to vehicle control) respectively and it shows very good tolerability. Initial pharmacokinetic studies in tumor bearing mice demonstrate a more than 10-fold improved tumor/plasma ratio of free toxophore when administered as a conjugate as compared with direct administration of unconjugated toxophore. In summary, our results show potent, selective, in vivo anticancer activity against three solid tumor subtypes with a novel small molecule drug conjugate consisting of the conjugation of an integrin antagonist with a cytotoxic agent via a tailored linker enabling cleavage in tumor stroma.

Citation Format: Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Charlotte Kopitz, Melanie Heroult, Dmitry Zubov, Joerg Willuda, Thomas Schlange, Antje Kahnert, Raquel Izumi, Ahmed Hamdy. A novel small molecule drug conjugate -avb3 integrin antagonist linked to a cytotoxic camptothecin derivative- for the treatment of multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1314.