Abstract
Abstract Background: Antibody-drug conjugates (ADCs) have been recognized as a promising anticancer agent, despite their stringent requirements of antibody affinity, internalization, payload potency, and linker stability. To drive the next generation of ADCs and improve versatility of the component combination, we have designed, prepared and recently developed Antibody/Drug-Conjugated Micelle (ADCM) system. ADCM is composed of polyethylene glycol-poly (amino acid derivative) polymers, which can form a micellar nanoparticle spontaneously in aqueous media with a diameter of 20-100 nm. Antibodies are attached to the surface of the nanoparticle, while payloads are incorporated in the inner core at a payload-to-antibody molecular ratio of 100-200. In this study, monoclonal antibody, trastuzumab or cetuximab, and anticancer drug, anthracycline antibiotic epirubicin or novel hemiasterlin analogue E7974, were used as a targeting sensor and a payload of the ADCM, respectively. Here we report the results of in vitro and in vivo studies. Methods: The ADCMs were prepared as described previously (Japan Patent No.4538666) with slight modification. To examine the cell binding behavior, flow cytometry analysis was performed using an Accuri C6 system. The antigen affinity was evaluated using a Biacore system. The cellular uptake was examined fluorescently using ADCMs employing Alexa 488-labeled antibodies. To compare the in vivo antitumor effects, ADCM, untargeted micelle and the payload were administered intravenously 3 times weekly at the same payload-equivalent dose to nude mice bearing human tumor xenografts with HER2 (NCI-N87 gastric or trastuzumab-resistant JIMT-1 breast tumor) or EGFR (BxPC-3 pancreatic or LS174T colon tumor) expression. Tumor volumes and animal body weights were monitored 2 or 3 times a week. Results: The ADCMs showed similar cell-binding behavior and antigen affinity to the original antibodies. They were found to be internalized more efficiently than the original antibodies. In vivo efficacy studies demonstrated that the ADCMs inhibited tumor growth most effectively compared to control formulations. The therapeutic indexes were significantly improved in terms of the maximum tolerated dose/ED50 (50% effective dose) compared to untargeted micelles and native payloads. These results suggest the potential clinical application of the ADCMs. Conclusion: These data showed improved versatility of the component combination and increased therapeutic indexes of ADCM system, indicating a promising next generation of ADCs. Citation Format: Mitsunori Harada. Antibody/drug-conjugated micelle as a versatile platform technology for targeted tumor delivery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5525. doi:10.1158/1538-7445.AM2015-5525
Published Version
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