Abstract 66: Anthracycline-based antibody drug conjugates with potent immune-stimulatory functions

Abstract

Abstract Antibody drug conjugates (ADCs) are highly potent and selective anti-tumor drugs, combining the specific targeting of monoclonal antibodies with the potency of small molecule toxic payloads. Here, we employed enzymatic, site-specific conjugation to generate homogenous ADCs based on a derivative of the highly potent anthracycline toxin PNU-159682 and a non-cleavable peptide linker, using the anti-HER-2 antibody trastuzumab (part of trastuzumab emtansine) and the anti-CD30 antibody cAC10 (part of brentuximab vedotin). Characterization of the resulting ADCs in vitro and in vivo showed that they were highly stable and exhibited potencies exceeding those of ADCs based on conventional tubulin-targeting payloads, such as trastuzumab emtansine and brentuximab vedotin. Anti-tumor activity in an immune-competent host involved activation of the immune system, as shown by evaluation of a trastuzumab-PNU ADC in a Kadcyla-resistant HER2-positive orthotopic breast cancer model. Depletion of CD8 T cells severely reduced the anti-tumor activity of the ADC, demonstrating an important role for T cells in driving tumor regression. Furthermore, when tumor free animals were re-challenged with the same tumor, tumor growth was entirely inhibited in the absence of any further ADC administration, indicating the development of an immunological memory. In summary, we present a novel ADC format endowed not only with highly potent cytotoxicity, but also effective immune-stimulatory functions. Citation Format: Roger R. Beerli. Anthracycline-based antibody drug conjugates with potent immune-stimulatory functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 66. doi:10.1158/1538-7445.AM2017-66