Abstract 3646: Characterization of the novel antibody drug conjugate MEN1309 and its target antigen Ly75

Autor: Keith T. Wilson, San Lin Lou, Dee Aud, To Uyen T. Do, Sudha Swaminathan, Christian Rohlff, Jonathan Alexander Terrett, Alessandro Bressan, Giuseppe Merlino, Alessio Fiascarelli, Rachel L. Dusek, Monica Binaschi, Daniela Bellarosa, Corrado Carrisi, Arnima Bisht, Rahel Awdew
Rok vydání: 2017
Předmět:
Zdroj: Cancer Research. 77:3646-3646
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2017-3646
Popis: Ly75 (CD205, DEC-205) is a type I transmembrane glycoprotein and a C-type lectin receptor involved in antigen uptake and processing, mainly expressed by antigen presenting cells (APC). The short cytoplasmic tail contains motifs for amino acid-based endocytosis, making this receptor an ideal target antigen for an antibody drug conjugate (ADC)-based antitumoral therapy. MEN1309 is a novel fully humanized ADC which binds to Ly75 with high affinity as shown by ELISA and FACS analysis. The antibody is conjugated to a maytansinoid DM4, a potent tubulin inhibitor, through a cleavable linker.The ability of Ly75 to internalize the antibody after binding was determined using an immunoflourescence assay that showed a rapid, efficient, and near complete internalization over a one hour time course.The expression of Ly75 mRNA and protein was investigated in human cancer cell lines derived from different histotypes and revealed high expression in pancreas, bladder, triple negative breast cancer (TNBC) cells and in diffuse large B-cell lymphoma (DLBCL). Indeed, MEN1309 shows a powerful (pM range) in vitro cytotoxic activity on different cancer cell lines expressing Ly75, whereas it exerts a weaker effect on antigen-negative cells. Besides the mechanism of action (MoA) of MEN1309 as an ADC, the putative efficacy of the antibody to drive an ADCC response was investigated through in vitro binding and functional assays. In spite of a high binding affinity of MEN1309 to FcγRIIIa, no ADCC response was observed, suggesting that the high internalization rate of the antigen could hamper the triggering of NK responses.Moreover, in order to characterize the functional role of Ly75 in cancer cell lines, its expression was downregulated by siRNA demonstrating an inhibition of the proliferation rate in cells from different histotypes.Finally, we investigated if some cancer cell lines could show a higher expression of two intergenically spliced forms derived from Ly75 and DCL-1 genes recently reported in literature. We found that the intergenically spliced forms were expressed on average 30 fold less than CD205 mRNA in all the cancer cell lines analyzed, suggesting that these variants derive just from an intergenic readthrough without a specific transcriptional regulation. Citation Format: Alessandro Bressan, Alessio Fiascarelli, Giuseppe Merlino, Corrado Carrisi, Daniela Bellarosa, Rachel Dusek, Rahel Awdew, Sudha Swaminathan, Arnima Bisht, To Uyen T. Do, San Lin Lou, Dee Aud, Jonathan Terrett, Keith Wilson, Christian Rohlff, Monica Binaschi. Characterization of the novel antibody drug conjugate MEN1309 and its target antigen Ly75 [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 3646. doi:10.1158/1538-7445.AM2017-3646
Databáze: OpenAIRE
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