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Enfortumab vedotin (EV) is a monomethyl auristatin E (MMAE) containing antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder cancers. Preclinically, EV has demonstrated tumor cell-killing by direct cytotoxicity, bystander toxicity, and induction of the hallmarks of immunogenic cell death. In EV-301, a phase 3 clinical study, EV monotherapy showed an overall survival (OS) benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles 2021). EV also has encouraging activity in combination with pembrolizumab in previously untreated la/mUC (73% ORR)(Friedlander 2021). Most newly diagnosed bladder cancer cases are non-muscle invasive (Chang 2016; Woldu 2017; Kates 2020; Li 2020). Standard treatment of high risk NMIBC involves transurethral resection of the bladder tumor followed by intravesical (IVES) Bacillus Calmette-Guerin (BCG) or chemotherapy. Although response to BCG is high, many patients recur within 1-5 years (Matulay 2021). For patients unresponsive to BCG, treatment options are limited; radical cystectomy remains the standard of care. Due to the morbidity associated with radical cystectomy there remains a significant unmet need for a safe and effective therapy. We demonstrate that NMIBC have a high Nectin-4 expression pattern by RNA analyses and immunohistochemistry (IHC) similar to la/mUC, using an anti-Nectin-4 antibody (clone M22-321b41.1). The anti-tumor activity of EV was demonstrated in vitro and in vivo in human bladder cancer cells overexpressing Nectin-4. The superiority of EV vs MMAE alone was shown via in vitro pulsed (2hr) exposure cytotoxicity assays mimicking IVES administration. In a luciferase expressing orthotopic xenograft mouse model of NMIBC, EV-mediated anti-tumor activity was confirmed by both bioluminescence imaging of tumor burden and IHC for h-Nectin-4 expressing cancer cells. Tumor uptake of EV was further confirmed by IHC detection of EV in the engrafted tumor cells. Repeat-dose IVES administration of EV was well tolerated in a GLP study with minimal local and no systemic toxicities at doses up to 6-fold the intravenous maximum tolerated dose. Consistent with the lack of systemic toxicities, IVES administration was associated with low systemic absorption ( Citation Format: Christopher Carosino, Devra Olson, Katie Snead, Anthony Lee, Lauren Farr, Amit Garg, Christine O'Day, Esther Trueblood, Jennifer Wright, Mark Bieda, Charles Caldwell, Kelly Hensley, Sean Allred, Bernard Liu, Masashi Shimazaki, Sharsti Sandall. Enfortumab vedotin, a Nectin-4 directed ADC, demonstrates compelling tolerability and anti-tumor activity with intravesical instillation in preclinical models of non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1140.

Recognition of phosphotyrosine-containing sequences by SH2 domains confers specificity in tyrosine kinase pathways. By assessing interactions between isolated SH2 domains and their binding proteins, it is possible to gain insight into otherwise inaccessible complex cellular systems. Far-Western, pull-down, and fluorescence polarization (FP) have been frequently used for characterization of phosphotyrosine signaling. Here, we outline standard protocols for these established assays using recombinant SH2 domain, emphasizing the importance of appropriate sample preparation and assay controls.

The ability of a cancer cell to avoid apoptosis is crucial to tumorigenesis and can also contribute to chemoresistance. The Bcl-2 family of prosurvival proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) plays a key role in these processes. We previously reported the discovery of ABT-263 (navitoclax), a potent small-molecule inhibitor of Bcl-2, Bcl-XL, and Bcl-w. While navitoclax exhibits single-agent activity in tumors dependent on Bcl-2 or Bcl-XL for survival, the expression of Mcl-1 has been shown to confer resistance to navitoclax, most notably in solid tumors. Thus, therapeutic agents that can downregulate or neutralize Mcl-1 are predicted to synergize potently with navitoclax. Here, we report the activity of navitoclax in combination with 19 clinically relevant agents across a panel of 46 human solid tumor cell lines. Navitoclax broadly enhanced the activity of multiple therapeutic agents in vitro and enhanced efficacy of both docetaxel and erlotinib in xenograft models. The ability of navitoclax to synergize with docetaxel or erlotinib corresponded to an altered sensitivity of the mitochondria toward navitoclax, which was associated with the downmodulation of Mcl-1 and/or upregulation of Bim. These data provide a rationale to interrogate these combinations clinically. Mol Cancer Ther; 10(12); 2340–9. ©2011 AACR.

Assembly Mold SDM (Shape Deposition Manufacturing) has been used in combination with Gel Casting to fabricate ceramic micro gas turbine components. Full 3-dimensional ceramic turbines and compressors with a feature size down to 200 μm were built. The turbine has been tested and been spun up to 456,000 rpm. During the research, it was found that the development of a ceramic air bearing is desirable. Thus, a process utilizing MEMS techniques has been developed to fabricate patterns with 125 μm feature size. In this paper, the techniques used to fabricate functional rotor groups, improve accuracy, and pattern micro features will be discussed.