Abstract 4502: Nonclinical characterization and tolerability of a surrogate anti-mesothelin-MMAE antibody-drug conjugate
Authors: Gupta Nidhi , Solis Willy A. , Fuji Reina N. , Oldendorp Amy , Pacheco Glenn , Luis Elizabeth , Chuh Josefa , French Dorothy M. , Drake Elizabeth , Dennis Mark S. , Kozak Katherine R. , Ross Sarajane , Tibbitts Jay , Spencer Susan D. , Scales Suzie J. 
Published: May 2015

Abstract
Mesothelin (MSLN) is a cell surface glycoprotein widely expressed in several cancers with normal expression limited to the serosal mesothelia, features of an ideal target for antibody-based therapy. SS1P, a (dsFv)-PE38 immunotoxin to MSLN that kills cells by inhibition of protein synthesis, exhibits minor clinical responses as monotherapy, but was dose-limited by pleuritis, likely an antigen-dependent toxicity (Hassan et al., (2007) Clin Cancer Res 13 p3144). As mesothelial cells divide infrequently, we evaluated whether an anti-mitotic antibody-drug conjugate (ADC) directed to MSLN would be better tolerated. Our humanized lead anti-MSLN-MMAE (mc-vc-PAB-monomethylauristatin E) conjugate shows excellent preclinical activity (see accompanying abstract by Scales et al), but is specific to human MSLN, so a surrogate ADC that cross-reacts with cynomolgus monkey and rat MSLN was generated for non-clinical toxicity studies.
While both the lead and the surrogate antibodies recognize human MSLN, they bound to different epitopes and the surrogate binding was sensitive to glycosylation, only recognizing a subset of cell lines expressing human MSLN with high affinity. The affinity of the surrogate antibody for cynomolgus monkey MSLN is 5 to 22-fold lower than that of the lead antibody for human MSLN, depending on its glycosylation pattern in the human parental cell line to which it was compared. Nonetheless, the surrogate antibody detects endogenous MSLN in monkey pleura and the surrogate ADC exhibits robust cytotoxic activity against monkey MSLN-expressing cells in vitro. Importantly, the surrogate ADC demonstrated comparable in vivo efficacy to the lead ADC against BJAB xenografts expressing monkey or human MSLN respectively, thus validating its use in safety studies. We thus conducted a repeat-dose monkey toxicity study with a clinically relevant (q3w x5) dosing schedule, which yielded similar results for both surrogate and lead ADCs (the primary finding being reversible myelotoxicity, an antigen-independent toxicity similar to those of other IgG1-MMAE ADCs (Li et al., (2013), Mol Can Thera 12 p1255)). Unlike SS1P, there was no evidence of target-dependent pleuritis, nor any other serositis. Our data suggest that anti-MSLN-MMAE ADCs may be safer than SS1P and helped define the Phase I starting dose.
Citation Format: Nidhi Gupta, Willy A. Solis, Reina N. Fuji, Amy Oldendorp, Glenn Pacheco, Elizabeth Luis, Josefa Chuh, Dorothy M. French, Elizabeth Drake, Mark S. Dennis, Katherine R. Kozak, Sarajane Ross, Jay Tibbitts, Susan D. Spencer, Suzie J. Scales. Nonclinical characterization and tolerability of a surrogate anti-mesothelin-MMAE antibody-drug conjugate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4502. doi:10.1158/1538-7445.AM2014-4502