An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models

Abstract

Mesothelin (MSLN) is an attractive target for antibody-drug conjugate therapy because it is highly expressed in various epithelial cancers, with normal expression limited to nondividing mesothelia. We generated novel antimesothelin antibodies and conjugated an internalizing one (7D9) to the microtubuledisrupting drugs monomethyl auristatin E (MMAE) and MMAF, finding the most effective to be MMAE with a lysosomal protease-cleavable valine-citrulline linker. The humanized (h7D9.v3) version, aMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC 50 of 0.3 nmol/L. Because the antitumor activity of an antimesothelin immunotoxin (SS1P) in transfected mesothelin models did not translate to the clinic, we carefully selected in vivo efficacy models endogenously expressing clinically relevant levels of mesothelin, after scoring mesothelin levels in ovarian, pancreatic, and mesothelioma tumors by immunohistochemistry. We found that endogenous mesothelin in cancer cells is upregulated in vivo and identified two suitable xenograft models for each of these three indications. A single dose of aMSLN-MMAE profoundly inhibited or regressed tumor growth in a dosedependent manner in all six models, including two patient-derived tumor xenografts. The robust and durable efficacy of aMSLN-MMAE in preclinical models of ovarian, mesothelioma, and pancreatic cancers justifies the ongoing phase I clinical trial. Mol Cancer Ther; 13(11); 2630-40. Ó2014 AACR.

Phase I Study of DMOT4039A, an Antibody–Drug Conjugate Targeting Mesothelin, in Patients with Unresectable Pancreatic or Platinum-Resistant Ovarian Cancer

“…Among the evaluable tumors for pancreatic cancer, the distribution of mesothelin membranous IHC staining scores was 0 (17%), 1þ (7%), 2þ (67%), and 3þ (10%); and for ovarian tumors, 0 (4%), 2þ (28%), and 3 þ (68%). Although the mesothelin staining frequency is consistent with prior published results (3)(4)(5)(6)16), some bias for higher frequency of expression may exist due to selection of IHC 3þ patients in the expansion cohorts. Representative images of IHC staining in both pancreatic and ovarian tumor specimens are shown in Fig.…”

“…Potential reasons for this include the inherent variability of assessing small cohorts, the inaccessibility of the ADC to tumor cells due to its relative hypovascular nature, as a result of the dense stromal structure of pancreatic lesions (32). In addition, mesothelin expression in pancreatic cancer may be heterogeneous, inaccessible (i.e., apical) or lost (3,16). Finally, primary resistance to chemotherapy in pancreatic cancer may be more prevalent.…”

“…Free MMAE subsequently results in disruption of the microtubule network, inhibition of cell division and growth to promote tumor cell death by mitotic catastrophe (17)(18)(19)(20). DMOT4039A has specific antiproliferative activity against mesothelin-expressing cancer cells in vitro and potent antitumor activity in xenograft cancer models expressing clinically relevant levels of mesothelin (16). Although DMOT4039A does not cross-react with cynomolgus monkey mesothelin, it was similarly well tolerated as a crossreactive surrogate ADC, with off-target toxicities common to other MMAE conjugates, including neutropenia (21).…”

Novel systemic therapy against malignant pleural mesothelioma

“…Using antibody-drug conjugate technology, the humanized mouse anti-mesothelin antibody 7D9 was linked to monomethyl auristatin E via a lysosomal protease-cleavable valine-citrulline dipeptide linker, and has demonstrated promising activity in preclinical models (152). A phase Ia/ II study of a mesothelin-directed antibody drug conjugate with an undisclosed cytotoxic drug (BMS-986148) was initiated in patients with advanced solid tumors, including mesothelioma, and this study is currently recruiting patients for enrollment (clinicaltrials.gov NCT02341625).…”

An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer

“…29 According to the previous studies, therapeutic antibodies conjugated with MMAE showed high antitumor efficiency in patients with hematologic malignancies and solid tumors. [30][31][32][33][34][35][36] We utilized a humanized anti-HER2 antibody, hertuzumab, conjugated with MMAE via a cleavable linker to generate hertuzumab-MC-Val-Cit-PAB-MMAE (hertuzumabvcMMAE for short). Our previous study has proven this ADC agent has a potent antitumor activity in HER2 positive breast cancer.…”