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 microtubule-disrupting 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, αMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC50 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 αMSLN-MMAE profoundly inhibited or regressed tumor growth in a dose-dependent manner in all six models, including two patient-derived tumor xenografts. The robust and durable efficacy of αMSLN-MMAE in preclinical models of ovarian, mesothelioma, and pancreatic cancers justifies the ongoing phase I clinical trial.
Highlights
Mesothelin (MSLN) is a glycoprotein limited to the surface of the single mesothelial cell layer lining the pericardia, pleura, and peritoneum [1]
Hybridoma supernatants were screened by ELISA, followed by FACS and IHC analysis of cells stably transfected with mesothelin to select those capable of detecting native glycosylated and formalin-fixed mature mesothelin, respectively
Because internalizing antibody–drug conjugate (ADC) are generally more efficacious due to greater drug release from lysosomes [12, 13, 36], we selected 7D9 for conjugation because it internalized to lysosomes to a greater extent in H226, OVCAR3, and MSLN-PC3 cells (Fig. 1D and data not shown), all known to express mesothelin [34, 37]
Summary
Mesothelin (MSLN) is a glycoprotein limited to the surface of the single mesothelial cell layer lining the pericardia, pleura, and peritoneum [1]. It is expressed as an approximately 75 kDa fusion protein with the so-called megakaryocyte-promoting factor (MPF), which is removed by furin cleavage, leaving an approximately 50 kDa glycosylphosphatidylinositol-anchored mature mesothelin on the cell surface [2]. The high tumor versus normal expression makes mesothelin an attractive target for cancer therapy. In a phase I trial, SS1P produced only 4 of 34 minor responses in mesothelin-selected cancers, and was dose limited by pleuritis [7], likely because PE38 inhibited protein synthesis in the mesothelin-positive pleura. Chimeric SS1 IgG without PE38 (MORAb-009, amatuximab) exerts modest preclinical activity via antibody-dependent cell-mediated cytotoxicity [10], but no clinical activity [11]
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