An anti-mesothelin-monomethyl auristatin E conjugate with potent anti-tumor activity in ovarian, pancreatic and mesothelioma models
Molecular Cancer Therapeutics. 2014 September 23 [Epub ahead of print] [Link]
Scales SJ, Gupta N, Pacheco G, Firestein R, French DM, Koeppen H, Rangell L, Barry-Hamilton V, Luis E, Chuh J, Zhang Y, Ingle GS, Fourie-O’Donohue A, Kozak KR, Ross S, Dennis MS, Spencer SD.
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 non-dividing mesothelia. We generated novel anti-mesothelin 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, alphaMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC50 of 0.3nM. Because the anti-tumor activity of an anti-mesothelin 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 alphaMSLN-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 alphaMSLN-MMAE in preclinical models of ovarian, mesothelioma and pancreatic cancers justifies the ongoing phase I clinical trial.
