title: 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 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.
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, California. sscales@gene.com.
authors.forename: Suzie J
authors.initials: SJ
authors.lastname: Scales
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, California.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, California.
authors.forename: Glenn
authors.initials: G
authors.lastname: Pacheco
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California.
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: French
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California.
authors.forename: Linda
authors.initials: L
authors.lastname: Rangell
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, California.
authors.forename: Vivian
authors.initials: V
authors.lastname: Barry-Hamilton
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California.
authors.forename: Josefa
authors.initials: J
authors.lastname: Chuh
authors.affiliation: Department of Antibody Engineering, Genentech, South San Francisco, California.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, California.
authors.forename: Gladys S
authors.initials: GS
authors.lastname: Ingle
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California.
authors.forename: Aimee
authors.initials: A
authors.lastname: Fourie-O'Donohue
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Kozak
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, California.
authors.forename: Sarajane
authors.initials: S
authors.lastname: Ross
authors.affiliation: Department of Antibody Engineering, Genentech, South San Francisco, California.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, California.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Spencer
mesh_terms: D000818:Animals; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D000922:Immunotoxins / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D000090204:Mesothelin; D008654:Mesothelioma / Q000188:drug therapy*; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011897:Random Allocation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D058851:GPI-Linked Proteins; D000922:Immunotoxins; C000715527:MSLN protein, human; C000715528:Msln protein, mouse; D009842:Oligopeptides; D000090204:Mesothelin; C495575:monomethyl auristatin E