title: Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET.
abstract: Antibody-drug conjugates (ADC) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr)-labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3×2.1, pancreatic cancers Capan-2, HPAC, AsPC-1, and HPAF-II, or mesothelioma MSTO-211H. Ex vivo analysis of mesothelin expression was performed using immunohistochemistry. AMA-MMAE showed the greatest growth inhibition in OVCAR-3×2.1, Capan-2, and HPAC tumors, which showed target-specific tumor uptake of89Zr-AMA. The less responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did not show89Zr-AMA uptake despite confirmed mesothelin expression. ImmunoPET can demonstrate the necessary delivery, binding, and internalization of an ADC antibody in vivo and this correlates with the efficacy of mesothelin-targeted ADC in tumors vulnerable to the cytotoxic drug delivered. Mol Cancer Ther; 16(1); 134-42. ©2016 AACR.
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.|Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Anton G T
authors.initials: AG
authors.lastname: Terwisscha van Scheltinga
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Annie
authors.initials: A
authors.lastname: Ogasawara
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Glenn
authors.initials: G
authors.lastname: Pacheco
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Vanderbilt
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Jeff N
authors.initials: JN
authors.lastname: Tinianow
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Li
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Jan
authors.initials: J
authors.lastname: Marik
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California.
authors.forename: Suzie J
authors.initials: SJ
authors.lastname: Scales
authors.affiliation: Genentech Research and Early Development, Genentech, Inc,. South San Francisco, California. williams.simon@gene.com.
authors.forename: Simon-Peter
authors.initials: SP
authors.lastname: Williams
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000090204:Mesothelin; D051379:Mice; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; C000715528:Msln protein, mouse; D019275:Radiopharmaceuticals; D015040:Zirconium; D000090204:Mesothelin