Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET

• Published in: Molecular cancer therapeutics 2017-01, Vol.16 (1), p.134-142
• Main Authors: Terwisscha van Scheltinga, Anton G T, Ogasawara, Annie, Pacheco, Glenn, Vanderbilt, Alexander N, Tinianow, Jeff N, Gupta, Nidhi, Li, Dongwei, Firestein, Ron, Marik, Jan, Scales, Suzie J, Williams, Simon-Peter
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biomarkers, Tumor; Cancer; Cell Line, Tumor; Cytotoxicity; Disease Models, Animal; Dose-Response Relationship, Drug; Drug delivery systems; Drug Evaluation, Preclinical; Drugs; Effectiveness; Female; Flow Cytometry; Gene Expression; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Humans; Immunoconjugates - pharmacokinetics; Immunoconjugates - pharmacology; Immunohistochemistry; Inhibition; Internalization; Mesothelioma; Mice; Molecular Targeted Therapy; Monoclonal antibodies; Neoplasms - diagnosis; Neoplasms - drug therapy; Neoplasms - metabolism; Ovarian cancer; Pancreas; Pancreatic cancer; Positron-Emission Tomography; Radiopharmaceuticals; Target recognition; Tumor Burden - drug effects; Tumor Burden - radiation effects; Tumor cells; Tumors; Xenograft Model Antitumor Assays; Xenografts; Zirconium
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0449

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 ( Zr)-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 by Zr 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 of Zr-AMA. The less responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did not show Zr-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.