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

Mol Cancer Ther. 2017 Jan;16(1):134-142. doi: 10.1158/1535-7163.MCT-16-0449. Epub 2016 Oct 19.

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 by 89Zr 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 89Zr-AMA. The less responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did not show 89Zr-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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Female
  • Flow Cytometry
  • GPI-Linked Proteins / antagonists & inhibitors*
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • Gene Expression
  • Humans
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / pharmacology*
  • Mice
  • Molecular Targeted Therapy
  • Neoplasms / diagnosis
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Positron-Emission Tomography*
  • Radiopharmaceuticals*
  • Tumor Burden / drug effects
  • Tumor Burden / radiation effects
  • Xenograft Model Antitumor Assays
  • Zirconium*

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • GPI-Linked Proteins
  • Immunoconjugates
  • Radiopharmaceuticals
  • Zirconium
  • mesothelin