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The erythropoietin-producing hepatoma A2 receptor (EphA2) is a tyrosine kinase overexpressed by tumor stroma and cancer cells. A high expression level of EphA2 predicts poor prognosis, correlating with disease progression and metastasis. Therefore, EphA2 is a relevant therapeutic target for human cancer. Antibodies, selectively bound to EphA2, can induce rapid receptor phosphorylation that results in antibody internalization and degradation. This internalization mechanism has been exploited with the development of antibody-drug conjugates (ADCs) for cancer chemotherapy. In this study, we used PET imaging to study the pharmacokinetics and tumor delivery of a panel of anti-EphA2 monoclonal antibodies (mAbs) with and without drug conjugates. Methods: A library of human anti-EphA2 mAbs were screened and evaluated for EphA2 internalization rate, binding affinity, epitope binding, and hydrophobicity. We chose 3 of these antibodies, denoted as 1C1, 3B10, and 2H7, which recognize different epitopes, for further evaluation. ADCs were generated by S239C mutation to give a ratio of 2 drug molecules per antibody. Native mAbs and ADCs were characterized, after conjugation to a DFO chelator and 89 Zr radiolabeling, in assays including cell uptake, internalization, hydrophobicity, and in vivo imaging using PET. Results: All 3 mAbs had high affinities for EphA2 but exhibited different internalization rates following the order of 1C1 &gt; 3B10 &gt; 2H7. Internalization rate is only 1 factor that affects in vitro cell uptake and in vivo tumor accumulation. Interestingly, the hydrophobicity of the mAbs, which followed the order of 2H7 &gt; 1C1 &gt; 3B10, had a strong correlation with in vivo tumor uptake measured by PET, with the least hydrophobic antibody, 3B10, showing the highest tumor uptake. ADC significantly reduced the in vivo uptake of all 3 mAbs. Conclusion: Tumor uptake of mAb is a complex process that is affected by multiple parameters, including internalization, hydrophobicity, and chemical modification. Our results suggest that the addition of drug molecules to mAb increases the clearance of the mAb presumably due to the increased hydrophobicity. Understanding the complexity of antibody-based tumor delivery may help improve ADC engineering for better tumor targeting and reduced side effects.

PET-Guided Evaluation and Optimization of Internalized Antibody–Drug Conjugates Targeting Erythropoietin-Producing Hepatoma A2 Receptor