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Supplementary Table from Targeting a Radiosensitizing Antibody–Drug Conjugate to a Radiation-Inducible Antigen

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posted on 2023-03-31, 22:43 authored by Calvin D. Lewis, Abhay K. Singh, Fong-Fu Hsu, Dinesh Thotala, Dennis E. Hallahan, Vaishali Kapoor
Supplementary Table from Targeting a Radiosensitizing Antibody–Drug Conjugate to a Radiation-Inducible Antigen

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NCI

Institutional Clinical and Translational Science

NIH

National Institute of General Medical Sciences

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ARTICLE ABSTRACT

We recently discovered that anti-TIP1 antibody activates endocytosis in cancer cells, which facilitates retention of antibody and dissociation of a conjugated drug. To improve the pharmacokinetics and cancer specificity of radiosensitizing drugs, we utilized antibody–drug conjugates (ADCs) that bind specifically to radiation-inducible antigen, TIP1, on non–small cell lung cancer (NSCLC). This approach exploits the long circulation time of antibodies to deliver a radiosensitizing drug to cancer each day during radiotherapy. Antibodies to TIP1 were prioritized based on affinity, cancer-specific binding, and internalization. The lead antibody, 7H5, was conjugated with a cytotoxic drug MMAE because of its ability to radiosensitize cancer. Cytotoxicity, colony formation, and tumor growth studies were performed with 7H5-VcMMAE in combination with radiation. 7H5 showed a high affinity to recombinant TIP1 protein and radiation-inducible TIP1 on the cancer cell surface. 7H5 undergoes endocytosis in NSCLC cells in vitro. We obtained an average drug-to-antibody ratio (DAR) of 4.25 for 7H5-VcMMAE. A 70% reduction in viable cells was observed following 7H5-VcMMAE treatment compared with 7H5 alone in both A549 and H1299 cells. 7H5-VcMMAE sensitized NSCLC cells to radiation, thereby significantly decreasing the surviving fraction. The ADC combined with radiation showed a prolonged delay in tumor growth and improved survival in A549 and H1299 tumor models. Targeting radiation-inducible TIP1 with a radiosensitizing ADC is a promising strategy to enhance the therapeutic efficacy of NSCLC. This novel approach of targeting with ADCs to radiation-inducible antigens will lead to clinical trials in lung cancer patients treated with radiotherapy.

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