American Association for Cancer Research
Browse

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

Download (149.39 kB)
figure
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 Figure from Targeting a Radiosensitizing Antibody–Drug Conjugate to a Radiation-Inducible Antigen

Funding

NCI

Institutional Clinical and Translational Science

NIH

National Institute of General Medical Sciences

History

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.

Usage metrics

    Clinical Cancer Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC