1. Academic Validation
  2. Targeting a Radiosensitizing Antibody-Drug Conjugate to a Radiation-Inducible Antigen

Targeting a Radiosensitizing Antibody-Drug Conjugate to a Radiation-Inducible Antigen

  • Clin Cancer Res. 2021 Jun 1;27(11):3224-3233. doi: 10.1158/1078-0432.CCR-20-1725.
Calvin D Lewis  # 1 2 Abhay K Singh  # 1 Fong-Fu Hsu 3 Dinesh Thotala 1 4 Dennis E Hallahan 5 4 Vaishali Kapoor 5
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.
  • 2 Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
  • 3 Division of Endocrinology, Metabolism and Lipid Research, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.
  • 4 Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri.
  • 5 Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri. [email protected] [email protected].
  • # Contributed equally.
Abstract

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: 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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