Dataset Information

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

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.

SUBMITTER: Lewis CD

PROVIDER: S-EPMC9167454 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Lewis Calvin D CD Singh Abhay K AK Hsu Fong-Fu FF Thotala Dinesh D Hallahan Dennis E DE Kapoor Vaishali V

Clinical cancer research : an official journal of the American Association for Cancer Research 20210601 11

<h4>Purpose</h4>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 ...[more]

PMID: 34074654

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Dataset Information

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

Purpose

Experimental design

Results

Conclusions

Publications

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

Similar Datasets

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