Abstract 1215: Targeting TIP1 with a novel radiosensitizing antibody-drug conjugate (ADC) enhances the therapeutic efficacy of radiation for non-small cell lung carcinoma treatment

Abstract

Abstract Tax-interacting protein 1 (TIP1) is a multifunctional protein involved in cellular motility, cellular adhesion, migration, cancer cell protection from ionizing radiation, and metastasis. We found that TIP1 is a radiation inducible antigen that is translocated to the cancer cell surface. Antibody-drug-conjugates (ADCs) are emerging as promising anti-cancer immunoconjugates. ADCs carry antitumor payloads and allow site-specific targeting of cancer with increased cytotoxicity and decreased side effect profiles as compared to conventional chemotherapy. Monomethyl auristatin E (MMAE) is a potent radiosensitizing microtubule inhibitor with enhanced cancer cytotoxicity in combination with radiotherapy. We developed ADCs against radiation-inducible TIP1 for lung cancer treatment in combination with radiation. Out of the various anti-TIP1 antibodies, we prioritized the lead antibody that shows high affinity to TIP1 protein on the cancer cell surface and in vivo irradiated lung cancers. Our lead antibody, 7H5 undergoes endocytosis in cancer cells in vitro. We conjugated 7H5 to VcMMAE. Hydrophobic interaction chromatography (HIC) was performed to determine drug-to-antibody ratio (DAR). We obtained an average DAR of 3.7. Cytotoxic potential of 7H5-VcMMAE was evaluated in A549 and H1299 NSCLC cells. Cells were exposed to 7H5-VcMMAE or 7H5-antibody alone at various doses. At 10nM concentration, ~70% reduction in viable cells was observed following 7H5-VcMMAE treatment compared to 7H5 alone in both A549 (p=0.0032) and H1299 cells (p=0.0010). 7H5-VcMMAE sensitized A549 and H1299 cells to radiation as observed by significantly decreased (p<0.001) surviving fraction compared to 7H5 alone. In vivo therapeutic efficacy of the 7H5-VcMMAE was determined using mice bearing hind-limb human NSCLC tumors. The ADC showed a prolonged delay in tumor growth and improved tumor control was achieved with IR + 7H5-VcMMAE in A549 and H1299 hind-limb tumor models. Furthermore, mice in all groups displayed no toxicity associated with treatment. Our study suggests that targeting radiation-inducible TIP1 with a radiosensitizing ADC is a promising strategy to enhance therapeutic efficacy in lung cancer. This novel approach of targeting cancer using ADCs to radiation-inducible antigens will lead to clinical trials in lung cancer patients treated with radiotherapy. Citation Format: Calvin Lewis, Abhay K. Singh, Dinesh Thotala, Dennis E. Hallahan, Vaishali Kapoor. Targeting TIP1 with a novel radiosensitizing antibody-drug conjugate (ADC) enhances the therapeutic efficacy of radiation for non-small cell lung carcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1215.