Radiation-guided antibody-drug conjugates for cancer therapy

Lung cancer is the leading cause of cancer death in both men and women, with non-small cell lung cancer (NSCLC) comprising about 85% of cases. Standard-of-care for locally advanced, non-metastatic NSCLC includes cytotoxic chemotherapy, external beam radiation therapy (XRT), and immunotherapy. Despite noted benefits, many patients do not respond favorably, and a majority who initially respond experience progression, underscoring the urgent need for improved treatment strategies. We propose a transformative approach using antibody-drug conjugates (ADCs) for targeted delivery of cytotoxic drugs that act as radiosensitizers, leveraging our breakthrough discovery of radiation-inducible antigens. Specifically, we identified Tax-interacting protein 1 (TIP1) as significantly upregulated on NSCLC cells post-XRT, positioning TIP1 as a prime target for ADCs. Preliminary data demonstrate that anti-TIP1 antibodies, which undergo endocytosis and deliver payloads specifically to tumor cells, dramatically enhance XRT efficacy. Our second-generation anti-human TIP1 ADCs feature a human antibody, an advanced drug-linking strategy to minimize premature drug release, and a highly potent payload, ensuring a robust therapeutic index. We hypothesize that these ADCs will markedly enhance the therapeutic index of XRT over chemotherapy and significantly improve the durability of immune checkpoint blockade responses, potentially transforming NSCLC treatment. Aim 1 will test the hypothesis that radiosensitization by anti-TIP1 ADCs in NSCLC is independent of mutational status. We will assess TIP1 upregulation, enhanced drug delivery, and therapeutic efficacy across NSCLC cell lines and patient-derived xenografts (PDXs), stratifying patients to identify those most benefit from ADC therapy. Aim 2 will investigate how anti-human TIP1 ADCs improve XRT-induced tumor immunity and response to immunotherapy. We will examine the impact of the ADC+XRT combination on anti-tumor immunity and response to immune checkpoint blockade in immunocompetent mice and genetically engineered mouse models (GEMMs), providing a direct comparison to chemotherapy + XRT. Aim 3 will assess the pharmacokinetics (PK), maximum tolerated dose (MTD), and payload release of anti-human TIP1 ADCs in normal tissues. We will conduct these evaluations in immunocompetent mice, leveraging the near-identical similarity between mouse and human TIP1. This research can potentially revolutionize the integration of ADCs with XRT in NSCLC, significantly improving the therapeutic index and efficacy of XRT. It will also provide critical insights into how ADC/XRT combinations modulate the tumor microenvironment and enhance anti-tumor immunity, offering new avenues to bolster checkpoint blockade responses. Our preclinical evaluation of human TIP1-ADCs will pave the way for clinical development, presenting a groundbreaking strategy for NSCLC treatment that could extend survival and improve the quality of life for patients. Project Number: 1R01CA298938-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Vaishali Kapoor | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $542,644 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CTH-E (82)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293926