Abstract 4775: Combination therapy with TB511 and anti-nectin-4 antibody drug conjugate in a human pancreatic cancer mouse model

Abstract Pancreatic cancer is a type of cancer that occurs in the pancreas and occurs in the pancreatic duct in more than 90% of cases and is known as the 10th most common cause of cancer deaths worldwide. Recently, tumor-associated macrophages (TAMs) in tumor microenvironment (TME) have been known to closely associate with progression of pancreatic cancer. Among TAMs, M2 type macrophages constitute the majority within the TME and are associated with tumor progression and drug resistance. Targeting M2 macrophages represents a promising therapeutic strategy to reprogram the TME and enhance anti-tumor immunity. In our previous study, we developed TB511, a peptide drug conjugate that preferentially binds to M2 macrophages and induces apoptosis through mitochondrial targeting by conjugating with dKLA. Furthermore, in pancreatic cancer, the nectin-4 expression has been known to contribute to tumor proliferation, angiogenesis, and patient prognosis. Nectin-4 has been considered a potential new target for the treatment of pancreatic cancer. However, therapeutic efficacy of anti-nectin-4 antibody has not been established in pancreatic cancer. This study aims to evaluate the efficacy of the combination therapy of TB511 and anti-nectin-4 antibody drug conjugate (ADC) in reducing tumor growth and modulating the immune cells of tumor microenvironment in a humanized pancreatic cancer mouse model. In this study, humanized mice bearing subcutaneous pancreatic cancer using the PANC1 cell line were treated with TB511, ADC, their combination, or PBS as a control. As a result, TB511, PADCEV, and their combination significantly reduced tumor growth and Ki67 expression. EMT marker analysis revealed increased E-cadherin and decreased vimentin expression in combination therapy groups. TB511 and combination therapy reduced M2 macrophages (CD163, CD18, Kim127, CD11b) and increased CD8 T cells in the TME, while ADC alone showed no significant immune modulation. Spatial transcriptomics highlighted decreased epithelial cancer cells, increased M1 macrophages, and elevated CD8 T and NK cells in the TB511 and combination groups. Immune checkpoint markers (CTLA4, FOXP3, LAG3) were downregulated, and cytotoxic markers (GZMB, IFNG) were upregulated with TB511 and combination therapy. No significant off-target effects were observed in the spleen, liver, lung, or brain. In conclusion, combination therapy with TB511 and ADC effectively suppresses pancreatic tumor growth and reprograms the immune microenvironment by decreasing M2 macrophages and enhancing cytotoxic T and NK cell responses, offering a promising strategy for pancreatic cancer treatment. Citation Format: Ik-Hwan Han, Ilseob Choi, Soyoung Kim, Juwon Yang, Heekyung Lee, Geumseong Yun, Hyunju Lee, Hyunsu Bae. 4775: Combination therapy with TB511 and anti-nectin-4 antibody drug conjugate in a human pancreatic cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4775.