A humanized LIF-targeting antibody synergistically enhances chemo- and immunotherapy in pancreatic cancer

Abstract

Background: Pancreatic cancer is associated with a low survival rate due to its late diagnosis, and the patients’ resistance to chemotherapy and immunotherapy. Leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, promotes the development and progression of pancreatic cancer and has emerged as a promising therapeutic target. Here, our objectives were to validate the druggability of LIF as a therapeutic target and establish an innovative treatment strategy for pancreatic ductal adenocarcinoma (PDAC) by leveraging antibody-mediated LIF blockade to enhance the efficacy of gemcitabine-based chemotherapy or PD-1-targeted immunotherapy. Method: We generated a humanized anti-LIF antibody using a murine framework as the basis. To minimize immunogenicity, we performed structural optimization of VL/VH domains and employed rational design strategies. Surface plasmon resonance (SPR) was used to determine the binding affinity of the antibody for the LIF antigen. Antitumor efficacy was evaluated across multiple preclinical models, including cancer cell lines, patient-derived organoids (PDOs), cell-derived xenografts（CDXs）, and patient-derived organoid xenografts (PDOXs). The humanized anti-LIF (h-anti-LIF) antibody was co-administered with either chemotherapy or immunotherapy in these models to assess the impact of the combination on tumor growth. Results: The h-anti-LIF antibody demonstrated higher specificity and affinity for LIF compared with its murine counterpart and exhibited superior efficacy in inhibiting tumor growth relative to the murine antibody. Furthermore, our findings revealed that selective targeting of LIF not only enhanced the chemosensitivity of pancreatic cancer to gemcitabine but also improved the efficacy of PD-1-targeted immunotherapy. Conclusion: Our study demonstrates that the humanized anti-LIF antibody emerges as a promising adjuvant for enhancing the efficacy of both chemotherapy and immunotherapy in pancreatic cancer.