Immune Stimulating Antibody‐Photosensitizer Conjugates via Fc‐Mediated Dendritic Cell Phagocytosis and Phototriggered Immunogenic Cell Death for <i>KRAS</i>‐Mutated Pancreatic Cancer Treatment
Dahye Kim, Sanghee Lee, Kun Na
Abstract
Abstract Although cetuximab (CTX) is a chimeric epidermal growth factor receptor (EGFR) antibody, the antitumor efficacy of CTX has a negligible effect in patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutated pancreatic adenocarcinoma. Given that all extant treatments are ineffective due to the undruggable characteristics of KRAS ‐mutated cancer, alternative strategies have been investigated. In this work, CTX‐conjugated maleimide‐polyethylene glycol‐chlorin e6 (CMPC) is designed to strengthen its antitumor efficacy. With strong affinity for EGFR overexpressing Aspc‐1 cells, CMPC with laser exerts the greatest cytotoxicity (90%) and induction of immunogenic cell death. Through a combination of fragment crystallizable region‐mediated antigen uptake by CTX and danger‐associated molecular patterns released by photodynamic therapy (PDT), phagocytosis and maturation of dendritic cells treated with CMPC plus laser show dramatic increases. In vivo biodistribution and antitumor effect also demonstrate that CMPC has significant tumor selectivity and tumor ablation efficacy upon laser irradiation. Furthermore, a large number of CD4 + , CD8 + T cells and mature DCs and natural killer cells are infiltrated in CMPC with laser‐treated tumor tissues and tumor‐draining lymph nodes, revealing both innate and adaptive cellular immune stimulation. This synergistic effect with CMPC and laser treatment provides an effective approach for pancreatic cancer immunotherapy attributed to both CTX and PDT.