Synergistic Approach of Antibody‐Photosensitizer Conjugate Independent of KRAS‐Mutation and Its Downstream Blockade Pathway in Colorectal Cancer

Abstract

AbstractHere, a novel approach is presented to improve the efficacy of antibody‐drug conjugates (ADC) by integrating antibody‐mediated immunotherapy and photodynamic therapy (PDT) in a combination therapy system utilizing an antibody‐photosensitizer conjugate (APC) platform based on a poloxamer polymer linker. To specifically target Kirsten rat sarcoma 2 viral oncogene homolog (KRAS)‐mutated cancer cells, an antibody antiepidermal growth factor receptor (EGFR), cetuximab, with a poloxamer linker coupled with the photosensitizer chlorin e6 through click chemistry (cetuximab‐maleimide‐poly(ethylene oxide)‐poly(propylene oxide)‐poly(ethylene oxide)‐chlorine e6 conjugate, CMPXC) is synthesized. CMPXC is cytotoxic upon laser treatment, achieving a 90% cell death by suppressing KRAS downstream signaling pathways associated with ERK and AKT proteins, confirmed using RNA sequencing analysis. In KRAS‐mutated colorectal cancer mouse models, CMPXC significantly enhances antitumor efficacy compared with cetuximab treatment alone, resulting in an 86% reduction in tumor growth. Furthermore, CMPXC treatment leads to a 2.24‐ and 1.75‐fold increase in dendritic and priming cytotoxic T cells, respectively, highlighting the immune‐activating potential of this approach. The findings suggest that the APC platform addresses the challenges associated with ADC development and EGFR‐targeted therapy, including the synergistic advantages of antibody‐mediated immunotherapy and PDT.