Synergistic Approach of Antibody-Photosensitizer Conjugate Independent of KRAS-mutation and its Downstream Blockade Pathway in Colorectal Cancer.

Here, we present a novel approach 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 KRAS-mutated cancer cells, we synthesized an antibody anti-epidermal growth factor receptor (EGFR), cetuximab, with a poloxamer linker coupled with the photosensitizer chlorin e6 (MPXC) through click chemistry (CMPXC). CMPXC was 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 (CRC) mouse models, CMPXC significantly enhanced antitumor efficacy compared with cetuximab treatment alone, resulting in an 86% reduction in tumor growth. Furthermore, CMPXC treatment led 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. Our 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. This article is protected by copyright. All rights reserved.