Therapeutic Targeting Tongue Squamous Cell Carcinoma via ICAM1 Antibody-Drug Conjugates in Preclinical Models

Abstract To date, the treatment options for metastatic and recurrent tongue squamous cell carcinoma (TSCC) remain limited due to the lack of effective drug targets and therapeutics. Here we report the identification of ICAM1 as a TSCC target candidate for the development of antibody-drug conjugates (ADC), an emerging class of targeted therapeutics. We first performed an unbiased and quantitative screening of a panel of 69 TSCC cell surface antigens that identified ICAM1 as the most abundant hit. The overexpression level of ICAM1 was validated in 26 TSCC clinical specimens and four cell lines along with genomic information of 153 TSCC patients from the TCGA database. Subsequently, two ICAM1-targeted ADCs were designed and synthesized using two cytotoxic payloads of different mechanisms of action: monomethyl auristatin E (MMAE), a microtubule inhibitor, and deruxtecan (DXd), a type I DNA topoisomerase inhibitor, respectively. The therapeutic efficacy of these ICAM1 ADCs was determined in vitro and in vivo. Both ADCs selectively and potently ablate TSCC tumors in the established SAS cell line and patient-derived xenograft models. Our experimental results strongly support ICAM1 as a promising ADC target candidate for TSCC therapy.