Immunotargeting of Cartilage Oligomeric Matrix Protein (COMP) for anti-neoplastic applications

Cartilage Oligomeric Matrix Protein (COMP) is a complex and multifunctional extracellular matrix glycoprotein particularly abundant in cartilaginous, tendinous, and ligamentous tissues. Its unique multi-domain structure confers a crucial role in the organization and maintenance of the function of extracellular matrix, actively contributing to the stability and renewal of connective tissues through interactions with various Matrisome components, including collagen, glycoproteins, and proteoglycans, thereby influencing tissue homeostasis processes. Recently, COMP has attracted growing interest in the field of cancer research, as it has been identified as a potential biomarker with both diagnostic and prognostic value. Its high and aberrant expression in several epithelial carcinomas is strongly correlated with its functional role in tumor progression, influencing key processes such as cell proliferation, migration, and adhesion, which are associated with more aggressive tumor phenotypes and poor clinical outcomes. In this context, the present study has taken advantage of a broad panel of monoclonal antibodies specific for COMP, not only aimed at producing diagnostic and therapeutic agents with high specificity and affinity, but also at deepening the understanding of COMP biology of soft-tissue sarcomas and certain epithelial tumor types. The structural and functional characterization of the anti-COMP antibodies, combining bioinformatic, biochemical, and cellular techniques, enabled the identification of two candidate antibodies with an high clinical potential and perspective to be developed as novel therapeutics with enhanced efficacy across multiple tumor types exhibiting high constitutive expression of COMP. The strong potential of monoclonal antibody 2127F5/F3 in imaging diagnostics for osteosarcoma, soft tissue sarcomas, colon adenocarcinomas and gastric carcinomas was demonstrated by its marked recognition of COMP in tumor tissue compared to healthy tissue, suggesting promising applications in nuclear medicine and precision surgery. In vitro studies further supported the role of COMP as a regulator of cell motility and a promising therapeutic target, demonstrating its contribution to tumor migration both through interactions with matrix proteins and as a functional component of the matrix itself. Interference of these interactions by antibody 484D1/A3 led to a marked inhibition of migration in breast and gastric cancer cell models, suggesting a matrix and microenvironment-dependent mechanism of action. The anti-tumor activity of antibody 484D1/A3 was also validated through inhibition of tumor growth in gastric cancer, and more markedly in gastric adenocarcinoma, where significant cytotoxic activity was observed, suggesting interference with COMP-mediated resistance to programmed cell death. These findings lay the groundwork for the use of anti-COMP monoclonal antibodies in the development of advanced diagnostic tools and targeted therapeutic strategies against COMP, with promising applications in the clinical management of highly aggressive solid tumors.