EGFR-Targeted Antibody–Drug Conjugate to Different Aminobisphosphonates: Direct and Indirect Antitumor Effects on Colorectal Carcinoma Cells.

Simple Summary: Colorectal carcinoma (CRC) is a prevalent form of cancer globally. Despite advancements in diagnosing and treating CRC patients, the current therapies and control measures are insufficient in improving outcomes. This study aims to assess the potential effectiveness of immunotherapy utilizing γδ T cells for CRC. To accomplish this, conventional in vitro cultures and spheroids, a practical 3D culture system, were employed as a reliable in vitro model to examine the characteristics and behavior of CRC tumor cells. New antibody–drug conjugates (ADCs) were developed to specifically target EGFR+ CRC cells and activate the Vδ2-T-cell-mediated response by delivering an aminobisphosphonate, ultimately leading to the killing of CRC cells. The efficacy and cytotoxicity of these ADCs were assessed to determine the relevance of this conjugation approach for eliminating tumor cells. Antibody––drug conjugates (ADCs) are a promising delivery system that involves linking a monoclonal antibody (mAb) to a specific drug, such as a cytotoxic agent, to target tumor cells. This new class of antitumor therapy acts as a "biological missile" that can destroy tumor cells while increasing the therapeutic index and decreasing toxicity. One of the most critical factors in ADC design is selecting a target antigen that is highly expressed on the surface of cancer cells. In this study, we conjugated Cetuximab (Cet), a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), to aminobisphosphonates (N-BPs) such as ibandronate (IBA) or risedronate (RIS) or zoledronate (ZA). Cetuximab is administered to patients with metastatic colorectal carcinoma (mCRC) with a wild-type (WT) EGFR transduction pathway. Also, it is well established that N-BPs can trigger the antitumor activity of Vδ2 T cells in both in vitro and in vivo experimental models. The resulting ADCs were added in co-culture to assess the effect on CRC cell line proliferation and sensitivity to Vδ2 T antitumor lymphocytes in comparison with the native antibody. These assays have been performed both in conventional and 3D spheroid cultures. We found that all three ADCs can increase the inhibitory effect on cell proliferation of the WT-EGFR cell line Caco-2 while only Cet-RIS and Cet-ZA can increase the cytotoxicity mediated by Vδ2 T cells against both WT and EGFR-mutated CRC cell lines (Caco-2, DLD-1, and HCT-116). Also, the ADCs can trigger the cell proliferation of Vδ2 T cells present in peripheral blood and tumor specimens. Our findings indicate that anti-EGFR antibodies bound to N-BPs can improve the antitumor effects of the native antibody possibly increasing the therapeutic effect. [ABSTRACT FROM AUTHOR]