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.
抗体药物偶联物（ADC）是一种前景广阔的递送系统，其通过将单克隆抗体（mAb）与细胞毒性药物等特定药物连接，实现对肿瘤细胞的靶向治疗。这类新型抗肿瘤疗法如同"生物导弹"，能在提高治疗指数的同时降低毒性。ADC设计中最关键的因素之一是选择在癌细胞表面高表达的靶抗原。本研究将靶向表皮生长因子受体（EGFR）的单克隆抗体西妥昔单抗（Cet）与氨基双膦酸盐类药物（N-BPs）——伊班膦酸钠（IBA）、利塞膦酸钠（RIS）或唑来膦酸（ZA）进行偶联。西妥昔单抗目前用于治疗具有野生型EGFR信号通路的转移性结直肠癌患者。已有研究证实，N-BPs在体外和体内实验模型中均能激活Vδ2 T细胞的抗肿瘤活性。我们将制备的ADC加入共培养体系，评估其对结直肠癌细胞系增殖的影响及对Vδ2 T抗肿瘤淋巴细胞的敏感性，并与天然抗体进行对比。实验分别在传统培养体系和3D球体培养体系中进行。研究发现：三种ADC均能增强对野生型EGFR细胞系Caco-2增殖的抑制作用；而仅Cet-RIS和Cet-ZA能增强Vδ2 T细胞对野生型和EGFR突变型结直肠癌细胞系（Caco-2、DLD-1和HCT-116）的细胞毒性。此外，ADC还能促进外周血和肿瘤样本中Vδ2 T细胞的增殖。研究结果表明，与N-BPs结合的抗EGFR抗体可增强天然抗体的抗肿瘤效果，有望提升临床疗效。
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