Napolitano Stefania, Martini Giulia, Martinelli Erika, Della Corte Carminia Maria, Morgillo Floriana, Belli Valentina, Cardone Claudia, Matrone Nunzia, Ciardiello Fortunato, Troiani Teresa
Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy.
Oncotarget. 2017 Aug 2;8(47):82773-82783. doi: 10.18632/oncotarget.19797. eCollection 2017 Oct 10.
We investigated the effect of triple monoclonal antibody inhibition of EGFR to overcome acquired resistance to first generation of anti-EGFR inhibitors.
MM151 is a mixture of three different monoclonal IgG1 antibodies directed toward three different, non-overlapping, epitopes of the EGFR. We performed an study by using human CRC cell lines (SW48, LIM 1215 and CACO2) which are sensitive to EGFR inhibitors, in order to evaluate the activity of MM151 as compared to standard anti-EGFR mAbs, such as cetuximab, as single agent or in a sequential strategy of combination MM151 with irinotecan (induction therapy) followed by MM151 with a selective MEK1/2 inhibitor (MEKi) (maintenance therapy). Furthermore, the ability of MM151 to overcome acquired resistance to cetuximab has been also evaluated in cetuximab-refractory CRC models.
MM151 shown stronger antitumor activity as compared to cetuximab. The maintenance treatment with MM151 plus MEKi resulted the most effective therapeutic modality. In fact, this combination caused an almost complete suppression of tumor growth in SW48, LIM 1215 and CACO2 xenografts model at 30 week. Moreover, in this treatment group, mice with no evidence of tumor were more than double as compared to single agent treated mice. Its superior activity has also been demonstrated, in cetuximab-refractory CRC models.
These results provide experimental evidence that more efficient and complete EGFR blockade may determine better antitumor activity and could contribute to prevent and/or overcome acquired resistance to EGFR inhibitors.
我们研究了三联单克隆抗体抑制表皮生长因子受体（EGFR）以克服对第一代抗EGFR抑制剂获得性耐药的效果。
MM151是三种不同的单克隆IgG1抗体的混合物，它们分别针对EGFR的三个不同的、不重叠的表位。我们使用对EGFR抑制剂敏感的人结肠直肠癌细胞系（SW48、LIM 1215和CACO2）进行了一项研究，以评估MM151与标准抗EGFR单克隆抗体（如西妥昔单抗）相比作为单一药物的活性，或评估MM151与伊立替康联合（诱导治疗）后再与选择性MEK1/2抑制剂（MEKi）联合（维持治疗）的序贯联合策略的活性。此外，还在西妥昔单抗难治性结直肠癌模型中评估了MM151克服对西妥昔单抗获得性耐药的能力。
与西妥昔单抗相比，MM151显示出更强的抗肿瘤活性。MM151加MEKi的维持治疗是最有效的治疗方式。事实上，这种联合在30周时几乎完全抑制了SW48、LIM 1215和CACO2异种移植模型中的肿瘤生长。此外，在该治疗组中，无肿瘤证据的小鼠数量是单药治疗小鼠的两倍多。在西妥昔单抗难治性结直肠癌模型中也证明了其卓越的活性。
这些结果提供了实验证据，即更有效和完全的EGFR阻断可能决定更好的抗肿瘤活性，并可能有助于预防和/或克服对EGFR抑制剂的获得性耐药。
