Authors' Affiliations: Genmab, Utrecht, the Netherlands; Genmab, Copenhagen, Denmark; and Center for Thrombosis Research, Florida Hospital, Orlando, Florida.
Cancer Res. 2014 Feb 15;74(4):1214-26. doi: 10.1158/0008-5472.CAN-13-2440. Epub 2013 Dec 26.
Tissue factor (TF) is aberrantly expressed in solid cancers and is thought to contribute to disease progression through its procoagulant activity and its capacity to induce intracellular signaling in complex with factor VIIa (FVIIa). To explore the possibility of using tissue factor as a target for an antibody-drug conjugate (ADC), a panel of human tissue factor-specific antibodies (TF HuMab) was generated. Three tissue factor HuMab, that induced efficient inhibition of TF:FVIIa-dependent intracellular signaling, antibody-dependent cell-mediated cytotoxicity, and rapid target internalization, but had minimal impact on tissue factor procoagulant activity in vitro, were conjugated with the cytotoxic agents monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). Tissue factor-specific ADCs showed potent cytotoxicity in vitro and in vivo, which was dependent on tissue factor expression. TF-011-MMAE (HuMax-TF-ADC) was the most potent ADC, and the dominant mechanism of action in vivo was auristatin-mediated tumor cell killing. Importantly, TF-011-MMAE showed excellent antitumor activity in patient-derived xenograft (PDX) models with variable levels of tissue factor expression, derived from seven different solid cancers. Complete tumor regression was observed in all PDX models, including models that showed tissue factor expression in only 25% to 50% of the tumor cells. In conclusion, TF-011-MMAE is a promising novel antitumor agent with potent activity in xenograft models that represent the heterogeneity of human tumors, including heterogeneous target expression.
组织因子（TF）在实体瘤中异常表达，被认为通过其促凝活性及其与因子 VIIa（FVIIa）结合诱导细胞内信号转导的能力促进疾病进展。为了探索将组织因子作为抗体药物偶联物（ADC）的靶点的可能性，生成了一组人组织因子特异性抗体（TF HuMab）。三种组织因子 HuMab 诱导了有效的 TF:FVIIa 依赖性细胞内信号转导抑制、抗体依赖性细胞介导的细胞毒性和快速的靶内化，但对体外组织因子促凝活性的影响最小，与细胞毒性剂单甲基奥瑞他汀 E（MMAE）或单甲基奥瑞他汀 F（MMAF）偶联。组织因子特异性 ADC 在体外和体内均表现出强大的细胞毒性，这依赖于组织因子的表达。TF-011-MMAE（HuMax-TF-ADC）是最有效的 ADC，体内的主要作用机制是奥瑞他汀介导的肿瘤细胞杀伤。重要的是，TF-011-MMAE 在源自七种不同实体瘤的具有不同组织因子表达水平的患者来源异种移植（PDX）模型中表现出优异的抗肿瘤活性。在所有 PDX 模型中均观察到完全肿瘤消退，包括在仅 25%至 50%的肿瘤细胞中显示组织因子表达的模型。总之，TF-011-MMAE 是一种有前途的新型抗肿瘤药物，在代表人类肿瘤异质性的异种移植模型中具有强大的活性，包括异质性靶标表达。
