An Antibody-Drug Conjugate That Targets Tissue Factor Exhibits Potent Therapeutic Activity against a Broad Range of Solid Tumors
An Antibody-Drug Conjugate That Targets Tissue Factor Exhibits Potent Therapeutic Activity against a Broad Range of Solid Tumors
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DOI：
10.1158/0008-5472.can-13-2440
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发表时间：
2014-02-15
期刊：
影响因子：
11.2
通讯作者：
Parren, Paul W. H. I.
中科院分区：
文献类型：
--
作者：
Breij, Esther C. W.;de Goeij, Bart E. C. G.;Parren, Paul W. H. I.
组织因子（TF）在实体癌中异常表达，并被认为通过其促凝活性和与VIIa因子（FVIIa）复合诱导细胞内信号传导的能力促进疾病进展。为了探索使用组织因子作为抗体-药物偶联物（ADC）靶点的可能性，我们制作了一组人组织因子特异性抗体（TF HuMab）。三种组织因子HuMab与细胞毒性药物单甲基auristatin E （MMAE）或单甲基auristatin F （MMAF）偶联，诱导了TF的有效抑制：fviia依赖性细胞内信号传导、抗体依赖性细胞介导的细胞毒性和快速靶点内化，但对组织因子促凝活性的影响最小。组织因子特异性adc在体外和体内表现出强大的细胞毒性，其毒性依赖于组织因子的表达。TF-011-MMAE （HuMax-TF-ADC）是最有效的ADC，在体内的主要作用机制是耳道素介导的肿瘤细胞杀伤。重要的是，TF-011-MMAE在来自7种不同实体癌的组织因子表达水平不同的患者来源的异种移植瘤（PDX）模型中显示出出色的抗肿瘤活性。在所有PDX模型中，包括仅在25%至50%的肿瘤细胞中显示组织因子表达的模型，均观察到肿瘤完全消退。总之，TF-011-MMAE是一种很有前景的新型抗肿瘤药物，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，包括异种靶点表达。AACR (C) 2013人。
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. (C)2013 AACR.