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A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers
Cancer Biology & Therapy ( IF 4.4 ) Pub Date : 2020-03-19 , DOI: 10.1080/15384047.2020.1737490
Ryo Fujita 1 , Vincent Blot 1 , Eley Wong 1 , Christine Stewart 1 , Vincent Lieuw 1 , Robyn Richardson 1 , Ammar Banah 1 , Jose Villicana 1 , Anjuli Timmer 1 , Julia Coronella 1 , Roland Newman 1 , Marco Gymnopoulos 1
Affiliation  

ABSTRACT

c-Met is a well-characterized oncogene that is associated with poor prognosis in many solid tumor types. While responses to c-Met inhibitors have been observed in clinical trials, activity appears to be limited to those with MET gene amplifications or mutations. We developed a c-Met targeted antibody-drug conjugate (ADC) with preclinical activity in the absence of MET gene amplification or mutation, and activity even in the context of moderate protein expression. The ADC utilized a high-affinity c-Met antibody (P3D12), that induced c-Met degradation with minimal activation of c-Met signaling, or mitogenic effect. P3D12 was conjugated to the tubulin inhibitor toxin MMAF via a cleavable linker (vc-MMAF). P3D12-vc-MMAF demonstrated potent in vitro activity in c-Met protein-expressing cell lines regardless of MET gene amplification or mutation status, and retained activity in cell lines with medium-low c-Met protein expression. In contrast, the c-Met tyrosine kinase inhibitor (TKI) PHA-665752 slowed tumor cell growth in vitro only in the context of MET gene amplification or very high protein expression. This differential activity was even more marked in vivo. P3D12-vc-MMAF demonstrated robust inhibition of tumor growth in the MET gene amplified MKN-45 xenograft model, and similar results in H1975, which expresses moderate levels of wild type c-Met without genomic amplification. By comparison, the c-Met TKI, PHA-665752, demonstrated modest tumor growth inhibition in MKN-45, and no inhibition at all in H1975. Taken together, these data suggest that P3D12-vc-MMAF may have a superior clinical profile in treating c-Met positive malignancies in contrast to c-Met pathway inhibitors.



中文翻译:

一种新型的非激动剂c-Met抗体药物偶联物,在c-Met扩增和非扩增癌症中具有优于c-Met酪氨酸激酶抑制剂的功效

摘要

c-Met是特征明确的致癌基因,与许多实体瘤类型的预后不良有关。尽管在临床试验中已观察到对c-Met抑制剂的反应,但活性似乎仅限于具有MET基因扩增或突变的活性。我们开发了具有c-Met靶向的抗体-药物偶联物(ADC),在没有MET基因扩增或突变的情况下具有临床前活性,甚至在中等蛋白表达的情况下也具有活性。ADC使用了高亲和力的c-Met抗体(P3D12),该抗体可诱导c-Met降解,同时最小化c-Met信号激活或促有丝分裂作用。P3D12通过可裂解的接头(vc-MMAF)与微管蛋白抑制剂毒素MMAF偶联。无论MET基因扩增或突变状态如何,P3D12-vc-MMAF均可在表达c-Met蛋白的细胞系中发挥强大的体外活性,并在c-Met蛋白表达水平较低的细胞系中保留了活性。相反,仅在MET基因扩增或非常高的蛋白表达的情况下,c-Met酪氨酸激酶抑制剂(TKI)PHA-665752在体外减慢了肿瘤细胞的生长。这种差异活性在体内甚至更为明显。P3D12-vc-MMAF在MET基因扩增的MKN-45异种移植模型中显示出对肿瘤生长的强大抑制作用,在H1975中得到了类似的结果,H1975表达了中等水平的野生型c-Met,而没有基因组扩增。相比之下,c-Met TKI PHA-665752在MKN-45中显示出适度的肿瘤生长抑制作用,而在H1975中则完全没有抑制作用。综上所述,这些数据表明,与c-Met途径抑制剂相比,P3D12-vc-MMAF在治疗c-Met阳性恶性肿瘤方面可能具有更好的临床特征。

更新日期:2020-04-20
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