TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV), and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasma samples were tested for angiogenic and inflammatory biomarkers at baseline and on-treatment. To provide broader context of this combination biomarker study, direct cross-study comparisons were made to biomarker studies previously conducted in patients treated with either BEV or TRC105 monotherapy. Upon treatment with BEV and TRC105, pharmacodynamic changes in response to both BEV (PlGF increase) and TRC105 (soluble endoglin increase) were noted. In addition, distinct patterns of change were identified (similar, opposing, neutralizing). Similar patterns were observed when the combination elicited similar effects to those observed with monotherapy treatment (i.e., decreases of Ang-2, increases of IL6 and VCAM-1). Opposing patterns were observed when the combination led to opposing effects compared with monotherapy treatment (i.e., TGFβ1, PDGF-AA and PDGF-BB, PAI-1). Lastly, neutralizing patterns were observed when one drug led to increase, whereas the other drug led to decrease, and the combination elicited no overall effect on the marker (i.e., VEGF-A, VEGF-D, and IGFBP-3). Patients achieving partial responses or stable disease from the combination exhibited significantly lower expression of E-Cadherin, HGF, ICAM-1, and TSP-2 at baseline. Taken together, the novel biomarker modulations identified may deepen our understanding of the underlying biology in patients treated with BEV and TRC105 compared with either drug alone. Mol Cancer Ther; 17(10); 2248–56. ©2018 AACR.

中文翻译：

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接受贝伐单抗和抗内皮糖蛋白抗体 TRC105 的癌症患者中循环蛋白生物标志物的调节

TRC105 是一种抗内皮糖蛋白抗体，目前正在与 VEGF 抑制剂联合进行测试。在 Ib 期试验中，38 名患者同时接受了 TRC105 和贝伐珠单抗 (BEV) 治疗，并观察到临床结果有所改善，尽管 30 名患者 (79%) 对先前的抗 VEGF 治疗无效。在基线和治疗中测试血浆样品的血管生成和炎症生物标志物。为了提供该组合生物标志物研究的更广泛背景，我们将之前在接受 BEV 或 TRC105 单药治疗的患者中进行的生物标志物研究进行了直接交叉研究比较。在用 BEV 和 TRC105 治疗后，注意到响应 BEV（PlGF 增加）和 TRC105（可溶性内皮糖蛋白增加）的药效学变化。此外，还确定了不同的变化模式（相似的、相反的、中和）。当组合引起与单药治疗观察到的效果相似时，观察到相似的模式（即，Ang-2 降低，IL6 和 VCAM-1 增加）。与单一疗法（即 TGFβ1、PDGF-AA 和 PDGF-BB、PAI-1）相比，当组合导致相反的效果时，观察到相反的模式。最后，当一种药物导致增加，而另一种药物导致减少时，观察到中和模式，并且组合未引起对标记物（即，VEGF-A、VEGF-D 和 IGFBP-3）的总体影响。从组合中获得部分缓解或疾病稳定的患者在基线时表现出显着降低的 E-钙粘蛋白、HGF、ICAM-1 和 TSP-2 表达。综合起来，与单独使用任何一种药物相比，发现的新型生物标志物调节可能加深我们对 BEV 和 TRC105 治疗患者潜在生物学的理解。摩尔癌症治疗; 17(10); 2248-56。©2018 AACR。