CovX Research, Pfizer Inc., San Diego, California 92121, USA.
Clin Cancer Res. 2011 Mar 1;17(5):1001-11. doi: 10.1158/1078-0432.CCR-10-2317. Epub 2011 Jan 13.
Angiopoietin-1 (Ang1) plays a key role in maintaining stable vasculature, whereas in a tumor Ang2 antagonizes Ang1's function and promotes the initiation of the angiogenic switch. Specifically targeting Ang2 is a promising anticancer strategy. Here we describe the development and characterization of a new class of biotherapeutics referred to as CovX-Bodies, which are created by chemical fusion of a peptide and a carrier antibody scaffold.
Various linker tethering sites on peptides were examined for their effect on CovX-Body in vitro potency and pharmacokinetics. Ang2 CovX-Bodies with low nmol/L IC(50)s and significantly improved pharmacokinetics were tested in tumor xenograft studies alone or in combination with standard of care agents. Tumor samples were analyzed for target engagement, via Ang2 protein level, CD31-positive tumor vasculature, and Tie2 expressing monocyte penetration.
Bivalent Ang2 CovX-Bodies selectively block the Ang2-Tie2 interaction (IC(50) < 1 nmol/L) with dramatically improved pharmacokinetics (T(½) > 100 hours). Using a staged Colo-205 xenograft model, significant tumor growth inhibition (TGI) was observed (40%-63%, P < 0.01). Ang2 protein levels were reduced by approximately 50% inside tumors (P < 0.01), whereas tumor microvessel density (P < 0.01) and intratumor proangiogenic Tie2(+)CD11b(+) cells (P < 0.05) were significantly reduced. When combined with sunitinib, sorafenib, bevacizumab, irinotecan, or docetaxel, Ang2 CovX-Bodies produced even greater efficacy (∼80% TGI, P < 0.01).
CovX-Bodies provide an elegant solution to overcome the pharmacokinetic-pharmacodynamic problems of peptides. Long-acting Ang2 specific CovX-Bodies will be useful as single agents and in combination with standard-of-care agents.
血管生成素-1（Ang1）在维持稳定的血管方面发挥着关键作用，而在肿瘤中，Ang2 拮抗 Ang1 的功能并促进血管生成开关的启动。特异性靶向 Ang2 是一种很有前途的抗癌策略。本文描述了一类新的生物治疗药物的开发和表征，称为 CovX 体，它是通过化学融合肽和载体抗体支架而产生的。
研究了各种连接子连接位点对 CovX 体在体外效力和药代动力学的影响。对具有低纳摩尔 IC（50）和显著改善药代动力学的 Ang2 CovX 体进行了单独或与标准治疗药物联合的肿瘤异种移植研究。通过 Ang2 蛋白水平、CD31 阳性肿瘤血管和表达 Tie2 的单核细胞渗透来分析肿瘤样本的靶标结合。
二价 Ang2 CovX 体选择性阻断 Ang2-Tie2 相互作用（IC（50）<1 纳摩尔/升），药代动力学显著改善（T（1/2）>100 小时）。使用 Colo-205 异种移植模型，观察到显著的肿瘤生长抑制（TGI）（40%-63%，P<0.01）。肿瘤内 Ang2 蛋白水平降低约 50%（P<0.01），而肿瘤微血管密度（P<0.01）和肿瘤内促血管生成 Tie2（+）CD11b（+）细胞（P<0.05）明显减少。当与舒尼替尼、索拉非尼、贝伐单抗、伊立替康或多西他赛联合使用时，Ang2 CovX 体产生了更大的疗效（约 80%的 TGI，P<0.01）。
CovX 体为克服肽的药代动力学-药效学问题提供了一种优雅的解决方案。长效 Ang2 特异性 CovX 体将作为单一药物和与标准治疗药物联合使用非常有用。
