Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Curr Drug Deliv. 2011 Jan;8(1):135-43. doi: 10.2174/156720111793663570.
Vascular-targeting antiangiogenic therapy (VTAT) of cancer can be advantageous over conventional tumor cell targeted cancer therapy if an appropriate target is found. Our hypothesis is that endoglin (ENG; CD105) is an excellent target in VTAT. ENG is selectively expressed on vascular and lymphatic endothelium in tumors. This allows us to target both tumor-associated vasculature and lymphatic vessels to suppress tumor growth and metastasis. ENG is essential for angiogenesis/vascular development and a co-receptor of TGF-β. Our studies of selected anti-ENG monoclonal antibodies (mAbs) in several animal models and in vitro studies support our hypothesis. These mAbs and/or their immunoconjugates (immunotoxins and radioimmunoconjugates) induced regression of preformed tumors as well as inhibited formation of new tumors. In addition, they suppressed metastasis. Several mechanisms were involved in the suppressive activity of the naked (unconjugated) anti-ENG mAbs. These include direct growth suppression of proliferating endothelial cells, induction of apoptosis, ADCC (antibody-dependent cell-mediated cytotoxicity) and induction of T cell immunity. To facilitate clinical application, we generated a human/mouse chimeric anti-ENG mAb termed c-SN6j and performed studies of pharmacokinetics, toxicology and immunogenicity of c-SN6j in nonhuman primates. No significant toxicity was detected by several criteria and minimal immune response to the murine part of c-SN6j was detected after multiple i.v. injections. The results support our hypothesis that c-SN6j can be safely administered in cancer patients. This hypothesis is supported by the ongoing phase 1 clinical trial of c-SN6j (also known as TRC105) in patients with advanced or metastatic solid cancer in collaboration with Tracon Pharma and several oncologists (NCT00582985).
血管靶向抗血管生成治疗（VTAT）在找到合适的靶点的情况下可能优于传统的肿瘤细胞靶向癌症治疗。我们的假设是，内皮糖蛋白（ENG；CD105）是 VTAT 的一个很好的靶点。ENG 选择性地在肿瘤的血管和淋巴管内皮细胞上表达。这使我们能够靶向肿瘤相关的血管和淋巴管，以抑制肿瘤生长和转移。ENG 是血管生成/血管发育所必需的，也是 TGF-β的共受体。我们在几种动物模型和体外研究中对选定的抗 ENG 单克隆抗体（mAbs）的研究支持我们的假设。这些 mAbs 和/或它们的免疫偶联物（免疫毒素和放射性免疫偶联物）诱导已形成的肿瘤消退，并抑制新肿瘤的形成。此外，它们还抑制了转移。裸（未缀合）抗 ENG mAbs 的抑制活性涉及几种机制。这些包括对增殖的内皮细胞的直接生长抑制、诱导细胞凋亡、ADCC（抗体依赖性细胞介导的细胞毒性）和诱导 T 细胞免疫。为了促进临床应用，我们生成了一种人/鼠嵌合抗 ENG mAb，称为 c-SN6j，并在非人类灵长类动物中进行了 c-SN6j 的药代动力学、毒性和免疫原性研究。根据几个标准，没有检测到明显的毒性，并且在多次静脉注射后，仅检测到对 c-SN6j 的鼠部分的最小免疫反应。这些结果支持我们的假设，即 c-SN6j 可以安全地用于癌症患者。这一假设得到了正在进行的 c-SN6j（也称为 TRC105）在 Tracon Pharma 和几位肿瘤学家合作的晚期或转移性实体癌患者中的 I 期临床试验的支持（NCT00582985）。
