Affecizx TM (Anti-VEGF mAb, STW-hPV19) 阿伐珠单抗


Overview

Affecizx (STW-hPV19) 阿伐珠单抗 is a humanized IgG1/kappa monoclonal antibody (mAb) that binds with high affinity to the human vascular endothelial growth factor (VEGF). The antigen binding site (epitope) of Affecizx (STW-hPV19) is different from that of Bevacizumab (Trade name: Avastin, the FDA-approved anti-VEGF mAb drug, produced and marked by Roche/Genentech).  Both in-vitro and in-vivo dada demonstrated that the bio-activity of Affecizx (STW-hPV19) is more than 6-8 fold stronger than that of Bevacizumab (Avastin).  

In a phase 1a clinical study in patients with advanced solid tumors refractory to standard therapy, Affecizx (STW-hPV19) was found to be safe and well-tolerated (no  dose-limiting toxicity DLT was detected,maximum tolerated dose was not reached) , and also demonstrated promising single-agent anti-tumor activity.  

A phase 1b clinical trial to evaluate the safety and efficacy of Affecizx (STW-hPV19) in combination with standard chemotherapy in treatment of patients with advanced solid tumor is ongoing.

AffecizxSTW-hPV19)阿伐珠单抗是一种特异与人血管内皮生长因子(VEGF)高亲和力结合的人源化单克隆抗体(IgG1/kappa型)。Affecizx(STW-hPV19)结合VEGF的抗原位点(表位)不同于目前市售的抗VEGF单抗药物Bevacizumab(商品名: Avastin,Roche/美国Genentech公司产品)。体内外研究数据表明,Affecizx (STW-hPV19) 的生物学活性比Bevacizumab(Avastin)强6-8倍。 在Affecizx(STW-hPV19)单独给药治疗难治性晚期实体瘤患者的临床1a期研究中,Affecizx(STW-hPV19)表现有良好的安全性和耐受性(未出现DLT,也未达到MTD),并呈现出令人鼓舞的单药抗肿瘤活性。目前,Affecizx(STW-hPV19)联合标准化疗治疗晚期实体瘤的安全性和有效性的临床1b期研究正在开展中。

 

1.1 VEGF与肿瘤血管新生angiogenesis

血管新生或增生(angiogenesis)在肿瘤的发生发展、与转移扩散中起着关键作用:伴有血管新生的肿瘤增长快速、易转移且预后差。血管内皮生长因子(vascular endothelial growth factor,VEGF)是已知的最重要及最强烈的促血管新生的物质 [1-2]VEGF在多种恶性肿瘤组织中(如结直肠癌、胃癌、肝癌、肺癌、肾癌、乳腺癌、脑瘤、卵巢癌及宫颈癌等)呈过度表达[3-5],且其表达水平高低与肿瘤生长与转移复发程度呈高度正相关[5]。近年来国内外一系列临床前研究及多项临床试验已证明如通过基因调控或给予VEGF拮抗剂如人源化抗VEGF单抗药物Avastin[6]来阻断体内VEGF及其受体(VEGF-R)介导的促血管增生,则可导致肿瘤组织缺血坏死,从而达到抑制肿瘤生长和转移及延长患者生存期的良好疗效[7-10]

图1血管新生(angiogenesis)与肿瘤增长关系示意图



1.2  抗VEGF单抗Affecizx (STW-hPV19) 药物作用机理

图2 Affecizx单抗竞争阻断VEGF与其受体VEGFR结合

 

 

1.3  Affecizx具有全新的氨基酸序列及不同于Avastin的抗原识别位点

 

 

图3 鼠源PV19单抗 (Affecizx的前身)与鼠源A4.6.1单抗(Avastin的前身)

轻链可变区的氨基酸序列对比分析

 

1.4  Affecizx (STW-hPV19) 单抗生物活性强于Avastin 6-8 倍

 

 

图4 体外分析Affecizx及Avastin阻断VEGF与其受体VEGFR结合活性

 

Public presentation on the study of Affecizx (STW-hPV19): ASCO2018Click link to see the details

 

References

1.        Leung DW, Cachianes G, Kuang WJ, Goeddel DV, and Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989, 246:1306-09.

2.        Carmeliet PFerreira VBreier G,  et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996, 380:435-439

3.        Dvorak HFSioussat TMBrown LF, et al. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med. 1991, 174: 1275–1278.

4.        Brown LFBerse BJackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res. 1993,  53 :4727-4235.

5.        Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM: Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995, 55:3964-3968.

6.        Ferrara N, Hillan KJ, Novotny W.  Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005,333:328–335.

7.        Gordon MS, Margolin K, Sledge GW et al.: Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. Journal of Clinical Oncology 2001, 19:843-50.

8.        Margolin K, Gordon MS, Holmgren E, et al.: Phase Ib trail of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced caner: pharmacologic and long-term safety data. J Clin. Oncol 2001,19:851-856.

9.        Fairooz Kabbinavar, Herbert I. et al. Phase II, randomized trial comparing Bevacizumab plus Fluorouracil (FU)/Leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.  Journal of Clinical Oncology 2003, 21:60-65.

10.     Herbert Hurwitz, Louis Fehrenbacher, William Novotny, et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N Engl J Med. 2004, 350:2335-2342.