Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.
J Virol. 2013 Apr;87(7):3792-800. doi: 10.1128/JVI.02394-12. Epub 2013 Jan 23.
Oncolytic virus (OV) therapies of cancer are based on the use of replication-competent, tumor-selective viruses with limited toxicity. Newcastle disease virus (NDV), an avian paramyxovirus, is a promising OV and is inherently tumor selective and cytotoxic only to tumor cells. Replication is restricted in normal cells. Despite encouraging phase I/II clinical trials with NDV, further refinements for tumor-specific targeting are needed to enhance its therapeutic index. Systemically delivered NDV fails to reach solid tumors in therapeutic concentrations and also spreads poorly within the tumors due to barriers including complement, innate immunity, and the extracellular matrix. Overcoming these hurdles is paramount to realizing the exceptional oncolytic efficacy of NDV. We engineered the F protein of NDV and generated a recombinant NDV (rNDV) whose F protein is cleavable exclusively by prostate-specific antigen (PSA). The rNDV replicated efficiently and specifically in prostate cancer (CaP) cells and 3-dimensional prostaspheres but failed to replicate in the absence of PSA. Induction of intracellular PSA production by a synthetic androgen analog (R1881) enhanced fusogenicity in androgen-responsive CaP cells. Further, PSA-cleavable rNDV caused specific lysis of androgen-independent and androgen-responsive/nonresponsive CaP cells and prostaspheres, with a half-maximal effective concentration (EC50) ranging from a multiplicity of infection of 0.01 to 0.1. PSA-retargeted NDV efficiently lysed prostasphere tumor mimics, suggesting efficacy in vivo. Also, PSA-cleavable NDV failed to replicate in chicken embryos, indicating no pathogenicity for chickens. Prostate-specific antigen targeting is likely to enhance the therapeutic index of rNDV owing to tumor-restricted replication and enhanced fusogenicity.
溶瘤病毒 (OV) 疗法是基于使用复制能力强、对肿瘤具有选择性且毒性有限的病毒。新城疫病毒 (NDV) 是一种禽副黏病毒，是一种很有前途的溶瘤病毒，对肿瘤细胞具有固有选择性和细胞毒性，而对正常细胞的复制则受到限制。尽管 NDV 的 I/II 期临床试验令人鼓舞，但需要进一步改进肿瘤特异性靶向，以提高其治疗指数。全身给予 NDV 无法达到治疗浓度的实体瘤，并且由于包括补体、先天免疫和细胞外基质在内的障碍，在肿瘤内传播也很差。克服这些障碍对于实现 NDV 的卓越溶瘤疗效至关重要。我们对 NDV 的 F 蛋白进行了工程改造，并生成了一种重组 NDV(rNDV)，其 F 蛋白只能被前列腺特异性抗原 (PSA) 切割。rNDV 在前列腺癌 (CaP) 细胞和 3 维前列腺球体中高效且特异性复制，但在缺乏 PSA 的情况下无法复制。合成雄激素类似物 (R1881) 诱导细胞内 PSA 产生，增强了对雄激素反应性 CaP 细胞的融合能力。此外，PSA 可切割的 rNDV 导致雄激素非依赖性和雄激素反应性/非反应性 CaP 细胞和前列腺球体的特异性裂解，半最大有效浓度 (EC50) 范围从感染复数 0.01 到 0.1。PSA 靶向 NDV 有效地裂解前列腺球体肿瘤模拟物，表明体内疗效。此外，PSA 可切割的 NDV 无法在鸡胚中复制，表明对鸡没有致病性。PSA 靶向可能会提高 rNDV 的治疗指数，因为肿瘤限制复制和增强融合能力。
