In Vivo Fate of Cowpea Mosaic Virus In Situ Vaccine: Biodistribution and Clearance.
In Vivo Fate of Cowpea Mosaic Virus In Situ Vaccine: Biodistribution and Clearance.
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DOI：
10.1021/acsnano.2c06143
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发表时间：
2022-11-22
期刊：
影响因子：
17.1
通讯作者：
Steinmetz, Nicole F.
中科院分区：
文献类型：
--
作者：
de Oliveira, Jessica Fernanda Affonso;Chan, Soo Khim;Omole, Anthony O.;Agrawal, Vanshika;Steinmetz, Nicole F.
豇豆花叶病毒（CPMV）是一种核蛋白纳米颗粒，在瘤内给药时可作为一种高效的免疫调节剂，并可用作原位疫苗。CPMV原位接种重塑肿瘤微环境，并引发针对治疗和未治疗的远处转移部位的高度有效、全身性和持久的抗肿瘤免疫应答（远位效应）。在多种肿瘤小鼠模型中，最重要的是，在患有自发性肿瘤的犬癌症患者中证明了有效性。数据表明抗CPMV抗体的存在不是中和的，并且事实上调理作用导致增强的功效。植物病毒是食物链的一部分，但迄今为止，没有关于人类暴露于CPMV的信息。因此，测试患者血清中抗CPMV的免疫球蛋白的存在，并且实际上，>50%的去识别患者样品测试为CPMV抗体阳性。为了更广泛地了解植物病毒暴露和人体免疫原性，我们还检测了血清中的抗烟草花叶病毒（>90%的患者检测呈阳性）、马铃薯X病毒（<20%的患者检测呈阳性）和豇豆褪绿斑驳病毒（未检测到抗体）的抗体。此外，分析患者血清中是否存在针对大肠杆菌噬菌体Qβ的抗体，这是一种目前正在进行原位疫苗接种临床试验的平台技术;我们发现60%的患者存在抗Q β抗体。因此，数据表明人类接触CPMV和其他植物病毒和真菌。接下来，我们考虑解决农艺安全问题;即，我们检查了肿瘤内处理和口服管饲法（模拟食物消耗）后CPMV的命运。由于使用了活的CPMV，一个重要的问题是是否有任何证据表明感染性颗粒从小鼠或患者身上脱落。CPMV对哺乳动物无感染性;然而，它对包括黑眼豌豆和其他豆类在内的植物具有感染性。荷瘤小鼠和健康小鼠中的生物分布数据表明，几乎没有从肿瘤中浸出，并通过网状内皮系统清除，然后通过胆汁排泄。虽然有证据表明粪便中的RNA脱落，但当用粪便提取物攻击植物时，没有证据表明感染性颗粒，因此表明农艺学安全性。这些数据共同有助于CPMV作为癌症免疫治疗候选药物的翻译开发。
Cowpea mosaic virus (CPMV) is a nucleoprotein nanoparticle that functions as a highly potent immunomodulator when administered intratumorally and is used as an in situ vaccine. CPMV in situ vaccination remodels the tumor microenvironment and primes a highly potent, systemic, and durable antitumor immune response against the treated and untreated, distant metastatic sites (abscopal effect). Potent efficacy was demonstrated in multiple tumor mouse models and, most importantly, in canine cancer patients with spontaneous tumors. Data indicate that presence of anti-CPMV antibodies are not neutralizing and that in fact opsonization leads to enhanced efficacy. Plant viruses are part of the food chain, but to date, there is no information on human exposure to CPMV. Therefore, patient sera were tested for the presence of immunoglobulins against CPMV, and indeed, >50% of deidentified patient samples tested positive for CPMV antibodies. To get a broader sense of plant virus exposure and immunogenicity in humans, we also tested sera for antibodies against tobacco mosaic virus (>90% patients tested positive), potato virus X (<20% patients tested positive), and cowpea chlorotic mottle virus (no antibodies were detected). Further, patient sera were analyzed for the presence of antibodies against the coliphage Qβ, a platform technology currently undergoing clinical trials for in situ vaccination; we found that 60% of patients present with anti-Qβ antibodies. Thus, data indicate human exposure to CPMV and other plant viruses and phages. Next, we thought to address agronomical safety; i.e., we examined the fate of CPMV after intratumoral treatment and oral gavage (to mimic consumption by food). Because live CPMV is used, an important question is whether there is any evidence of shedding of infectious particles from mice or patients. CPMV is noninfectious toward mammals; however, it is infectious toward plants including black-eyed peas and other legumes. Biodistribution data in tumor-bearing and healthy mice indicate little leaching from tumors and clearance via the reticuloendothelial system followed by biliary excretion. While there was evidence of shedding of RNA in stool, there was no evidence of infectious particles when plants were challenged with stool extracts, thus indicating agronomical safety. Together these data aid the translational development of CPMV as a drug candidate for cancer immunotherapy.
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影响因子：
4.6
作者：
通讯作者：
--
影响因子：
6.7
作者：
Berardi A;Evans DJ;Baldelli Bombelli F;Lomonossoff GP
通讯作者：
Lomonossoff GP
影响因子：
4.6
作者：
Aguado-Garcia, Yarenci;Taboada, Blanca;Arias, Carlos F.
通讯作者：
Arias, Carlos F.
DOI：
10.3390/v13050822
发表时间：
2021-05-02
期刊：
Viruses
影响因子：
--
作者：
de Almeida NAA;Ribeiro CRA;Raposo JV;de Paula VS
通讯作者：
de Paula VS
影响因子：
3.2
作者：
Chan, Soo Khim;Steinmetz, Nicole F.
通讯作者：
Steinmetz, Nicole F.