Development of a low-seroprevalence, αvβ6 integrin-selective virotherapy based on human adenovirus type 10.
Development of a low-seroprevalence, αvβ6 integrin-selective virotherapy based on human adenovirus type 10.
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基于人类腺病毒10型的低渗透价值，αVβ6整联蛋白选择性疗法的发展。
DOI：
10.1016/j.omto.2022.03.007
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发表时间：
2022-06-16
期刊：
影响因子：
--
通讯作者：
Parker AL
中科院分区：
文献类型：
--
作者：
Bates EA;Davies JA;Váňová J;Nestić D;Meniel VS;Koushyar S;Cunliffe TG;Mundy RM;Moses E;Uusi-Kerttula HK;Baker AT;Cole DK;Majhen D;Rizkallah PJ;Phesse T;Chester JD;Parker AL
溶瘤病毒疗法(OV)具有巨大的临床潜力。基于人腺病毒(HAdV)的OV具有自然低的预先存在免疫率，将有利于未来的临床翻译。我们构建了一种低血清阳性率的HAdV-D10血清型载体，该载体含有αvβ6整合素选择性多肽A20，用于靶向αvβ6阳性肿瘤细胞类型。HAdV-D10具有有限的自然趋向性。HAdV-D10结蛋白的结构和生物学研究强调了它与自然腺病毒受体CAR和唾液酸的低亲和力。HAdV-D10不能结合凝血因子X，从而有可能在体内消除“非靶点”的肝隔离。我们设计了一种A20肽，它选择性地将αvβ6整合素结合到HAdV-D10纤维旋钮的DG环中。显微镜下证实，在αvβ6+癌细胞系中的检测表明，αvβ6靶向变异体介导的转导显著高于对照组。HAdV-D10.A20通过中和HAdV-C5血清来抵抗中和。系统注射HAdV-D10.A20可显著增加BT20肿瘤细胞中GFP的表达。具有复制能力的HAdV-D10.A20在体外和体内均显示αvβ6整合素选择性杀伤细胞。HAdV-D10具有很有前途的病毒治疗的特点，结合了低血清阳性率、弱受体相互作用和减少靶外摄取。αvβ6整合素选择性多肽的掺入导致了HAdVD10.A20，具有显著的临床翻译潜力。到目前为止，基于腺病毒的OV的疗效一直受到缺乏肿瘤选择性的阻碍，加上先前存在的抗HAdV-C5免疫率很高。我们设计了一种低血清阳性率的腺病毒(HAdV-D10)来选择性地感染αvβ6+肿瘤细胞。HAdV-D10.A20具有巨大的潜力，为临床翻译提供了一个诱人的平台。
Oncolytic virotherapies (OV) hold immense clinical potential. OV based on human adenoviruses (HAdV) derived from HAdV with naturally low rates of pre-existing immunity will be beneficial for future clinical translation. We generated a low-seroprevalence HAdV-D10 serotype vector incorporating an αvβ6 integrin-selective peptide, A20, to target αvβ6-positive tumor cell types. HAdV-D10 has limited natural tropism. Structural and biological studies of HAdV-D10 knob protein highlighted low-affinity engagement with native adenoviral receptors CAR and sialic acid. HAdV-D10 fails to engage blood coagulation factor X, potentially eliminating “off-target” hepatic sequestration in vivo. We engineered an A20 peptide that selectively binds αvβ6 integrin into the DG loop of HAdV-D10 fiber knob. Assays in αvβ6+ cancer cell lines demonstrated significantly increased transduction mediated by αvβ6-targeted variants compared with controls, confirmed microscopically. HAdV-D10.A20 resisted neutralization by neutralizing HAdV-C5 sera. Systemic delivery of HAdV-D10.A20 resulted in significantly increased GFP expression in BT20 tumors. Replication-competent HAdV-D10.A20 demonstrated αvβ6 integrin-selective cell killing in vitro and in vivo. HAdV-D10 possesses characteristics of a promising virotherapy, combining low seroprevalence, weak receptor interactions, and reduced off-target uptake. Incorporation of an αvβ6 integrin-selective peptide resulted in HAdV-D10.A20, with significant potential for clinical translation. To date, the efficacy of adenoviral-based OV has been hampered by a lack of tumor selectivity, coupled with high rates of pre-existing anti-HAdV-C5 immunity. We engineered a low-seroprevalence adenovirus (HAdV-D10) to selectively infect αvβ6+ tumor cells. HAdV-D10.A20 has significant potential and provides an enticing platform for clinical translation.
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影响因子：
4.1
作者：
DAROUGAR, S;WALPITA, P;MCSWIGGAN, DA
通讯作者：
MCSWIGGAN, DA
影响因子：
82.9
作者：
Gaggar, A;Shayakhmetov, DM;Lieber, A
通讯作者：
Lieber, A
影响因子：
158.5
作者：
KNOWLES, MR;HOHNEKER, KW;BOUCHER, RC
通讯作者：
BOUCHER, RC
影响因子：
6.4
作者：
Korn, W. M.;Macal, M.;Ferrell, L.
通讯作者：
Ferrell, L.
影响因子：
4.2
作者：
HUEBNER, RJ;ROWE, WP
通讯作者：
ROWE, WP