Potent Neutralizing Humanized Antibody With Topical Therapeutic Potential Against HPV18-Related Cervical Cancer.
Potent Neutralizing Humanized Antibody With Topical Therapeutic Potential Against HPV18-Related Cervical Cancer.
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具有局部治疗 HPV18 相关宫颈癌潜力的强效中和人源化抗体
DOI：
10.3389/fimmu.2021.678318
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发表时间：
2021
影响因子：
7.3
通讯作者：
Wu Z
中科院分区：
文献类型：
--
作者：
Huang B;Zhu L;Wei H;Shi H;Zhang D;Yuan H;Luan L;Zheng N;Xu S;Nawaz W;Hong Y;Wu X;Wu Z
由人乳头瘤病毒（HPV）感染引起的宫颈癌是世界上第四大最常见的女性癌症。目前预防性HPV疫苗在预防HPV感染方面取得了可喜的成功。然而，2018年仍报告了57万例新病例。目前宫颈癌患者的主要治疗方法是手术或放化疗。子宫颈癌仍然缺乏标准的药物治疗。与其他HPV感染相比，HPV18诱导的宫颈癌预后最差，死亡率高。与宫颈恶性肿瘤相关的HPV18的发展需要HPV18亚型持续感染宫颈阴道上皮，这可能需要数年的时间才能转化上皮。这段反复感染的时期为治疗干预提供了一个窗口期。中和抗体配制为局部剂，抑制HPV18感染应减少宫颈恶性肿瘤的机会。我们之前已经证明，在哺乳动物细胞中产生的HPV18病毒样颗粒（VLP）可以诱导有效的抗HPV18感染的中和抗血清。因此，我们从用HPV18 VLP免疫小鼠制备的3810多株杂交瘤中分离出两种有效的中和抗体2A12和8H4。2A12和8H4的50%病毒抑制浓度（IC50）分别为0.4和0.9 ng/ml。此外，2A12和8H4识别出不同且不重叠的四元表位，并与HPV18特异性结合。人源化2A12 （Hu2A12）在各种酸性pH环境和水凝胶制剂中对HPV18感染保持相当的中和活性，IC50值为0.04至0.77 ng/ml，这表明Hu2A12将是临床开发的有希望的外用阴道生物制药剂，可用于抗HPV18感染。
Cervical cancer caused by human papillomavirus (HPV) infections is the fourth most common cancer in women worldwide. Current prophylactic HPV vaccines have achieved promising success in preventing HPV infection. However, still 570,000 new cases were reported in 2018. The current primary treatment for the patient with cervical cancer is either surgery or chemoradiotherapy. Cervical cancer still lacks standard medical therapy. HPV18 induced cervical cancer has the worst prognosis and high mortality compared to other HPV infections. The development of HPV18 related with cervical malignancy requires the persistent infection of cervical–vaginal epithelium by HPV18 subtype, which can take years to transform the epithelium. This period of repeated infection provides a window for therapeutic intervention. Neutralizing antibodies formulated as topical agents that inhibit HPV18 infection should reduce the chance of cervical malignancy. We previously demonstrated that potent neutralizing anti-sera against HPV18 infection were induced by HPV18 viral like particle (VLP) generated in mammalian cells. We, therefore, isolated two potent neutralizing antibodies, 2A12 and 8H4, from over 3,810 hybridomas prepared from mice immunized with HPV18 VLP. 2A12 and 8H4 exhibited excellent potency, with 50% virus-inhibitory concentrations (IC50) of 0.4 and 0.9 ng/ml, respectively. Furthermore, 2A12 and 8H4 recognized distinct and non-overlapping quaternary epitopes and bound specifically with HPV18. Humanized 2A12 (Hu2A12) retained comparable neutralizing activity against HPV18 infection in various acidic pH settings and in hydrogel formulation with IC50 values of 0.04 to 0.77 ng/ml, indicating that Hu2A12 will be a promising candidate for clinical development as a topical vaginal biopharmaceutical agent against HPV18 infection.
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影响因子：
7.3
作者：
Dadar M;Chakraborty S;Dhama K;Prasad M;Khandia R;Hassan S;Munjal A;Tiwari R;Karthik K;Kumar D;Iqbal HMN;Chaicumpa W
通讯作者：
Chaicumpa W
影响因子：
4.6
作者：
Laniewski, Pawel;Cui, Haiyan;Herbst-Kralovetz, Melissa M.
通讯作者：
Herbst-Kralovetz, Melissa M.
影响因子：
34.3
作者：
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通讯作者：
Bray, Freddie
影响因子：
5.4
作者：
Giroglou, T;Florin, L;Sapp, M
通讯作者：
Sapp, M
影响因子：
9.7
作者：
Epstein-Barash, Hila;Stefanescu, Cristina F.;Kohane, Daniel S.
通讯作者：
Kohane, Daniel S.