Pharmacokinetics and immunogenicity of broadly neutralizing HIV monoclonal antibodies in macaques.
Pharmacokinetics and immunogenicity of broadly neutralizing HIV monoclonal antibodies in macaques.
复制标题
DOI：
10.1371/journal.pone.0120451
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Jiang X
中科院分区：
文献类型：
--
作者：
Rosenberg Y;Sack M;Montefiori D;Labranche C;Lewis M;Urban L;Mao L;Fischer R;Jiang X
针对HIV-1的高效广谱中和抗体（bnAb）的鉴定以及被动给药后预防SHIV感染的成功，增加了采用免疫策略预防和治疗HIV-1感染的可能性。然而，虽然广泛和有效的中和活性是一个必要的先决条件，体内性质，如良好的循环稳定性和非免疫原性是同样重要的开发人类治疗。在本研究中，bnAb 10-1074、NIH 45 - 46 G54 W、10 E8、PGT 121、PGT 128、PGT 145、PGT 135、PG 9、PG 16、VRC 01和b12的糖型通过农杆菌介导的本氏烟草瞬时转染产生，并在恒河猴中施用后进行评估。结果表明：（i）VL结构域内的N-聚糖损害植物来源的bnAb的血浆稳定性，和（ii）虽然PGT 121和b12在多次注射后在恒河猴中不表现出免疫原性，但VRC 01、10-1074和NIH 45 - 46 G54 W在第二次注射后引发高滴度抗独特型抗体。这些抗独特型抗体特异性结合所施用的bnAb或近亲，并在中和测定中抑制bnAb。这些发现表明，某些bnAb中的特定突变有助于其免疫原性，并引起人们对这些突变的bnAb在人类中具有免疫原性的前景的关注，这可能会损害其用于预防和治疗HIV-1的价值。
The identification of highly potent broadly neutralizing antibodies (bnAbs) against HIV-1, and success in preventing SHIV infection following their passive administration, have increased the likelihood that immunotherapeutic strategies can be adopted to prevent and treat HIV-1 infection. However, while broad and potent neutralizing activity is an essential prerequisite, in vivo properties such as good circulatory stability and non-immunogenicity are equally critical for developing a human treatment. In the present study, glycoforms of the bnAbs 10-1074, NIH45-46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, PG9, PG16, VRC01 and b12 were produced by Agrobacterium-mediated transient transfection of Nicotiana benthamiana and assessed following administration in rhesus macaques. The results indicate that (i) N-glycans within the VL domain impair plasma stability of plant-derived bnAbs and (ii) while PGT121 and b12 exhibit no immunogenicity in rhesus macaques after multiple injections, VRC01, 10-1074 and NIH45-46G54W elicit high titer anti-idiotypic antibodies following a second injection. These anti-idiotypic antibodies specifically bind the administered bnAb or a close family member, and inhibit the bnAb in neutralization assays. These findings suggest that specific mutations in certain bnAbs contribute to their immunogenicity and call attention to the prospect that these mutated bnAbs will be immunogenic in humans, potentially compromising their value for prophylaxis and therapy of HIV-1.
登录
查看更多内容
影响因子：
64.8
作者：
Huang J;Ofek G;Laub L;Louder MK;Doria-Rose NA;Longo NS;Imamichi H;Bailer RT;Chakrabarti B;Sharma SK;Alam SM;Wang T;Yang Y;Zhang B;Migueles SA;Wyatt R;Haynes BF;Kwong PD;Mascola JR;Connors M
通讯作者：
Connors M
影响因子：
56.9
作者：
Haynes, BF;Fleming, J;Alam, SM
通讯作者：
Alam, SM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.4
作者：
Pancera, Marie;McLellan, Jason S.;Kwong, Peter D.
通讯作者：
Kwong, Peter D.