Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody
Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody
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DOI：
10.1182/blood-2010-06-288068
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发表时间：
2010-11-11
期刊：
影响因子：
20.3
通讯作者：
Park, Chae Gyu
中科院分区：
文献类型：
--
作者：
Cheong, Cheolho;Choi, Jae-Hoon;Park, Chae Gyu
用于T细胞免疫的蛋白质疫苗由于免疫原性差而未被优先考虑。为了克服这一障碍，在针对DC受体的单克隆抗体（mAb）中，蛋白质被靶向成熟的树突状细胞（DC）。为了将这一概念扩展到人类，我们用人DEC 205（hDEC 205）胞外结构域免疫表达人免疫球蛋白的小鼠。选择3D 6和3G 9 mAb用于与hDEC 205的高亲和力结合。此外，产生CD 11 c启动子hDEC 205转基因小鼠，并且3G 9选择性地靶向这些动物中的DC。当mAb重链被工程化以表达HIV Gag p24时，如果将多诺霉素多胞苷酸作为佐剂共同施用，则融合mAb在hDEC 205转基因小鼠中诱导产生干扰素-γ和白细胞介素-2的CD 4（+）T细胞。T细胞应答是广泛的，识别至少3种Gag肽，并产生高滴度的抗人免疫球蛋白G抗体。抗hDEC 205抗体还改善了Gag对HIV感染者的致敏CD 8（+）T细胞的交叉呈递。在所有测试中，3D 6和3G 9靶向相对于非结合对照mAb大大增强免疫。这些结果提供了临床前证据，表明体内hDEC 205靶向增加了蛋白质引发特异性免疫的效率，为这些新蛋白质疫苗在人类受试者中的概念验证研究奠定了基础。（血。2010;116（19）：3828-3838）
Protein vaccines for T-cell immunity are not being prioritized because of poor immunogenicity. To overcome this hurdle, proteins are being targeted to maturing dendritic cells (DCs) within monoclonal antibodies (mAbs) to DC receptors. To extend the concept to humans, we immunized human immunoglobulin-expressing mice with human DEC205 (hDEC205) extracellular domain. 3D6 and 3G9 mAbs were selected for high-affinity binding to hDEC205. In addition, CD11c promoter hDEC205 transgenic mice were generated, and 3G9 was selectively targeted to DCs in these animals. When mAb heavy chain was engineered to express HIV Gag p24, the fusion mAb induced interferon-gamma- and interleukin-2-producing CD4(+) T cells in hDEC205 transgenic mice, if polynocinic polycytidylic acid was coadministered as an adjuvant. The T-cell response was broad, recognizing at least 3 Gag peptides, and high titers of antihuman immunoglobulin G antibody were made. Anti-hDEC205 also improved the cross-presentation of Gag to primed CD8(+) T cells from HIV-infected individuals. In all tests, 3D6 and 3G9 targeting greatly enhanced immunization relative to nonbinding control mAb. These results provide preclinical evidence that in vivo hDEC205 targeting increases the efficiency with which proteins elicit specific immunity, setting the stage for proof-of-concept studies of these new protein vaccines in human subjects. (Blood. 2010;116(19):3828-3838)