Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines.
Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines.
复制标题
DOI：
10.3389/fimmu.2021.786144
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Zurawski G
中科院分区：
文献类型：
--
作者：
Ceglia V;Zurawski S;Montes M;Kroll M;Bouteau A;Wang Z;Ellis J;Igyártó BZ;Lévy Y;Zurawski G
CD 40是免疫系统的抗原呈递细胞（APC）上表达的有效活化受体。CD 40通过与活化T细胞上表达的CD 40 L相互作用调节B和T细胞免疫的许多方面。通过激动性抗CD 40抗体融合物将抗原靶向CD 40促进体液和细胞免疫，但目前的抗CD 40抗体-抗原疫苗原型需要共佐剂施用以获得显著的体内功效。这可能是通过抗原融合减弱抗CD 40激动剂活性的结果。我们先前证明了CD 40 L与抗CD 40抗体的直接融合赋予超激动剂性质。在这里，我们表明，抗-CD 40-CD 40 L-抗原融合构建体保留强激动剂活性，特别是对树突状细胞（DC）的活化。因此，我们测试了与抗原融合的抗CD 40-CD 40 L抗体在体外和体内引发免疫应答。在来自HIV-1感染供体的PBMC培养物中，与类似的抗CD 40-抗原构建体相比，与HIV-1抗原融合的抗CD 40-CD 40 L优先扩增HIV-1特异性CD 8 + T细胞而不是CD 4 + T细胞。在正常供体中，与抗CD 40介导的递送相比，抗CD 40-CD 40 L介导的流感M1蛋白递送在较低剂量下引起M1特异性T细胞扩增。此外，在人骨髓来源的树突状细胞上，与抗CD 40-gp 100肽相比，抗CD 40-CD 40 L-黑色素瘤gp 100肽诱导更持续的I类抗原呈递。在人CD 40转基因小鼠中，与不含融合CD 40 L的抗CD 40-gp 140抗原相比，在不含佐剂的情况下给予抗CD 40-CD 40 L-HIV-1 gp 140引起了更好的上级抗体反应。在人CD 40小鼠中，与抗CD 40溶剂相比，Eα 52-68肽的抗CD 40-CD 40 L递送引起TCR I-Eα 52 -68 CD 4 + T细胞增殖，产生细胞因子IFNγ。此外，与对照组相比，仅人CD 40小鼠的抗CD 40-CD 40 L-Cyclin D1疫苗接种减少了植入的EO771.LMB乳腺肿瘤细胞生长。这些数据表明，与抗原融合的人CD 40-CD 40 L抗体保持高度激动活性，并产生不同于现有低激动剂抗CD 40靶向形式的免疫应答。这些优势是在体外偏向CD 8 + T细胞的反应，在低剂量下增加的功效，以及MHC I类肽展示的寿命;在小鼠模型中，更强大的体液反应，更多活化的CD 4 + T细胞，以及肿瘤生长的控制。因此，抗-CD 40-CD 40 L形式提供了具有独特性质（包括内在佐剂活性）的替代DC靶向平台。
CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses in vitro and in vivo. In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8+ T cells versus CD4+ T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4+ T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were in vitro skewing responses towards CD8+ T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4+ T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.
登录
查看更多内容
影响因子：
3.8
作者：
Barnes, DM;Gillett, CE
通讯作者：
Gillett, CE
DOI：
10.1093/protein/9.7.617
发表时间：
1996-07-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Ridgway, JBB;Presta, LG;Carter, P
通讯作者：
Carter, P
影响因子：
1.6
作者：
Shi, Yunnuo;Halperin, Scott A.;Lee, Song F.
通讯作者：
Lee, Song F.
影响因子：
3.7
作者：
Flamar, Anne-Laure;Bonnabau, Henri;Levy, Yves
通讯作者：
Levy, Yves
影响因子：
15.9
作者：
Cheng, Liang;Wang, Qi;Su, Lishan
通讯作者：
Su, Lishan