An Anti-Programmed Death-1 Antibody (αPD-1) Fusion Protein That Self-Assembles into a Multivalent and Functional αPD-1 Nanoparticle.
An Anti-Programmed Death-1 Antibody (αPD-1) Fusion Protein That Self-Assembles into a Multivalent and Functional αPD-1 Nanoparticle.
复制标题
DOI：
10.1021/acs.molpharmaceut.6b01021
复制
发表时间：
2017-05-01
影响因子：
4.9
通讯作者：
Chen M
中科院分区：
文献类型：
--
作者：
Zhao P;Atanackovic D;Dong S;Yagita H;He X;Chen M
癌症免疫检查点疗法在各种癌症中取得了显著的临床成功。然而，目前的免疫检查点抑制剂不仅阻断对癌症治疗重要的免疫细胞的检查点，而且阻断与治疗无关的免疫细胞的检查点。这种不加选择的阻断限制了疗效并导致治疗的自身免疫毒性。使用载体将免疫检查点抑制剂靶向癌症反应性免疫细胞可能是有益的。在这里，我们探索了一种将抑制剂负载到载体中的方法。我们使用抗程序性死亡-1抗体（αPD-1）作为模型免疫检查点抑制剂。首先，我们构建了αPD-1的重组单链可变区片段（scFv）。然后，我们设计并产生了由scFv和两亲性免疫耐受弹性蛋白样多肽（iTEP）组成的融合蛋白。由于两亲性iTEP，融合物能够自组装成纳米颗粒（NP）。NP在体内外均能阻断PD-1免疫检查点。特别是，NP与天然完整的αPD-1一样有效地加剧了非肥胖糖尿病小鼠的糖尿病发展。综上所述，本研究成功表达了α PD-1重组蛋白，并将其与NP连接，为进一步开发αPD-1靶向免疫细胞的递送系统奠定了基础。
Cancer immune checkpoint therapy has achieved remarkable clinical successes in various cancers. However, current immune checkpoint inhibitors block the checkpoint of not only the immune cells that are important to cancer therapy but also the immune cells that are irrelevant to the therapy. Such an indiscriminate blockade limits the efficacy and causes the autoimmune toxicity of the therapy. It might be beneficial to use a carrier to target immune checkpoint inhibitors to cancer-reactive immune cells. Here, we explore a method to load the inhibitors into carriers. We used the anti-programmed death-1 antibody (αPD-1) as a model immune checkpoint inhibitor. First, we generated a recombinant single-chain variable fragment (scFv) of αPD-1. Then, we designed and generated a fusion protein consisting of the scFv and an amphiphilic immune-tolerant elastin-like polypeptide (iTEP). Because of the amphiphilic iTEP, the fusion was able to self-assemble into a nanoparticle (NP). The NP was proved to block the PD-1 immune checkpoint in vitro and in vivo. Particularly, the NP exacerbated diabetes development in non-obese diabetic mice as effectively as natural, intact αPD-1. In summary, we successfully expressed αPD-1 as a recombinant protein and linked αPD-1 to a NP, which lays a foundation to develop a delivery system to target αPD-1 to a subpopulation of immune cells.
登录
查看更多内容
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
3.7
作者：
Kochupurakkal NM;Kruger AJ;Tripathi S;Zhu B;Adams LT;Rainbow DB;Rossini A;Greiner DL;Sayegh MH;Wicker LS;Guleria I
通讯作者：
Guleria I
影响因子：
11.5
作者：
Fransen, Marieke F.;van der Sluis, Tetje C.;Melief, Cornelis J. M.
通讯作者：
Melief, Cornelis J. M.
DOI：
10.1073/pnas.192461099
发表时间：
2002-09-17
影响因子：
11.1
作者：
Iwai, Y;Ishida, M;Minato, N
通讯作者：
Minato, N
影响因子：
2.2
作者：
REIK, LM;MAINES, SL;THOMAS, PE
通讯作者：
THOMAS, PE