A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity.
A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity.
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DOI：
10.1038/s41467-018-07195-w
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发表时间：
2018-11-15
影响因子：
16.6
通讯作者：
Alvarez-Vallina L
中科院分区：
文献类型：
--
作者：
Compte M;Harwood SL;Muñoz IG;Navarro R;Zonca M;Perez-Chacon G;Erce-Llamazares A;Merino N;Tapia-Galisteo A;Cuesta AM;Mikkelsen K;Caleiras E;Nuñez-Prado N;Aznar MA;Lykkemark S;Martínez-Torrecuadrada J;Melero I;Blanco FJ;Bernardino de la Serna J;Zapata JM;Sanz L;Alvarez-Vallina L
第一代抗4-1BB单抗(MAbs)对免疫细胞的共刺激作用已在人体试验中显示出抗肿瘤活性。然而，进一步的临床开发受到与FCγR相互作用相关的重大肿瘤外毒性的限制。在这里，我们设计了一个无肿瘤靶向的4-1BB激动型三聚体1D8N/CEGa1，它由三个抗4-1BB单链可变片段和三个抗EGFR单域抗体组成，它们位于XVIII胶原蛋白同源三聚结构域周围的扩展的六角形构象中。1D8N/CEGa1三聚体与4-1BB和EGFR具有较高的亲和力，在EGFR存在的情况下具有较强的体外共刺激作用。这种三聚体在EGFR阳性的肿瘤中迅速聚集，并显示出类似于基于Ig G的4-1BB激动型单抗的抗肿瘤活性。重要的是，1D8N/CEGa1治疗不会诱导全身性炎症细胞因子的产生或与基于免疫球蛋白的4-1BB激动剂相关的肝毒性。这些结果提示FcγR在4-1BB激动剂相关的免疫异常中相互作用，并促进了本工作中提出的非正则抗体在癌症免疫治疗中安全有效的共刺激策略的使用。由于自身反应性T细胞的非特异性激活，使用系统给药的4-1BB靶向抗体治疗癌症通常与严重的毒性有关。在这里，作者开发了一种针对4-1BB和EGFR的三聚体抗体，它可以有效地激活T细胞，而细胞毒性可以忽略不计。
The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy. Cancer therapy using systemically administrated 4-1BB-targeting antibodies is often associated with severe toxicity due to the nonspecific activation of autoreactive T cells. Here, the authors have developed a trimeric antibody targeting both 4-1BB and EGFR, which activates T cells effectively and shows negligible cytotoxicity.
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影响因子：
5.3
作者：
Cuesta, Angel M.;Sanchez-Martin, David;Alvarez-Vallina, Luis
通讯作者：
Alvarez-Vallina, Luis
影响因子：
5.6
作者：
Boudko SP;Sasaki T;Engel J;Lerch TF;Nix J;Chapman MS;Bächinger HP
通讯作者：
Bächinger HP
影响因子：
82.9
作者：
Long, Adrienne H.;Haso, Waleed M.;Shern, Jack F.;Wanhainen, Kelsey M.;Murgai, Meera;Ingaramo, Maria;Smith, Jillian P.;Walker, Alec J.;Kohler, M. Eric;Venkateshwara, Vikas R.;Kaplan, Rosandra N.;Patterson, George H.;Fry, Terry J.;Orentas, Rimas J.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
DOI：
10.4049/jimmunol.0803241
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lee SW;Salek-Ardakani S;Mittler RS;Croft M
通讯作者：
Croft M
影响因子：
5.3
作者：
Blanco-Toribio A;Sainz-Pastor N;Álvarez-Cienfuegos A;Merino N;Cuesta ÁM;Sánchez-Martín D;Bonet J;Santos-Valle P;Sanz L;Oliva B;Blanco FJ;Álvarez-Vallina L
通讯作者：
Álvarez-Vallina L