A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity.
A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity.
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DOI：
10.1016/j.vaccine.2009.09.127
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发表时间：
2009-12-11
期刊：
影响因子：
5.5
通讯作者：
Shirwan H
中科院分区：
文献类型：
--
作者：
Schabowsky RH;Elpek KG;Madireddi S;Sharma RK;Yolcu ES;Bandura-Morgan L;Miller R;MacLeod KJ;Mittler RS;Shirwan H
选择CD 28和TNFR家族共刺激成员的激动性Ab已在各种临床前癌症免疫环境中显示出功效。然而，由于淋巴细胞的非特异性活化，使用激动性Ab通常与严重毒性相关。我们假设，天然共刺激配体可能作为更有效和更安全的替代激动抗体的免疫治疗。在这次交流中，我们专注于4-1BBL作为选择的分子，因为4-1BB信号传导在免疫系统中的多效性作用以及4-1BB激动性Ab在临床前癌症和感染模型中的治疗效果。我们报告了一种新形式的可溶性配体SA-4-1BBL，比激动性Ab向T细胞传递更有效和定性不同的信号。重要的是，虽然用激动性Ab治疗幼稚小鼠导致严重的毒性，如通过脾脏和外周淋巴结肿大、非特异性T细胞增殖、肝炎和全身炎性细胞因子产生所评估的，但用SA-4-1BBL治疗没有这些免疫异常。激动性Ab处理在FcγR−/−或补体C1 q −/−或C3−/−敲除小鼠中产生完全毒性，表明观察到的毒性中不涉及刺激性Fcγ R或补体系统。幼稚和记忆T细胞充当抗4-1BB Ab介导的毒性的直接靶标。有效的免疫刺激活性结合缺乏毒性使可溶性SA-4-1BBL作为针对癌症和慢性感染的治疗性疫苗的免疫调节组分的进一步开发合理化。
Agonistic Abs to select costimulatory members of CD28 and TNFR family have shown efficacy in various preclinical cancer immunotherapeutic settings. However, the use of agonistic Abs is often associated with severe toxicity due to nonspecific activation of lymphocytes. We hypothesized that natural costimulatory ligands may serve as more potent and safer alternative to agonistic Abs for immunotherapy. In this communication, we focused on 4-1BBL as the molecule of choice because of the pleiotropic effects of 4-1BB signaling in the immune system and the demonstrated therapeutic efficacy of 4-1BB agonistic Abs in preclinical cancer and infection models. We report that a novel form of soluble ligand, SA-4-1BBL, delivered more potent and qualitatively different signals to T cells than an agonistic Ab. Importantly, while treatment of naïve mice with the agonistic Ab resulted in severe toxicity, as assessed by enlarged spleen and peripheral LNs, non-specific T cell proliferation, hepatitis, and systemic inflammatory cytokine production, treatment with SA-4-1BBL lacked these immune anomalies. Agonistic Ab treatment produced full toxicity in FcγR−/− or complement C1q−/− or C3−/− knockout mice, suggesting lack of involvement of stimulatory FcγRs or complement system in the observed toxicity. Naïve and memory T cells served as direct targets of anti-4-1BB Ab mediated toxicity. Potent immunostimulatory activity combined with lack of toxicity rationalizes further development of soluble SA-4-1BBL as an immunomodulatory component of therapeutic vaccines against cancer and chronic infections.
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影响因子：
4.4
作者：
Dennehy, Kevin M.;Elias, Fernando;Luehder, Fred
通讯作者：
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影响因子：
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作者：
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DOI：
10.1053/bbmt.2001.v7.pm11302547
发表时间：
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作者：
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作者：
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