Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity.
Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity.
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DOI：
10.3390/biomedicines10071724
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发表时间：
2022-07-18
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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作者：
抗药物抗体的发展是以蛋白质为基础的疗法用于各种疾病的一个重大障碍。虽然抗体的形成速度可能会因采用的治疗方法和接受药物治疗的目标患者群体而有所不同，但导致抗药物抗体产生的抗原特异性免疫反应往往仍然难以确定。对于血友病A患者尤其如此，他们在暴露后产生了针对凝血因子VIII(FVIII)的抗体。能够以抗原特异性方式研究这种反应的模型一直缺乏。为了克服这一挑战，我们改造了FVIII，使其包含来自模型抗原卵清蛋白(OVA)的多肽(323-339)，OVA是一种用于研究抗原特异性免疫的非常常见的工具。带有OVA多肽的FVIII(FVIII-OVA)在体外保持凝血活性，并具有激活OVA323-339特异性CD4T细胞的能力。与单独的FVIII相比，FVIII-OVA也表现出类似水平的免疫原性，这表明OVA323-339的存在不会显著改变抗FVIII的免疫反应。有趣的是，虽然单独接触FVIII-OVA后几乎没有观察到CD4T细胞反应，但包括最近被证明有利于调节抗FVIII免疫反应的抗FVIII抗体，显著增强了FVIII-OVA暴露后的CD4T细胞激活。这些结果表明，模型抗原可以被结合到治疗性蛋白中来研究抗原特异性反应，更具体地说，可以通过预先存在的抗FVIII抗体来增强CD4T细胞对FVIII-OVA的反应。
The development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target patient population receiving the drug, the antigen-specific immune response underlying the development of anti-drug antibodies often remains difficult to define. This is especially true for patients with hemophilia A who, following exposure, develop antibodies against the coagulation factor, factor VIII (FVIII). Models capable of studying this response in an antigen-specific manner have been lacking. To overcome this challenge, we engineered FVIII to contain a peptide (323–339) from the model antigen ovalbumin (OVA), a very common tool used to study antigen-specific immunity. FVIII with an OVA peptide (FVIII-OVA) retained clotting activity and possessed the ability to activate CD4 T cells specific to OVA323–339 in vitro. When compared to FVIII alone, FVIII-OVA also exhibited a similar level of immunogenicity, suggesting that the presence of OVA323–339 does not substantially alter the anti-FVIII immune response. Intriguingly, while little CD4 T cell response could be observed following exposure to FVIII-OVA alone, inclusion of anti-FVIII antibodies, recently shown to favorably modulate anti-FVIII immune responses, significantly enhanced CD4 T cell activation following FVIII-OVA exposure. These results demonstrate that model antigens can be incorporated into a therapeutic protein to study antigen-specific responses and more specifically that the CD4 T cell response to FVIII-OVA can be augmented by pre-existing anti-FVIII antibodies.
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影响因子：
6.7
作者：
Biswas M;Rogers GL;Sherman A;Byrne BJ;Markusic DM;Jiang H;Herzog RW
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影响因子：
20.3
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DOI：
10.1084/jem.20151720
发表时间：
2016-05-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Calabro S;Gallman A;Gowthaman U;Liu D;Chen P;Liu J;Krishnaswamy JK;Nascimento MS;Xu L;Patel SR;Williams A;Tormey CA;Hod EA;Spitalnik SL;Zimring JC;Hendrickson JE;Stowell SR;Eisenbarth SC
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
20.3
作者：
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通讯作者：
Lollar, P