A novel mouse strain optimized for chronic human antibody administration.
A novel mouse strain optimized for chronic human antibody administration.
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DOI：
10.1073/pnas.2123002119
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发表时间：
2022-03-08
影响因子：
11.1
通讯作者：
Ravetch JV
中科院分区：
文献类型：
--
作者：
Gupta A;Smith P;Bournazos S;Ravetch JV
IgG Fc-Fc γ受体（FcγR）相互作用的种属差异使人源化小鼠模型成为评价人抗体疗效和毒性的有吸引力的策略。我们之前发表了一种人源化FcγR小鼠模型，该模型完全重现了这些受体在体内的表达和功能。然而，外源性人IgG的免疫原性使得抗体功能的长期评估具有挑战性，因为内源性小鼠抗人IgG应答限制了这些研究的持续时间和成功。在此，我们介绍了一种表达人IgG 1和Fcγ R的小鼠品系，从而赋予对人IgG长期给药的耐受性，并能够进行抗体的功能评估。由于这种菌株适用于慢性疾病模型，我们预计研究人员将从其使用中受益。治疗性人IgG抗体在肿瘤、感染和自身免疫性疾病的小鼠模型中进行常规测试。然而，评估这些药物长期给药的疗效和安全性受到内源性抗人IgG免疫应答的限制，这些免疫应答可从血清和相关组织中清除人IgG，从而降低其疗效并导致免疫复合物介导的病理学，混淆潜在毒性的评价。由于这个原因，小鼠中的人抗体治疗通常在持续时间和剂量方面受到限制，因此无法概括这些治疗剂的潜在临床应用。在这里，我们报告了一种小鼠模型的发展，是耐受慢性人抗体管理。该模型结合了人IgG 1重链敲入和人Fc受体（FcγR）表达的完全重现，为在短期内检测人单克隆抗体与相关受体的体内试验提供了独特的平台。与对照组相比，hIgG 1基因敲入小鼠产生最小的抗人IgG应答，即使在免疫性血小板减少性紫癜和转移性黑色素瘤慢性模型的治疗后期，也能持续存在治疗活性的循环人IgG。
Species differences in IgG Fc–Fcγ receptor (FcγR) interactions have made humanized mouse models an attractive strategy to evaluate the efficacy and toxicity of human antibodies. We previously published a humanized FcγR mouse model that fully recapitulates the expression and function of these receptors in vivo. However, the immunogenicity of exogenous human IgG has made long-term assessment of antibody function challenging, since endogenous mouse anti-human IgG responses limit the duration and success of these studies. Here, we present a mouse strain that expresses human IgG1 and FcγRs, thereby conferring tolerance to chronic administration of human IgG and enabling functional assessment of antibodies. Because this strain is appropriate for chronic disease models, we expect that researchers will benefit from its use. Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG immune responses that act to clear human IgG from serum and relevant tissues, thereby reducing their efficacy and contributing to immune complex–mediated pathologies, confounding evaluation of potential toxicity. For this reason, human antibody treatment in mice is generally limited in duration and dosing, thus failing to recapitulate the potential clinical applications of these therapeutics. Here, we report the development of a mouse model that is tolerant of chronic human antibody administration. This model combines both a human IgG1 heavy chain knock-in and a full recapitulation of human Fc receptor (FcγR) expression, providing a unique platform for in vivo testing of human monoclonal antibodies with relevant receptors beyond the short term. Compared to controls, hIgG1 knock-in mice mount minimal anti-human IgG responses, allowing for the persistence of therapeutically active circulating human IgG even in the late stages of treatment in chronic models of immune thrombocytopenic purpura and metastatic melanoma.
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影响因子：
64.8
作者：
Scheid, Johannes F.;Horwitz, Joshua A.;Bar-On, Yotam;Kreider, Edward F.;Lu, Ching-Lan;Lorenzi, Julio C. C.;Feldmann, Anna;Braunschweig, Malte;Nogueira, Lilian;Oliveira, Thiago;Shimeliovich, Irina;Patel, Roshni;Burke, Leah;Cohen, Yehuda Z.;Hadrigan, Sonya;Settler, Allison;Witmer-Pack, Maggi;West, Anthony P., Jr.;Juelg, Boris;Keler, Tibor;Hawthorne, Thomas;Zingman, Barry;Gulick, Roy M.;Pfeifer, Nico;Learn, Gerald H.;Seaman, Michael S.;Bjorkman, Pamela J.;Klein, Florian;Schlesinger, Sarah J.;Walker, Bruce D.;Hahn, Beatrice H.;Nussenzweig, Michel C.;Caskey, Marina
通讯作者：
Caskey, Marina
DOI：
10.1073/pnas.1307864110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Sondermann, Peter;Pincetic, Andrew;Ravetch, Jeffrey V.
通讯作者：
Ravetch, Jeffrey V.
影响因子：
3.7
作者：
Sorde, Laetitia;Spindeldreher, Sebastian;Karle, Anette
通讯作者：
Karle, Anette
DOI：
10.4049/jimmunol.1001152
发表时间：
2010-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Luo W;Wang XP;Kashtan CE;Borza DB
通讯作者：
Borza DB
DOI：
10.1073/pnas.0810163105
发表时间：
2008-12-16
影响因子：
11.1
作者：
Anthony, Robert M.;Wermeling, Fredrik;Ravetch, Jeffrey V.
通讯作者：
Ravetch, Jeffrey V.