Functional humanization of immunoglobulin heavy constant gamma 1 Fc domain human FCGRT transgenic mice.
Functional humanization of immunoglobulin heavy constant gamma 1 Fc domain human FCGRT transgenic mice.
复制标题
DOI：
10.1080/19420862.2020.1829334
复制
发表时间：
2020-01
期刊：
影响因子：
5.3
通讯作者：
Wiles MV
中科院分区：
文献类型：
--
作者：
Low BE;Christianson GJ;Lowell E;Qin W;Wiles MV
许多基于单克隆抗体（mAb）的生物制剂的主要优点是它们在循环中的持久性。MHC I类家族Fc受体FCGRT主要负责这种延长的药代动力学行为。FCGRT与可结晶片段（Fc）结构域的接合保护IgG免于分解代谢消除，从而延长IgG和相关的基于Fc的生物制剂的持久性和生物利用度。需要可靠的体内模型来促进基于IgG的新型生物制剂的临床前开发。FcRn人源化小鼠已被广泛接受为基于IgG的生物制剂评价的诊断相关替代物。尽管此类FCGRT-人源化小鼠，尤其是小鼠品系B6. Cg-Fcgrttm 1Dcr Tg（FCGRT）32 Dcr（缩写为Tg 32），已经基本上被验证用于建模基于人源化IgG的生物制剂，但存在公认的警告-它们缺乏代表人竞争条件的人IgG的内源性来源。在这里，我们使用CRISPR/Cas9介导的同源定向修复来使hFCGRT Tg 32菌株具有人IGHG 1 Fc结构域。这种替换现在导致小鼠产生生理相关水平的人IgG 1 Fc-小鼠IgG Fab 2嵌合抗体，这可以通过免疫进一步提高。这种内源性嵌合IgG 1以hFCGRT依赖性方式显著抑制所施用的人源化mAb的血清半衰期。因此，此类IgG 1-Fc人源化小鼠可为基于人IgG的生物制剂的临床前开发提供生理学上更相关的竞争性hFCGRT-人源化小鼠模型。
A major asset of many monoclonal antibody (mAb)-based biologics is their persistence in circulation. The MHC class I family Fc receptor, FCGRT, is primarily responsible for this extended pharmacokinetic behavior. Engagement of FCGRT with the crystallizable fragment (Fc) domain protects IgG from catabolic elimination, thereby extending the persistence and bioavailability of IgG and related Fc-based biologics. There is a need for reliable in vivo models to facilitate the preclinical development of novel IgG-based biologics. FcRn-humanized mice have been widely accepted as translationally relevant surrogates for IgG-based biologics evaluations. Although such FCGRT-humanized mice, especially the mouse strain, B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr (abbreviated Tg32), have been substantially validated for modeling humanized IgG-based biologics, there is a recognized caveat – they lack an endogenous source of human IgG that typifies the human competitive condition. Here, we used CRISPR/Cas9-mediated homology-directed repair to equip the hFCGRT Tg32 strain with a human IGHG1 Fc domain. This replacement now results in mice that produce human IgG1 Fc-mouse IgG Fab2 chimeric antibodies at physiologically relevant levels, which can be further heightened by immunization. This endogenous chimeric IgG1 significantly dampens the serum half-life of administered humanized mAbs in an hFCGRT-dependent manner. Thus, such IgG1-Fc humanized mice may provide a more physiologically relevant competitive hFCGRT-humanized mouse model for the preclinical development of human IgG-based biologics.
登录
查看更多内容
影响因子：
4.4
作者：
Petkova, Stefka B.;Akilesh, Shreeram;Roopenian, Derry C.
通讯作者：
Roopenian, Derry C.
影响因子：
5.3
作者：
Avery, Lindsay B.;Wang, Mengmeng;O'Hara, Denise M.
通讯作者：
O'Hara, Denise M.
影响因子：
5.3
作者：
Tam, Susan H.;McCarthy, Stephen G.;Scallon, Bernard J.
通讯作者：
Scallon, Bernard J.
影响因子：
5.3
作者：
Betts, Alison;Keunecke, Anne;Berkhout, Jan
通讯作者：
Berkhout, Jan
影响因子：
1.8
作者：
Haraya, Kenta;Tachibana, Tatsuhiko;Ishigai, Masaki
通讯作者：
Ishigai, Masaki