CXCL13 antibody for the treatment of autoimmune disorders.
CXCL13 antibody for the treatment of autoimmune disorders.
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DOI：
10.1186/s12865-015-0068-1
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发表时间：
2015-02-12
期刊：
影响因子：
3
通讯作者：
Zauderer M
中科院分区：
文献类型：
--
作者：
Klimatcheva E;Pandina T;Reilly C;Torno S;Bussler H;Scrivens M;Jonason A;Mallow C;Doherty M;Paris M;Smith ES;Zauderer M
稳态B细胞吸引趋化因子1（BCA-1），也称为CXCL 13，在次级淋巴器官中由滤泡树突状细胞（FDC）和巨噬细胞组成型表达。它是CXCR 5受体的唯一已知配体，CXCR 5受体在成熟B细胞、滤泡辅助性T细胞（Tfh）、Th 17细胞和调节性T（Treg）细胞上表达。CXCL 13在异位生发中心内的异常表达与自身免疫性疾病（例如风湿性关节炎、多发性硬化、系统性红斑狼疮）的发展有关。因此，我们假设抗体介导的CXCL 13信号通路的破坏会干扰靶器官中异位淋巴滤泡的形成并抑制自身免疫性疾病的进展。这项工作描述了人源抗CXCL 13抗体MAb 5261的临床前开发，并包括其小鼠对应物在小鼠自身免疫模型中的疗效数据。我们开发了一种人IgG 1单克隆抗体MAb 5261，其特异性结合人、啮齿动物和灵长类动物CXCL 13，亲和力约为5 nM，并且能够在体外功能试验中中和这些不同种属的CXCL 13活性。对于体内研究，我们已经设计了嵌合抗体，其含有相同的人重链和轻链可变基因沿着小鼠恒定区。用该抗体处理导致用与匙孔血蓝蛋白缀合的4-羟基-3-硝基苯乙酰半抗原（NP-KLH）免疫的小鼠中的生发中心数量减少，并且在过继转移研究中，干扰了B细胞向小鼠脾脏的B细胞区域的运输。此外，该小鼠抗CXCL 13抗体在风湿性关节炎（胶原诱导的关节炎（CIA））的小鼠模型和Th 17介导的多发性硬化症（被动诱导的实验性自身免疫性脑脊髓炎（EAE））的鼠模型中证明了功效。我们开发了一种新的治疗性抗体，靶向CXCL 13介导的信号通路，用于治疗自身免疫性疾病。
Homeostatic B Cell-Attracting chemokine 1 (BCA-1) otherwise known as CXCL13 is constitutively expressed in secondary lymphoid organs by follicular dendritic cells (FDC) and macrophages. It is the only known ligand for the CXCR5 receptor, which is expressed on mature B cells, follicular helper T cells (Tfh), Th17 cells and regulatory T (Treg) cells. Aberrant expression of CXCL13 within ectopic germinal centers has been linked to the development of autoimmune disorders (e.g. Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosis). We, therefore, hypothesized that antibody-mediated disruption of the CXCL13 signaling pathway would interfere with the formation of ectopic lymphoid follicles in the target organs and inhibit autoimmune disease progression. This work describes pre-clinical development of human anti-CXCL13 antibody MAb 5261 and includes therapeutic efficacy data of its mouse counterpart in murine models of autoimmunity. We developed a human IgG1 monoclonal antibody, MAb 5261 that specifically binds to human, rodent and primate CXCL13 with an affinity of approximately 5 nM and is capable of neutralizing the activity of CXCL13 from these various species in in vitro functional assays. For in vivo studies we have engineered a chimeric antibody to contain the same human heavy and light chain variable genes along with mouse constant regions. Treatment with this antibody led to a reduction in the number of germinal centers in mice immunized with 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Keyhole Limpet Hemocyanin (NP-KLH) and, in adoptive transfer studies, interfered with the trafficking of B cells to the B cell areas of mouse spleen. Furthermore, this mouse anti-CXCL13 antibody demonstrated efficacy in a mouse model of Rheumatoid arthritis (Collagen-Induced Arthritis (CIA)) and Th17-mediated murine model of Multiple Sclerosis (passively-induced Experimental Autoimmune Encephalomyelitis (EAE)). We developed a novel therapeutic antibody targeting CXCL13-mediated signaling pathway for the treatment of autoimmune disorders.
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影响因子：
3.7
作者：
Romme Christensen J;Börnsen L;Ratzer R;Piehl F;Khademi M;Olsson T;Sørensen PS;Sellebjerg F
通讯作者：
Sellebjerg F
影响因子：
5.4
作者：
Arnold, Carrie N.;Campbell, Daniel J.;Butcher, Eugene C.
通讯作者：
Butcher, Eugene C.
影响因子：
4.9
作者：
Henneken M;Dörner T;Burmester GR;Berek C
通讯作者：
Berek C
影响因子：
11.2
作者：
Darlington, Peter J.;Touil, Tarik;Bar-Or, Amit
通讯作者：
Bar-Or, Amit
DOI：
10.1073/pnas.0402455101
发表时间：
2004-07-27
影响因子：
11.1
作者：
Corcione, A;Casazza, S;Pistoia, V
通讯作者：
Pistoia, V