Alexion Pharmaceuticals, 100 College street New Haven CT, 06510, USA.
Division of Rheumatology, School of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, USA.
Mol Immunol. 2019 Jan;105:150-164. doi: 10.1016/j.molimm.2018.09.013. Epub 2018 Dec 1.
Complement activation in human diseases is characterized by the local covalent deposition of the long-lived C3 fragments iC3b/C3dg/C3d. Previously, TT30, a complement alternative pathway (AP)-selective inhibitor, was designed as a fusion protein linking the first four short consensus repeats (SCRs) of human complement receptor type 2 (CR2) with the first five SCRs of human factor H (fH). TT30 acts by utilizing CR2 SCR1-4 to bind the initially formed iC3b/C3dg/C3d fragments and delivering surface-targeted inhibition of AP C3 and C5 convertases through fH SCR 1-5. In order to combine classical (CP) and lectin (LP) pathway inhibitory abilities employing CR2-mediated targeting, TT32 was developed. TT32 is a CR2-CR1 fusion protein using the first ten SCRs of CR1, chosen because they contain both C3 and C5 convertase inhibitory activity through utilization of decay-acceleration and cofactor activity for both AP and CP. In Wieslab assays, TT32 showed potent inhibition of the CP and AP with IC of 11 and 46 nM, respectively. The TT32 inhibitory activity is partially blocked with a molar excess of a competing anti-CR2 mAb, thus demonstrating the importance of the CR2 targeting. TT32 was studied in the type II (CII) collagen-induced arthritis (CIA), an active immunization model, and the CII antibody-induced arthritis (CAIA) passive transfer model. In CIA, injection of 2.0 mg TT32 at day 21 and 28 post disease induction, but not untargeted CR1 alone, resulted in a 51.5% decrease in clinical disease activity (CDA). In CAIA, treatment with TT32 resulted in a 47.4% decrease in CDA. Therefore, a complement inhibitor that targets both the AP and CP/LP C3/C5 convertases was shown to limit complement-mediated tissue damage and inflammation in disease models in which all three complement activation pathways are implicated.
补体激活在人类疾病中的特征是长寿命 C3 片段 iC3b/C3dg/C3d 的局部共价沉积。先前，TT30 是一种补体旁路（AP）选择性抑制剂，设计为一种融合蛋白，将人类补体受体 2（CR2）的前四个短串联重复序列（SCR）与人类因子 H（fH）的前五个 SCR 相连。TT30 通过利用 CR2 SCR1-4 结合最初形成的 iC3b/C3dg/C3d 片段，并通过 fH SCR 1-5 输送针对 AP C3 和 C5 转化酶的表面靶向抑制作用。为了结合经典（CP）和凝集素（LP）途径的抑制能力，采用 CR2 介导的靶向作用，开发了 TT32。TT32 是一种 CR2-CR1 融合蛋白，使用 CR1 的前十个 SCR，选择它们是因为通过利用 AP 和 CP 的衰变加速和辅助因子活性，它们都包含 C3 和 C5 转化酶抑制活性。在 Wieslab 测定中，TT32 对 CP 和 AP 的抑制作用的 IC 分别为 11 和 46 nM。用摩尔过量的竞争抗 CR2 mAb 部分阻断 TT32 的抑制活性，从而证明了 CR2 靶向的重要性。TT32 在 II 型（CII）胶原诱导关节炎（CIA），一种主动免疫模型，和 CII 抗体诱导关节炎（CAIA）被动转移模型中进行了研究。在 CIA 中，在疾病诱导后第 21 天和第 28 天注射 2.0 mg TT32，但单独不靶向 CR1，则导致临床疾病活动度（CDA）降低 51.5%。在 CAIA 中，TT32 治疗导致 CDA 降低 47.4%。因此，一种靶向 AP 和 CP/LP C3/C5 转化酶的补体抑制剂被证明可限制补体介导的组织损伤和炎症在所有三种补体激活途径都涉及的疾病模型中。
