Function-blocking antithrombospondin-1 monoclonal antibodies
Function-blocking antithrombospondin-1 monoclonal antibodies
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DOI：
10.1111/j.1538-7836.2006.01723.x
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发表时间：
2006-02-01
影响因子：
10.4
通讯作者：
Mosher, DF
中科院分区：
文献类型：
--
作者：
Annis, DS;Murphy-Ullrich, JE;Mosher, DF
背景：凝血酶敏感蛋白-1(TSP-1)参与了许多不同的过程，部分是基于抗TSP-1单抗的抑制活性。目的：将13株抗TSP-1单抗的表位映射到跨越TSP-1和TSP-2同源物的单个或一组模块。结果：确定了4株单抗的表位，提纯了6株单抗的表位，确认了其余3株单抗的表位。ESTs10、P12和MA-II映射到N-末端结构域；5G11、TSP127.6和ESTs12映射到第三个备解素模块；c6.7、HB8432和P10映射到表皮生长因子样模块1和/或2；A6.1、mAb133、MA-I和D4.6映射到钙结合线模块。A6.1识别在老鼠和人类TSP-1中相同的导线区域，与这两个物种的TSP-1反应，也与人TSP-2反应弱。另外两株鼠抗人TSP-1单抗A4.1和D4.6也与鼠TSP-1发生反应。结论：参考以前的文献和绘制抑制性单抗的表位图表明，生物活性存在于整个TSP-1中，包括过去未涉及的EGF样模块。由于在钙含量丰富的TSP-1中，10种抗体的表位可能彼此相距18 nm以内，因此一些抑制作用可能是空间位阻造成的。MAb133似乎就是这样的情况，它结合了钙结合线，但仍然能够干扰备解素模块激活潜在的转化生长因子-β。
Background: Thrombospondin-1 (TSP-1) has been implicated in many different processes based in part on inhibitory activities of anti-TSP-1 monoclonal antibodies (mAbs). Objective: To map epitopes of 13 anti-TSP-1 mAbs to individual modules or groups of modules spanning TSP-1 and the closely related TSP-2 homolog. Results: The mapping has led to assignment or reassignment of the epitopes of four mAbs, refinement of the epitopes of six mAbs, and confirmation of the epitopes of the remaining three mAbs. ESTs10, P12, and MA-II map to the N-terminal domain; 5G11, TSP127.6, and ESTs12 to the third properdin module; C6.7, HB8432, and P10 to epidermal growth factor (EGF)-like modules 1 and/or 2; and A6.1, mAb133, MA-I, and D4.6 to the calcium-binding wire module. A6.1, which recognizes a region of the wire that is identical in mouse and human TSP-1, reacts with TSP-1 from both species, and also reacts weakly with human TSP-2. Two other mouse antihuman TSP-1 mAbs, A4.1 and D4.6, also react with mouse TSP-1. Conclusions: Consideration of previous literature and mapping of epitopes of inhibitory mAbs suggest that biological activities are present throughout TSP-1, including the EGF-like modules that have not been implicated in the past. Because the epitopes for 10 of the antibodies likely are within 18 nm of one another in calcium-replete TSP-1, some of the inhibitory effects may result from steric hindrance. Such seems to be the case for mAb133, which binds the calcium-binding wire but is still able to interfere with the activation of latent TGF-beta by the properdin modules.