Bindon C I, Hale G, Brüggemann M, Waldmann H
Department of Pathology, University of Cambridge, United Kingdom.
J Exp Med. 1988 Jul 1;168(1):127-42. doi: 10.1084/jem.168.1.127.
Humanized antibodies are likely to have a major role in therapy and it is important to define their interaction with physiological effectors. By comparing a matched series of chimeric human mAbs we found that igG1 was most efficient in complement lysis, although IgG3 bound more C1q. To resolve this paradox we compared the ability of human IgG1, IgG2, IgG3, IgG4, and IgE and rat IgG2b to cause C1q binding, C1 binding and activation, C4 activation, C4b binding, and C3b binding. Rat IgG2b was included because this isotype has already successfully been used for therapy. Human IgG1 was less efficient than IgG3 and fixing C1q and C1 on the cell surface, but the number of C4 molecules bound per C1 was 10-fold greater for IgG1 than for IgG3. This difference, amplified through later stages of the complement cascade, can account for the superiority of IgG1 for cell lysis. The efficiency of IgG1 in fixing C4 was not due to a favored binding site on the antibody molecule, since virtually all of the bound C4b was attached to the cells. Rather, it appeared that the activation of C4 by C1s was greatly favored by IgG1 compared with IgG3. It should be possible to combine the optimal properties of IgG1 and IgG3 antibodies to produce an improved therapeutic reagent.
人源化抗体在治疗中可能发挥重要作用，明确它们与生理效应器的相互作用很重要。通过比较一系列匹配的嵌合人源单克隆抗体，我们发现IgG1在补体裂解方面效率最高，尽管IgG3结合更多的C1q。为了解决这一矛盾，我们比较了人IgG1、IgG2、IgG3、IgG4、IgE以及大鼠IgG2b引起C1q结合、C1结合与激活、C4激活、C4b结合以及C3b结合的能力。纳入大鼠IgG2b是因为该同种型已成功用于治疗。人IgG1在将C1q和C1固定在细胞表面方面不如IgG3有效，但每一个C1结合的C4分子数量，IgG1比IgG3多10倍。这种差异在补体级联反应的后期阶段被放大，这可以解释IgG1在细胞裂解方面的优势。IgG1在固定C4方面的效率并非源于抗体分子上更有利的结合位点，因为几乎所有结合的C4b都附着在细胞上。相反，与IgG3相比，IgG1似乎极大地促进了C1s对C4的激活。应该有可能将IgG1和IgG3抗体的最佳特性结合起来，以生产出一种改进的治疗试剂。
