Zebedee S L, Koduri R K, Mukherjee J, Mukherjee S, Lee S, Sauer D F, Scharff M D, Casadevall A
R. W. Johnson Pharmaceutical Research Institute, San Diego, California 92121.
Antimicrob Agents Chemother. 1994 Jul;38(7):1507-14. doi: 10.1128/AAC.38.7.1507.
Passive antibody administration is a potentially useful approach for the therapy of human Cryptococcus neoformans infections. To evaluate the efficacy of the human immunoglobulin G1 (IgG1) constant region against C. neoformans and to construct murine antibody derivatives with reduced immunogenicities and longer half-lives in humans, two mouse-human IgG1 chimeric antibodies were generated from the protective murine monoclonal antibodies 2D10 (IgM) and 18B7 (IgG1). The 2D10 mouse-human IgG1 chimeric antibody (ch2D10) had significantly lower binding affinity than its parent murine antibody (m2D10), presumably because of a loss of avidity contribution on switching from IgM to IgG. The 18B7 mouse-human IgG1 chimeric antibody (ch18B7) had higher affinity for cryptococcal polysaccharide antigen than its parent murine antibody (m18B7). ch18B7 and ch2D10 promoted phagocytosis of C. neoformans by primary human microglial cells and the murine J774.16 macrophage-like cell line. ch18B7 and m18B7 enhanced fungistatic or fungicidal activity of J774.16 cells and prolonged the survival of lethally infected mice. We conclude that the human IgG1 constant chain can be effective in mediating antifungal activity against C. neoformans. ch18B7 or similar antibodies are potential candidates for passive antibody therapy of human cryptococcosis.
被动抗体给药是治疗人类新型隐球菌感染的一种潜在有用方法。为了评估人免疫球蛋白G1（IgG1）恒定区对新型隐球菌的疗效，并构建在人体内免疫原性降低且半衰期延长的鼠源抗体衍生物，从保护性鼠单克隆抗体2D10（IgM）和18B7（IgG1）产生了两种小鼠 - 人IgG1嵌合抗体。2D10小鼠 - 人IgG1嵌合抗体（ch2D10）与其亲本鼠抗体（m2D10）相比，结合亲和力显著降低，推测是因为从IgM转换为IgG时亲和力贡献丧失。18B7小鼠 - 人IgG1嵌合抗体（ch18B7）对隐球菌多糖抗原的亲和力高于其亲本鼠抗体（m18B7）。ch18B7和ch2D10促进原代人小胶质细胞和鼠J774.16巨噬细胞样细胞系对新型隐球菌的吞噬作用。ch18B7和m18B7增强了J774.16细胞的抑菌或杀菌活性，并延长了致死性感染小鼠的存活时间。我们得出结论，人IgG1恒定链可有效介导针对新型隐球菌的抗真菌活性。ch18B7或类似抗体是人类隐球菌病被动抗体治疗的潜在候选药物。
