Pardridge W M, Kang Y S, Diagne A, Zack J A
Department of Medicine, University of California at Los Angeles School of Medicine, USA.
J Pharmacol Exp Ther. 1996 Jan;276(1):246-52.
The in vivo pharmacokinetics and efficacy of cationized human immunoglobulins in the human-peripheral blood lymphocytes-severe combined immune deficiency mouse model were evaluated in the present studies using the severe combined immunodeficient mouse transplanted with human lymphocytes and infected with human immunodeficiency virus (HIV)-1. Immunoglobulins from noninfected humans and from HIV-infected individuals were cationized. The pharmacokinetic analysis showed that the cationized immunoglobulins have a markedly reduced mean residence time and a marked increase in organ uptake compared to the native immunoglobulins. The toxicity studies performed with homologous immunoglobulins in BALB/c mice demonstrated cationized homologous immunoglobulins have no tissue toxicity at a daily dose of 7.5 mg/kg. Treatment of HIV-infected severe combined immune deficiency mice that were transplanted with human lymphocytes demonstrated therapeutic efficacy for a 2-week treatment at a dose of 5 mg/kg cationized HIV immune globulin. In conclusion, cationized immunoglobulins are potential antibody-based therapeutics for the treatment of acquired immune deficiency syndrome; cationized antibodies undergo enhanced transport into lymphocytes and when homologous cationized immunoglobulins are administered there is no measurable tissue toxicity.
在本研究中，使用移植了人类淋巴细胞并感染了人类免疫缺陷病毒1型（HIV-1）的重症联合免疫缺陷小鼠，评估了阳离子化人免疫球蛋白在人外周血淋巴细胞-重症联合免疫缺陷小鼠模型中的体内药代动力学和疗效。对来自未感染人类和HIV感染个体的免疫球蛋白进行了阳离子化处理。药代动力学分析表明，与天然免疫球蛋白相比，阳离子化免疫球蛋白的平均驻留时间显著缩短，器官摄取显著增加。用同源免疫球蛋白在BALB/c小鼠中进行的毒性研究表明，阳离子化同源免疫球蛋白在每日剂量7.5mg/kg时无组织毒性。对移植了人类淋巴细胞的HIV感染重症联合免疫缺陷小鼠进行治疗，结果表明，以5mg/kg阳离子化HIV免疫球蛋白的剂量进行为期2周的治疗具有治疗效果。总之，阳离子化免疫球蛋白是治疗获得性免疫缺陷综合征的潜在抗体类治疗药物；阳离子化抗体向淋巴细胞的转运增强，并且当给予同源阳离子化免疫球蛋白时，没有可测量的组织毒性。
