Kahn J O, Allan J D, Hodges T L, Kaplan L D, Arri C J, Fitch H F, Izu A E, Mordenti J, Sherwin J E, Groopman J E
San Francisco General Hospital, California.
Ann Intern Med. 1990 Feb 15;112(4):254-61. doi: 10.7326/0003-4819-112-4-.
To evaluate the safety and pharmacokinetics of recombinant, soluble human CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The protein rCD4 binds to envelope protein, gp120, of the human immunodeficiency virus (HIV) and blocks HIV infection of CD4 lymphocytes in vitro.
Phase 1 trial with dose escalation.
Two university-affiliated hospital clinics.
Of 42 subjects enrolled, 29 had AIDS and 13 had AIDS-related complex.
The rCD4 was administered by rapid intravenous infusion on day 1, followed by a 3-day washout, then once a day for 10 days, followed by a 7-day washout, and then three times a week for 8 weeks. Doses of 1, 10, 30, 100, and 300 micrograms/kg body weight per day of rCD4 were administered intravenously to 6 subjects at each dose level. Twelve additional patients received 300 micrograms/kg.d of rCD4: 6 by intramuscular and 6 by subcutaneous injection. All subjects were monitored for toxicity. Immunologic and virologic variables were also monitored.
Administration of rCD4 was not associated with important toxicity as determined by clinical monitoring or by serum chemistry, hematologic, or immunologic variables. No subjects required dose reduction or discontinuation of therapy due to rCD4-related toxicity. No consistent or sustained changes in CD4 lymphocyte populations or HIV antigen levels were observed. The volume of distribution of rCD4 was small, and clearance remained constant over the dose range studied. The bioavailability of intramuscular injection and subcutaneous injection was 51% and 45%, respectively.
At the dose levels used in this study, rCD4 appears safe and well tolerated. Serum concentrations of rCD4 were achieved that were comparable to concentrations shown to have antiviral activity in vitro. Further studies are indicated to determine whether rCD4 or related molecules will be useful in treating HIV infection.
评估重组可溶性人CD4（rCD4）在获得性免疫缺陷综合征（AIDS）及AIDS相关综合征患者中的安全性和药代动力学。蛋白质rCD4可与人免疫缺陷病毒（HIV）的包膜蛋白gp120结合，并在体外阻断HIV对CD4淋巴细胞的感染。
剂量递增的1期试验。
两家大学附属医院诊所。
42名入选受试者中，29名患有AIDS，13名患有AIDS相关综合征。
第1天通过快速静脉输注给予rCD4，随后进行3天的洗脱期，然后每天给药1次，持续10天，接着进行7天的洗脱期，然后每周给药3次，持续8周。以每天1、10、30、100和300微克/千克体重的剂量静脉给予6名受试者rCD4，每个剂量水平各6名。另外12名患者接受300微克/千克·天的rCD4：6名通过肌肉注射，6名通过皮下注射。对所有受试者进行毒性监测，同时监测免疫和病毒学变量。
通过临床监测或血清化学、血液学或免疫学变量确定，给予rCD4未出现严重毒性。无受试者因rCD4相关毒性而需要降低剂量或停止治疗。未观察到CD4淋巴细胞群体或HIV抗原水平出现一致或持续的变化。rCD4的分布容积较小，在所研究的剂量范围内清除率保持恒定。肌肉注射和皮下注射的生物利用度分别为51%和45%。
在本研究使用的剂量水平下，rCD4似乎安全且耐受性良好。所达到的rCD4血清浓度与在体外显示具有抗病毒活性的浓度相当。需要进一步研究以确定rCD4或相关分子是否可用于治疗HIV感染。
