Matsushita Shuzo, Yoshimura Kazuhisa, Ramirez Kristel Paola, Pisupati Jaya, Murakami Toshio
aCenter for AIDS Research, Kumamoto University, Kumamoto bAIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan cQuintiles Inc., Overland Park, Kansas, USA dThe Chemo-Sero-Therapeutic Research Institute (Kaketsuken), Kumamoto, Japan.
AIDS. 2015 Feb 20;29(4):453-62. doi: 10.1097/QAD.0000000000000570.
Neutralizing antibodies against HIV-1 such as a humanized mAb KD-247 can mediate effector functions that attack infected cells in vitro. However, the clinical efficacy of neutralizing antibodies in infected individuals remains to be determined. We evaluated the safety, tolerability and pharmacokinetics of KD-247 infusion and its effect on plasma HIV-1 RNA load and CD4 T-cell count.
KD-1002 is a phase Ib, double-blind, placebo-controlled, dose-escalation study of KD-247 in asymptomatic HIV-1 seropositive individuals who did not need antiretroviral therapy. Individuals were randomized to 4, 8 or 16 mg/kg KD-247 or placebo, and received three infusions over a 2-week period.
Patients were randomized to receive one of the three doses of KD-247 and the treatment was well tolerated. We observed a significant decrease in HIV RNA in the 8 and 16 mg/kg KD-247 cohorts, with two individuals who achieved more than 1 log reduction of HIV RNA. Two patients in the 16 mg/kg cohort had selections and/or mutations in the V3-tip region that suggested evasion of neutralization. Long-term suppression of viral load was observed in one patient despite a significant decrease in plasma concentration of KD-247, suggesting effects of the antibody other than neutralization or loss of fitness of the evading virus.
The results indicate that KD-247 reduces viral load in patients with chronic HIV-1 infection and further clinical trials are warranted.
针对HIV-1的中和抗体，如人源化单克隆抗体KD-247，可在体外介导攻击受感染细胞的效应功能。然而，中和抗体在受感染个体中的临床疗效仍有待确定。我们评估了KD-247输注的安全性、耐受性和药代动力学及其对血浆HIV-1 RNA载量和CD4 T细胞计数的影响。
KD-1002是一项Ib期、双盲、安慰剂对照、剂量递增研究，研究对象为无症状的HIV-1血清阳性且无需抗逆转录病毒治疗的个体。个体被随机分为接受4、8或16mg/kg KD-247或安慰剂治疗，并在2周内接受三次输注。
患者被随机分配接受三种剂量的KD-247之一，治疗耐受性良好。我们观察到，在8mg/kg和16mg/kg KD-247组中，HIV RNA显著下降，有两名个体的HIV RNA下降超过1个对数。16mg/kg组的两名患者在V3尖端区域有选择和/或突变，提示存在中和逃逸。尽管KD-247的血浆浓度显著下降，但在一名患者中观察到病毒载量的长期抑制，这表明该抗体除了中和作用或逃逸病毒适应性丧失之外还有其他作用。
结果表明，KD-247可降低慢性HIV-1感染患者的病毒载量，有必要进行进一步的临床试验。
