Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.
Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial.
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DOI：
10.1038/s41591-022-01815-1
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发表时间：
2022-06
期刊：
影响因子：
82.9
通讯作者：
Barouch, Dan H.
中科院分区：
文献类型：
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作者：
Julg, Boris;Stephenson, Kathryn E.;Wagh, Kshitij;Tan, Sabrina C.;Zash, Rebecca;Walsh, Stephen;Ansel, Jessica;Kanjilal, Diane;Nkolola, Joseph;Walker-Sperling, Victoria E. K.;Ophel, Jasper;Yanosick, Katherine;Borducchi, Erica N.;Maxfield, Lori;Abbink, Peter;Peter, Lauren;Yates, Nicole L.;Wesley, Martina S.;Hassell, Tom;Gelderblom, Huub C.;deCamp, Allen;Mayer, Bryan T.;Sato, Alicia;Gerber, Monica W.;Giorgi, Elena E.;Gama, Lucio;Koup, Richard A.;Mascola, John R.;Monczor, Ana;Lupo, Sofia;Rolle, Charlotte-Paige;Arduino, Roberto;DeJesus, Edwin;Tomaras, Georgia D.;Seaman, Michael S.;Korber, Bette;Barouch, Dan H.
使用单一或双重广泛中和抗体（bNAbs）治疗HIV-1已显示出病毒逃逸，这表明至少需要三重bNAb治疗才能有效抑制病毒血症。我们进行了一项两部分的研究，包括单中心、随机、双盲、剂量递增、安慰剂对照的HIV-1 v2 -聚糖特异性抗体PGDM1400单独或与v3 -聚糖特异性抗体PGT121联合的首次人体试验（第一部分），以及PGDM1400联合的多中心、开放标签试验（第一部分）。第2部分（NCT03205917）： PGT121和cd4结合位点抗体VRC07-523LS在5名未接受抗逆转录病毒治疗（ART）的成年HIV病毒感染者中的应用在第二部分的研究中，主要终点是两部分的安全性、耐受性和药代动力学，以及未接受抗逆转录病毒治疗的艾滋病毒感染成人的抗病毒活性。次要终点是CD4+ T细胞计数的变化以及与PGDM1400、PGT121和VRC07-523LS耐药性相关的HIV-1序列变异的发展。静脉给药PGDM1400的安全性和耐受性良好，剂量高达30 mg kg - 1，并与PGT121和VRC07-523LS联合给药。单次静脉输注三种抗体各20 mg kg - 1，最大平均降低病毒血症个体血浆HIV RNA水平2.04 log10拷贝/ ml；然而，病毒反弹发生在所有参与者的最低点后的20天内。反弹病毒对PGDM1400和PGT121表现出部分或完全的体外抗性，而对VRC07-523LS则保持敏感性。尽管VRC07-523LS平均血清浓度为93µg ml−1，但病毒仍出现反弹。试验达到了预定的终点。我们的数据表明，未来的bNAb组合可能需要获得广泛的抗病毒活性，同时保持高血清浓度，以介导病毒控制。三种单克隆抗体的组合在HIV-1感染者中短暂地减少了病毒血症，但没有抗逆转录病毒治疗，但它不能防止病毒反弹。需要进一步的研究来确定这种方法是否可以优化。
HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 (NCT03205917). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg−1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg−1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml−1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control. A combination of three monoclonal antibodies transiently reduced viremia in people living with HIV-1 and not on antiretroviral therapy, but it did not prevent viral rebound. Further studies are needed to determine if this approach can be optimized.
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DOI：
10.1126/science.aaf1279
发表时间：
2016-05-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lu CL;Murakowski DK;Bournazos S;Schoofs T;Sarkar D;Halper-Stromberg A;Horwitz JA;Nogueira L;Golijanin J;Gazumyan A;Ravetch JV;Caskey M;Chakraborty AK;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
64.8
作者：
Scheid, Johannes F.;Horwitz, Joshua A.;Bar-On, Yotam;Kreider, Edward F.;Lu, Ching-Lan;Lorenzi, Julio C. C.;Feldmann, Anna;Braunschweig, Malte;Nogueira, Lilian;Oliveira, Thiago;Shimeliovich, Irina;Patel, Roshni;Burke, Leah;Cohen, Yehuda Z.;Hadrigan, Sonya;Settler, Allison;Witmer-Pack, Maggi;West, Anthony P., Jr.;Juelg, Boris;Keler, Tibor;Hawthorne, Thomas;Zingman, Barry;Gulick, Roy M.;Pfeifer, Nico;Learn, Gerald H.;Seaman, Michael S.;Bjorkman, Pamela J.;Klein, Florian;Schlesinger, Sarah J.;Walker, Bruce D.;Hahn, Beatrice H.;Nussenzweig, Michel C.;Caskey, Marina
通讯作者：
Caskey, Marina
影响因子：
64.8
作者：
Caskey M;Klein F;Lorenzi JC;Seaman MS;West AP Jr;Buckley N;Kremer G;Nogueira L;Braunschweig M;Scheid JF;Horwitz JA;Shimeliovich I;Ben-Avraham S;Witmer-Pack M;Platten M;Lehmann C;Burke LA;Hawthorne T;Gorelick RJ;Walker BD;Keler T;Gulick RM;Fätkenheuer G;Schlesinger SJ;Nussenzweig MC
通讯作者：
Nussenzweig MC
HIV-1 疫苗功效试验的免疫相关分析。
DOI：
10.1056/nejmoa1113425
发表时间：
2012-04-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Haynes BF;Gilbert PB;McElrath MJ;Zolla-Pazner S;Tomaras GD;Alam SM;Evans DT;Montefiori DC;Karnasuta C;Sutthent R;Liao HX;DeVico AL;Lewis GK;Williams C;Pinter A;Fong Y;Janes H;DeCamp A;Huang Y;Rao M;Billings E;Karasavvas N;Robb ML;Ngauy V;de Souza MS;Paris R;Ferrari G;Bailer RT;Soderberg KA;Andrews C;Berman PW;Frahm N;De Rosa SC;Alpert MD;Yates NL;Shen X;Koup RA;Pitisuttithum P;Kaewkungwal J;Nitayaphan S;Rerks-Ngarm S;Michael NL;Kim JH
通讯作者：
Kim JH
影响因子：
64.8
作者：
通讯作者：
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