Seaton Kelly E, Paez Carmen A, Yu Chenchen, Karuna Shelly T, Gamble Theresa, Miner Maurine D, Heptinstall Jack, Zhang Lu, Gao Fei, Yacovone Margaret, Spiegel Hans, Dumond Julie B, Anderson Maija, Piwowar-Manning Estelle, Dye Bonnie, Tindale India, Proulx-Burns Lori, Trahey Meg, Takuva Simbarashe, Takalani Azwidihwi, Bailey Veronique C, Kalams Spyros A, Scott Hyman, Mkhize Nonhlanhla N, Weiner Joshua A, Ackerman Margaret E, McElrath M Juliana, Pensiero Michael, Barouch Dan H, Montefiori David, Tomaras Georgia D, Corey Lawrence, Cohen Myron S, Huang Yunda, Mahomed Sharana, Siegel Marc, Kelley Colleen F
Duke Center for Human Systems Immunology, Departments of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Durham, NC, USA.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Lancet HIV. 2025 Jun;12(6):e405-e415. doi: 10.1016/S2352-3018(25)00012-8.
PGDM1400LS is a human monoclonal antibody targeting the HIV envelope V2 apex with a lysine-serine modification intended to enhance serum and tissue half-lives and is being considered for use in combination monoclonal antibody trials. We sought to test whether PGDM1400LS was safe and had favourable serum concentration, pharmacokinetics, and neutralising ability in healthy adults.
HVTN 140/HPTN 101 part A is an open-label, dose escalation, first-in-human phase 1 trial of PGDM1400LS given intravenously or subcutaneously to healthy adults aged 18-50 years without HIV-1. The study enrolled participants at four sites in the USA, across five groups, each receiving one dose of PGDM1400-LS intravenously (group 1: 5 mg/kg; group 2: 20 mg/kg; and group 4: 40 mg/kg) or subcutaneously (group 3: 20 mg/kg; and group 5: 40 mg/kg). Participants in group 1 were enrolled sequentially without random assignment. Participants in groups 2 and 3 were block randomised and enrolled simultaneously after group 1 safety review. Groups 4 and 5 followed the same process, contingent on groups 2 and 3 safety review. The primary endpoints were safety and tolerability of PGDM1400LS, serum concentration of PGDM1400LS, and serum neutralising activity after single administration of PGDM1400LS. Serum PGDM1400LS concentrations collected at seven timepoints (day 0, day 3, day 6, day 28, day 56, day 112, and day 168) were assessed via an anti-idiotype binding assay and characterised via non-compartmental pharmacokinetic analysis. Serum neutralisation activity (ID) was assessed by a TZM-bl assay. The study is registered with ClinicalTrials.gov, NCT05184452.
Between Nov 15, 2021, and March 4, 2022, 15 participants were enrolled into the five study groups (three participants per group) with 6 months of follow-up. Ten of 15 participants were female, 14 of 15 participants were non-Hispanic, and 11 of 15 participants were White, with a median age of 27 years (range 24-47). PGDM1400LS was safe and well tolerated, with mild to moderate solicited symptoms. Serum concentrations showed dose proportionality by administration route, with peak concentrations observed immediately after intravenous infusion (range 95·7-727·4 μg/mL) or on day 6 after subcutaneous infusion (205·6-547·1 μg/mL). The median elimination half-life was 55 days (range 48-59), representing a 2-to-3-times increase versus parental PDGM1400. Estimated subcutaneous (vs intravenous) bioavailability was 50-60%. ID titres showed agreement with concentration-predicted ID titres, indicating maintenance of neutralisation activity in vivo.
PGDM1400LS is a promising candidate for combination monoclonal antibody efficacy trials going forward.
National Institute of Allergy and Infectious Diseases-National Institutes of Health.
PGDM1400LS是一种靶向HIV包膜V2顶端的人源单克隆抗体，经过赖氨酸-丝氨酸修饰以延长血清和组织半衰期，目前正被考虑用于联合单克隆抗体试验。我们试图测试PGDM1400LS在健康成年人中是否安全，以及是否具有良好的血清浓度、药代动力学和中和能力。
HVTN 140/HPTN 101 A部分是一项开放标签、剂量递增的1期人体试验，将PGDM1400LS静脉或皮下注射给18-50岁未感染HIV-1的健康成年人。该研究在美国的四个地点招募参与者，分为五组，每组接受一剂PGDM1400-LS静脉注射（第1组：5 mg/kg；第2组：20 mg/kg；第4组：40 mg/kg）或皮下注射（第3组：20 mg/kg；第5组：40 mg/kg）。第1组参与者按顺序入组，不进行随机分配。第2组和第3组参与者进行区组随机化，并在第1组安全性审查后同时入组。第4组和第5组遵循相同程序，取决于第2组和第3组的安全性审查。主要终点是PGDM1400LS的安全性和耐受性、PGDM1400LS的血清浓度以及单次给药后PGDM1400LS的血清中和活性。在7个时间点（第0天、第3天、第6天、第28天、第56天、第112天和第168天）收集的血清PGDM1400LS浓度通过抗独特型结合试验进行评估，并通过非房室药代动力学分析进行表征。血清中和活性（ID）通过TZM-bl试验进行评估。该研究已在ClinicalTrials.gov注册，注册号为NCT05184452。
在2021年11月15日至2022年3月4日期间，15名参与者被纳入五个研究组（每组3名参与者），并进行了6个月的随访。15名参与者中有10名女性，15名参与者中有14名非西班牙裔，15名参与者中有11名白人，中位年龄为27岁（范围24-47岁）。PGDM1400LS安全且耐受性良好，出现轻度至中度的主动报告症状。血清浓度按给药途径显示出剂量比例关系，静脉输注后立即观察到峰值浓度（范围95.7-727.4 μg/mL），或皮下输注后第6天观察到峰值浓度（205.6-547.1 μg/mL）。中位消除半衰期为55天（范围48-59天），比亲本PDGM1400增加了2至3倍。估计皮下（相对于静脉）生物利用度为50-60%。ID滴度与浓度预测的ID滴度一致，表明体内中和活性得以维持。
PGDM1400LS是未来联合单克隆抗体疗效试验的一个有前景的候选药物。
美国国立卫生研究院国家过敏和传染病研究所。
