First-in-human study of two anti-SARS CoV-2 antibodies in health volunteers

对健康志愿者中的两种抗 SARS CoV-2 抗体进行的首次人体研究

• 批准号: 10291661
• 负责人: Luis J Montaner
• 金额: $ 157.16万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291661
• 关键词: 2019-nCoV; Amino Acid Substitution; Amino Acids; Animal Model; Animals; Antibodies; Antibody Therapy; Antigens; Antiviral Agents; Asparagine; Binding; Biological; COVID-19; COVID-19 pandemic; Clinical; Data; Disease; Dose; Drug Kinetics; Economics; Elderly; Exhibits; FDA Emergency Use Authorization; Fc domain; Grant; Half-Life; Hamsters; Health; Healthcare; Human Activities; Immune; Immune response; Immunocompromised Host; In Vitro; Individual; Infection; Intravenous; Intravenous infusion procedures; Leucine; Methionine; Modernization; Monoclonal Antibodies; Mus; Mutation; Outcome; Participant; Pathology; Pattern; Phase; Play; Population; Populations at Risk; Positioning Attribute; Prevention; Prophylactic treatment; Randomized Controlled Trials; Recombinants; Resistance; Resolution; Role; SARS-CoV-2 antibody; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Safety; Sanitation; Serine; Site; Sterility; Subcutaneous Injections; Therapeutic; Universities; Vaccination; Vaccines; Variant; Viral; World Health; clinical candidate; clinical development; convalescent plasma; design; experimental study; first-in-human; healthy volunteer; high risk; human monoclonal antibodies; human study; in vitro activity; in vivo; neutralizing monoclonal antibodies; nonhuman primate; open label; pandemic disease; phase 1 study; phase I trial; pre-clinical; pressure; prevent; receptor binding; research clinical testing; severe COVID-19; subcutaneous; volunteer

Project Summary The Coronavirus Disease 2019 (COVID-19) pandemic is currently gripping the world without a known cure or prevention. Aside from the health consequences, the necessary decrease in human activity has resulted in economic losses without modern precedent, especially in the developing world where health care and sanitation were not sufficient even prior to the pandemic. Innumerable efforts are being undertaken to develop vaccines to SARS-CoV-2 and it is likely that antibodies will be essential for protection. COVID-19 antibody therapy in the form of polyclonal plasma from convalescent individuals is currently being explored as a therapeutic option and has been granted an emergency use authorization (EUA) by the FDA. Monoclonal antibodies may prove to be particularly useful in preventing SARS-CoV-2 infection in populations who may not mount protective immune responses to vaccination (e.g. advanced age, immunocompromise) and for post-exposure prophylaxis in individuals at high risk to develop severe COVID-19. C135 and C144 are recombinant, fully human mAbs that specifically bind SARS-CoV-2 spike protein receptor binding domain (RBD) and exhibit exceptional neutralizing activity in vitro against SARS-CoV-2. Two one-amino acid mutations have been introduced to prolong half-life and allow dose sparing. The C135-LS and C144-LS combination has shown remarkable activity in both prophylaxis and therapy experiments in several relevant animal models in both prophylaxis and treatment experiments. These preclinical data support the clinical evahe from SARS-CoV-2 and accelerate viral clearance and disease resolution in SARS-CoV-2-infected individuals. The proposed study is a first-in-human, open label, single dose, dose-escalation phase 1 trial to evaluate the safety and pharmacokinetics of the C135-LS and C144-LS combination in healthy volunteers.

项目概要 2019 年冠状病毒病 (COVID-19) 目前正在席卷全球，且尚无已知的治疗方法或方法 预防。除了健康后果外，人类活动的必要减少还导致 现代史无前例的经济损失，特别是在医疗保健和卫生设施匮乏的发展中国家 即使在大流行之前，这些措施也是不够的。人们正在付出无数的努力来开发疫苗 SARS-CoV-2 和抗体很可能对于保护至关重要。 目前正在以来自康复者的多克隆血浆的形式进行 COVID-19 抗体治疗 作为一种治疗选择进行探索，并已获得 FDA 的紧急使用授权 (EUA)。 单克隆抗体可能被证明对于预防人群中的 SARS-CoV-2 感染特别有用 可能无法对疫苗接种产生保护性免疫反应的人（例如高龄、免疫功能低下）以及 用于对患有严重 COVID-19 的高风险个体进行暴露后预防。 C135 和 C144 是重组的全人源单克隆抗体，可特异性结合 SARS-CoV-2 刺突蛋白受体 结合域（RBD），并在体外表现出针对 SARS-CoV-2 的特殊中和活性。两个一氨基 引入酸突变以延长半衰期并允许节省剂量。 C135-LS 和 C144-LS 组合在几个相关的预防和治疗实验中显示出显着的活性 预防和治疗实验中的动物模型。这些临床前数据支持了临床评估 SARS-CoV-2，并加速 SARS-CoV-2 感染者的病毒清除和疾病解决。 拟议的研究是一项首次人体、开放标签、单剂量、剂量递增的 1 期试验，旨在评估 C135-LS 和 C144-LS 组合在健康志愿者中的安全性和药代动力学。

项目成果

Measuring replication competent HIV-1: advances and challenges in defining the latent reservoir.

测量复制能力的 HIV-1：确定潜在病毒库的进展和挑战。

• 发表时间: 2018
• 影响因子: 3.3
• 作者: Wang, Zheng;Simonetti, Francesco R;Siliciano, Robert F;Laird, Gregory M
• 通讯作者: Laird, Gregory M

Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges.

针对遗传性疾病的造血干细胞基因治疗：进展与挑战。

• 发表时间: 2019
• 作者: Cavazzana, Marina;Bushman, Frederic D;Miccio, Annarita;André;Six, Emmanuelle
• 通讯作者: Six, Emmanuelle

Breaking the Glyco-Code of HIV Persistence and Immunopathogenesis.

打破艾滋病毒持久性和免疫发病机制的糖代码。

• 发表时间: 2019-04
• 影响因子: 4.6
• 作者: Colomb, Florent;Giron, Leila B;Trbojevic;Lauc, Gordan;Abdel
• 通讯作者: Abdel

Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane.

携带有复制能力的 HIV-1 的扩增细胞克隆会持续存在、消亡。

• 发表时间: 2018
• 影响因子: 11.1
• 作者: Wang, Zheng;Gurule, Evelyn E;Brennan, Timothy P;Gerold, Jeffrey M;Kwon, Kyungyoon J;Hosmane, Nina N;Kumar, Mithra R;Beg, Subul A;Capoferri, Adam A;Ray, Stuart C;Ho, Ya;Hill, Alison L;Siliciano, Janet D;Siliciano, Robert F
• 通讯作者: Siliciano, Robert F

SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition.

SAMHD1 磷酸化通过多种干扰素和酪氨酸激酶抑制来协调抗 HIV-1 反应。

• 发表时间: 2018
• 影响因子: 6.4
• 作者: Szaniawski, Matthew A;Spivak, Adam M;Cox, James E;Catrow, Jonathan L;Hanley, Timothy;Williams, Elizabeth S C P;Tremblay, Michel J;Bosque, Alberto;Planelles, Vicente
• 通讯作者: Planelles, Vicente