A Phase 1, Open Label, Dose-escalation Study of the Safety and Pharmacokinetics of a Combination of Two Anti-SARS-CoV-2 mAbs (C144-LS and C135-LS) in Healthy Volunteers

This is a first-in-human, open label, single dose, dose-escalation phase 1 study to evaluate the safety and pharmacokinetics of a combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD) of the SARS-CoV-2 spike protein in healthy volunteers.

开始日期2021-01-11

申办/合作机构

The Rockefeller University

100 项与 C-135-LS 相关的临床结果

登录后查看更多信息

100 项与 C-135-LS 相关的转化医学

登录后查看更多信息

100 项与 C-135-LS 相关的专利（医药）

登录后查看更多信息

项与 C-135-LS 相关的文献（医药）

Antibody feedback regulation of memory B cell development in SARS-CoV-2 mRNA vaccination.

作者: Bieniasz, Paul D ; Muecksch, Frauke ; Cho, Alice ; Johnson, Brianna ; Millard, Katrina G ; Shimelovich, Irina ; Turroja, Martina ; Wang, Zijun ; Canis, Marie ; Yao, Kai-Hui ; Ramos, Victor ; Gaebler, Christian ; Gazumyan, Anna ; Dizon, Juan ; Raspe, Raphael ; Hatziioannou, Theodora ; DaSilva, Justin ; Nussenzweig, Michel C ; Oliveira, Thiago Y ; Caskey, Marina ; Schmidt, Fabian ; Schaefer-Babajew, Dennis

AbstractFeedback inhibition of humoral immunity by antibodies was initially documented in guinea pigs by Theobald Smith in 1909, who showed that passive administration of excess anti-Diphtheria toxin inhibited immune responses1. Subsequent work documented that antibodies can enhance or inhibit immune responses depending on antibody isotype, affinity, the physical nature of the antigen, and engagement of immunoglobulin (Fc) and complement (C’) receptors2, 3. However, little is known about how pre-existing antibodies might influence the subsequent development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity IgG1 anti-SARS-CoV-2 receptor binding domain (RBD)-specific monoclonal antibodies, C144-LS and C135-LS, and subsequently two doses of a SARS-CoV-2 mRNA vaccine. The two antibodies target Class 2 and 3 epitopes that dominate the initial immune response to SARS-CoV-2 infection and mRNA vaccination4–8. Antibody responses to the vaccine in C144-LS and C135-LS recipients produced plasma antigen binding and neutralizing titers that were fractionally lower but not statistically different to controls. In contrast, memory B cells enumerated by flow cytometry after the second vaccine dose were present in higher numbers than in controls. However, the memory B cells that developed in antibody recipients differed from controls in that they were not enriched in VH3-53, VH1-46 and VH3-66 genes and predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations. These antibodies showed altered RBD target specificity consistent with epitope masking, and only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The results indicate that pre-existing high-affinity antibodies bias memory B cell selection and have a profound effect on the development of immunological memory in humans that may in part explain the shifting target profile of memory antibodies elicited by the 3rd mRNA vaccine dose.

Frontiers in Cellular and Infection Microbiology

Effective Prophylaxis of COVID-19 in Rhesus Macaques Using a Combination of Two Parenterally-Administered SARS-CoV-2 Neutralizing Antibodies

Article

作者: Aye, Pyone Pyone ; Doyle-Meyers, Lara A ; Rappaport, Jay ; Montefiori, David ; Hope, Thomas J ; Gao, Hongmei ; Fears, Alyssa C ; Madden, Patrick J ; Carias, Ann M ; Blair, Robert V ; Russell-Lodrigue, Kasi ; Roy, Chad J ; Beddingfield, Brandon J ; Redondo, Ramon Lorenzo ; Maness, Nicholas J

SARS-CoV-2 is a respiratory borne pathogenic beta coronavirus that is the source of a worldwide pandemic and the cause of multiple pathologies in man. The rhesus macaque model of COVID-19 was utilized to test the added benefit of combinatory parenteral administration of two high-affinity anti-SARS-CoV-2 monoclonal antibodies (mAbs; C144-LS and C135-LS) expressly developed to neutralize the virus and modified to extend their pharmacokinetics. After completion of kinetics study of mAbs in the primate, combination treatment was administered prophylactically to mucosal viral challenge. Results showed near complete virus neutralization evidenced by no measurable titer in mucosal tissue swabs, muting of cytokine/chemokine response, and lack of any discernable pathologic sequalae. Blocking infection was a dose-related effect, cohorts receiving lower doses (6, 2 mg/kg) resulted in low grade viral infection in various mucosal sites compared to that of a fully protective dose (20 mg/kg). A subset of animals within this cohort whose infectious challenge was delayed 75 days later after mAb administration were still protected from disease. Results indicate this combination mAb effectively blocks development of COVID-19 in the rhesus disease model and accelerates the prospect of clinical studies with this effective antibody combination.

PLOS Pathogens1区 · 医学

Early treatment with a combination of two potent neutralizing antibodies improves clinical outcomes and reduces virus replication and lung inflammation in SARS-CoV-2 infected macaques

1区 · 医学

ArticleOA

作者: Elizaldi, Sonny R ; Pollard, Rachel E ; Muecksch, Frauke ; Sammak, Rebecca L ; Nussenzweig, Michel C ; Bieniasz, Paul D ; Lorenzi, Julio C C ; Van Rompay, Koen K A ; Nham, Peter B ; Deere, Jesse D ; Reader, J Rachel ; Lockwood, Sarah ; Allen, A Mark ; Usachenko, Jodie L ; Iyer, Smita S ; Ardeshir, Amir ; Hatziioannou, Theodora ; Patterson, Jean ; Dang, Que ; Immareddy, Ramya ; Hartigan-O'Connor, Dennis J ; Olstad, Katherine J ; Schmidt, Brian A ; Dutra, Joseph ; Yee, JoAnn L ; Verma, Anil ; Roh, Jamin W ; Shaan Lakshmanappa, Yashavanth ; Watanabe, Jennifer K

There is an urgent need for effective therapeutic interventions against SARS-CoV-2, including new variants that continue to arise. Neutralizing monoclonal antibodies have shown promise in clinical studies. We investigated the therapeutic efficacy of a combination of two potent monoclonal antibodies, C135-LS and C144-LS that carry half-life extension mutations, in the rhesus macaque model of COVID-19. Twelve young adult macaques (three groups of four animals) were inoculated intranasally and intra-tracheally with a high dose of SARS-CoV-2 and 24 hours later, treated intravenously with a high (40 mg/kg) or low (12 mg/kg) dose of the C135-LS and C144-LS antibody combination, or a control monoclonal antibody. Animals were monitored for 7 days. Compared to the control animals, animals treated with either dose of the anti-SARS-CoV-2 antibodies showed similarly improved clinical scores, lower levels of virus replication in upper and lower respiratory tract, and significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. In conclusion, this study provides proof-of-concept in support of further clinical development of these monoclonal antibodies against COVID-19 during early infection.

100 项与 C-135-LS 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
新型冠状病毒感染	临床1期	美国	The Rockefeller University	2021-01-11

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04700163 (RU, CTgov)	临床1期	新型冠状病毒感染	23	C144-LS+C-135-LS (S1 - Low Dose)	願鹹繭鏇範衊觸憲願願(鹹壓夢廠鹹顧膚鬱廠糧) = 願餘鏇鹹窪範糧繭鏇憲膚窪糧憲衊衊廠醖壓蓋 (淵餘窪願選獵膚繭製淵, 夢齋鏇鏇蓋顧蓋網鏇醖 ~ 選齋製鬱鬱簾膚製鑰觸) 更多	-	2025-03-13
				C144-LS+C-135-LS (S2 - Mid Dose)	願鹹繭鏇範衊觸憲願願(鹹壓夢廠鹹顧膚鬱廠糧) = 艱糧繭醖夢觸網鑰夢選膚窪糧憲衊衊廠醖壓蓋 (淵餘窪願選獵膚繭製淵, 鏇膚選鑰窪構衊襯夢鬱 ~ 窪鏇構衊製鏇襯鏇簾觸) 更多