A candidate antibody drug for prevention of malaria
-
Published:2024-01
Issue:1
Volume:30
Page:117-129
-
ISSN:1078-8956
-
Container-title:Nature Medicine
-
language:en
-
Short-container-title:Nat Med
Author:
Williams Katherine L.ORCID, Guerrero SteveORCID, Flores-Garcia Yevel, Kim Dongkyoon, Williamson Kevin S., Siska Christine, Smidt Pauline, Jepson Sofia Z.ORCID, Li Kan, Dennison S. MosesORCID, Mathis-Torres Shamika, Chen Xiaomu, Wille-Reece Ulrike, MacGill Randall S.ORCID, Walker Michael, Jongert Erik, King C. Richter, Ockenhouse Christian, Glanville Jacob, Moon James E., Regules Jason A., Tan Yann Chong, Cavet Guy, Lippow Shaun M., Robinson William H.ORCID, Dutta Sheetij, Tomaras Georgia D.ORCID, Zavala FidelORCID, Ketchem Randal R.ORCID, Emerling Daniel E.ORCID
Abstract
AbstractOver 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO’s preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.
Funder
The Bill and Melinda Gates Foundation Bill and Melinda Gates Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
Reference89 articles.
1. World Health Organization. World malaria report 2022. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022 (2022). 2. World Health Organization. Global technical strategy for malaria 2016-2030, 2021 update. www.who.int/publications/i/item/9789240031357 (2021). 3. Sinnis, P. & Fidock, D. A. The RTS,S vaccine—a chance to regain the upper hand against malaria? Cell 185, 750–754 (2022). 4. Collins, K. A., Snaith, R., Cottingham, M. G., Gilbert, S. C. & Hill, A. V. S. Enhancing protective immunity to malaria with a highly immunogenic virus-like particle vaccine. Sci. Rep. 7, 46621 (2017). 5. World Health Organization. WHO recommends R21/Matrix-M vaccine for malaria prevention in updated advice on immunization. www.who.int/news/item/02-10-2023-who-recommends-r21-matrix-m-vaccine-for-malaria-prevention-in-updated-advice-on-immunization (2023).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|