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A candidate antibody drug for prevention of malaria.
Williams, Katherine L; Guerrero, Steve; Flores-Garcia, Yevel; Kim, Dongkyoon; Williamson, Kevin S; Siska, Christine; Smidt, Pauline; Jepson, Sofia Z; Li, Kan; Dennison, S Moses; Mathis-Torres, Shamika; Chen, Xiaomu; Wille-Reece, Ulrike; MacGill, Randall S; 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; Dutta, Sheetij; Tomaras, Georgia D; Zavala, Fidel; Ketchem, Randal R; Emerling, Daniel E.
Afiliação
  • Williams KL; Atreca, Inc., San Carlos, CA, USA. kwilliams@atreca.com.
  • Guerrero S; Atreca, Inc., San Carlos, CA, USA.
  • Flores-Garcia Y; Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Kim D; Atreca, Inc., San Carlos, CA, USA.
  • Williamson KS; Initium Therapeutics, Inc., Natick, MA, USA.
  • Siska C; Atreca, Inc., San Carlos, CA, USA.
  • Smidt P; Just - Evotec Biologics, Seattle, WA, USA.
  • Jepson SZ; Just - Evotec Biologics, Seattle, WA, USA.
  • Li K; Just - Evotec Biologics, Seattle, WA, USA.
  • Dennison SM; Duke Center for Human Systems Immunology, Department of Surgery, Duke University, Durham, NC, USA.
  • Mathis-Torres S; Duke Center for Human Systems Immunology, Department of Surgery, Duke University, Durham, NC, USA.
  • Chen X; Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Wille-Reece U; Atreca, Inc., San Carlos, CA, USA.
  • MacGill RS; BioNTech US, Inc., Cambridge, MA, USA.
  • Walker M; PATH Center for Vaccine Innovation and Access, Washington DC, USA.
  • Jongert E; PATH Center for Vaccine Innovation and Access, Washington DC, USA.
  • King CR; Walker Bioscience, Carlsbad, CA, USA.
  • Ockenhouse C; GSK, Rixensart, Belgium.
  • Glanville J; PATH Center for Vaccine Innovation and Access, Washington DC, USA.
  • Moon JE; PATH Center for Vaccine Innovation and Access, Washington DC, USA.
  • Regules JA; Centivax, Inc., South San Francisco, CA, USA.
  • Tan YC; Center for Enabling Capabilities, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
  • Cavet G; Walter Reed Army Institute of Research, Silver Spring, MD, USA.
  • Lippow SM; Atreca, Inc., San Carlos, CA, USA.
  • Robinson WH; Nuevocor Pte. Ltd, Singapore, Singapore.
  • Dutta S; Atreca, Inc., San Carlos, CA, USA.
  • Tomaras GD; Paramune, Inc., San Carlos, CA, USA.
  • Zavala F; Atreca, Inc., San Carlos, CA, USA.
  • Ketchem RR; Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Emerling DE; Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Nat Med ; 30(1): 117-129, 2024 Jan.
Article em En | MEDLINE | ID: mdl-38167935
ABSTRACT
Over 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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Malária / Anticorpos Monoclonais Tipo de estudo: Guideline / Prognostic_studies Limite: Animals / Child, preschool / Humans / Infant Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Malária / Anticorpos Monoclonais Tipo de estudo: Guideline / Prognostic_studies Limite: Animals / Child, preschool / Humans / Infant Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos