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i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists.
Romei, Matthew G; Leonard, Brandon; Katz, Zachary B; Le, Daniel; Yang, Yanli; Day, Eric S; Koo, Christopher W; Sharma, Preeti; Bevers Iii, Jack; Kim, Ingrid; Dai, Huiguang; Farahi, Farzam; Lin, May; Shaw, Andrey S; Nakamura, Gerald; Sockolosky, Jonathan T; Lazar, Greg A.
Afiliação
  • Romei MG; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Leonard B; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Katz ZB; Department of Research Biology, Genentech Inc., South San Francisco, CA, USA.
  • Le D; Department of Microchemistry, Proteomic, Lipidomics, and Next Generation Sequencing, Genentech Inc., South San Francisco, CA, USA.
  • Yang Y; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Day ES; Department of Pharma Technical Development, Genentech Inc., South San Francisco, CA, USA.
  • Koo CW; Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA.
  • Sharma P; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Bevers Iii J; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Kim I; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Dai H; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Farahi F; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Lin M; Department of Protein Chemistry, Genentech Inc., South San Francisco, CA, USA.
  • Shaw AS; Department of Research Biology, Genentech Inc., South San Francisco, CA, USA.
  • Nakamura G; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA.
  • Sockolosky JT; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA. jsockolo@gmail.com.
  • Lazar GA; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA. gregorylazar@gmail.com.
Nat Commun ; 15(1): 642, 2024 Jan 20.
Article em En | MEDLINE | ID: mdl-38245524
ABSTRACT
The ability to leverage antibodies to agonize disease relevant biological pathways has tremendous potential for clinical investigation. Yet while antibodies have been successful as antagonists, immune mediators, and targeting agents, they are not readily effective at recapitulating the biology of natural ligands. Among the important determinants of antibody agonist activity is the geometry of target receptor engagement. Here, we describe an engineering approach inspired by a naturally occurring Fab-Fab homotypic interaction that constrains IgG in a unique i-shaped conformation. i-shaped antibody (iAb) engineering enables potent intrinsic agonism of five tumor necrosis factor receptor superfamily (TNFRSF) targets. When applied to bispecific antibodies against the heterodimeric IL-2 receptor pair, constrained bispecific IgG formats recapitulate IL-2 agonist activity. iAb engineering provides a tool to tune agonist antibody function and this work provides a framework for the development of intrinsic antibody agonists with the potential for generalization across broad receptor classes.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Anticorpos Biespecíficos Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Anticorpos Biespecíficos Idioma: En Ano de publicação: 2024 Tipo de documento: Article