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Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors.
Ortiz, Daniel F; Lansing, Jonathan C; Rutitzky, Laura; Kurtagic, Elma; Prod'homme, Thomas; Choudhury, Amit; Washburn, Nathaniel; Bhatnagar, Naveen; Beneduce, Christopher; Holte, Kimberly; Prenovitz, Robert; Child, Matthew; Killough, Jason; Tyler, Steven; Brown, Julia; Nguyen, Stephanie; Schwab, Inessa; Hains, Maurice; Meccariello, Robin; Markowitz, Lynn; Wang, Jing; Zouaoui, Radouane; Simpson, Allison; Schultes, Birgit; Capila, Ishan; Ling, Leona; Nimmerjahn, Falk; Manning, Anthony M; Bosques, Carlos J.
Afiliación
  • Ortiz DF; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Lansing JC; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Rutitzky L; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Kurtagic E; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Prod'homme T; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Choudhury A; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Washburn N; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Bhatnagar N; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Beneduce C; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Holte K; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Prenovitz R; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Child M; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Killough J; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Tyler S; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Brown J; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Nguyen S; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Schwab I; Department of Biology, Institute of Genetics, University of Erlangen-Nürnberg, 91058 Erlangen, Germany.
  • Hains M; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Meccariello R; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Markowitz L; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Wang J; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Zouaoui R; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Simpson A; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Schultes B; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Capila I; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Ling L; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Nimmerjahn F; Department of Biology, Institute of Genetics, University of Erlangen-Nürnberg, 91058 Erlangen, Germany.
  • Manning AM; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
  • Bosques CJ; Momenta Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA. cbosques@momentapharma.com.
Sci Transl Med ; 8(365): 365ra158, 2016 11 16.
Article en En | MEDLINE | ID: mdl-27856797
Autoantibody immune complex (IC) activation of Fcγ receptors (FcγRs) is a common pathogenic hallmark of multiple autoimmune diseases. Given that the IC structural features that elicit FcγR activation are poorly understood and the FcγR system is highly complex, few therapeutics can directly block these processes without inadvertently activating the FcγR system. To address these issues, the structure activity relationships of an engineered panel of multivalent Fc constructs were evaluated using sensitive FcγR binding and signaling cellular assays. These studies identified an Fc valency with avid binding to FcγRs but without activation of immune cell effector functions. These observations directed the design of a potent trivalent immunoglobulin G-Fc molecule that broadly inhibited IC-driven processes in a variety of immune cells expressing FcγRs. The Fc trimer, Fc3Y, was highly efficacious in three different animal models of autoimmune diseases. This recombinant molecule may represent an effective therapeutic candidate for FcγR-mediated autoimmune diseases.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Autoinmunes / Fragmentos Fc de Inmunoglobulinas / Receptores de IgG / Enfermedades del Complejo Inmune / Complejo Antígeno-Anticuerpo Límite: Animals / Humans / Male Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Buscar en Google
Añadir a Mi BVS
Imprimir
XML
PubMed Links

Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Autoinmunes / Fragmentos Fc de Inmunoglobulinas / Receptores de IgG / Enfermedades del Complejo Inmune / Complejo Antígeno-Anticuerpo Límite: Animals / Humans / Male Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos