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Novel protein therapeutic joint retention strategy based on collagen-binding Avimers.
Hulme, Joanne T; D'Souza, Warren N; McBride, Helen J; Yoon, Bo-Rin Park; Willee, Angela M; Duguay, Amy; Thomas, Melissa; Fan, Bin; Dayao, Maria Rosalyn; Rottman, James B; Merriam, Kim; Xie, Jiansong; Smith, Richard; Alba, Benjamin M; Case, Ryan B; Dang, Khue; Montalvan, Anielka; Grinberg, Natalia; Sun, Hong; Black, Roy A; Gabel, Christopher A; Sims, John E; Moore, Kevin; Bakker, Alice; Li, Peng.
Afiliación
  • Hulme JT; Inflammation, Amgen, Inc., Seattle, Washington.
  • D'Souza WN; Inflammation, Amgen, Inc., Thousand Oaks, California.
  • McBride HJ; Inflammation, Amgen, Inc., Thousand Oaks, California.
  • Yoon BP; Inflammation, Amgen, Inc., Seattle, Washington.
  • Willee AM; Inflammation, Amgen, Inc., Thousand Oaks, California.
  • Duguay A; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Thomas M; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Fan B; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Dayao MR; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Rottman JB; Comparative Biology & Safety Sciences, Amgen, Inc., Cambridge, Massachusetts.
  • Merriam K; Comparative Biology & Safety Sciences, Amgen, Inc., Cambridge, Massachusetts.
  • Xie J; Clinical Immunology, Amgen, Inc., Thousand Oaks, California.
  • Smith R; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Alba BM; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Case RB; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Dang K; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Montalvan A; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Grinberg N; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Sun H; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Black RA; Inflammation, Amgen, Inc., Seattle, Washington.
  • Gabel CA; Inflammation, Amgen, Inc., Seattle, Washington.
  • Sims JE; Inflammation, Amgen, Inc., Seattle, Washington.
  • Moore K; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Bakker A; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
  • Li P; Therapeutic Discovery, Amgen, Inc., South San Francisco, California.
J Orthop Res ; 36(4): 1238-1247, 2018 04.
Article en En | MEDLINE | ID: mdl-28971529
Designing drugs to treat diseases associated with articular joints, particularly those targeting chondrocytes, is challenging due to unique local environmental constraints including the avascular nature of cartilage, the absence of a closed joint compartment, and a highly cross-linked extracellular matrix. In an effort to address these challenges, we developed a novel strategy to prolong residence time of intra-articularly administered protein therapeutics. Avimer domains are naturally found in membrane polypeptides and mediate diverse protein-protein interactions. Screening of a phage Avimer domain library led to identification of several low affinity type II collagen-binding Avimers. Following several rounds of mutagenesis and reselection, these initial hits were transformed to high affinity, selective type II collagen-binding Avimers. One such Avimer (M26) persisted in rat knees for at least 1 month following intra-articular administration. Fusion of this Avimer to a candidate therapeutic payload, IL-1Ra, yielded a protein construct which simultaneously bound to type II collagen and to IL-1 receptor. In vitro, IL-1Ra_M26 bound selectively to cartilage explants and remained associated even after extensive washing. Binding appeared to occur preferentially to pericellular regions surrounding chondrocytes. An acute intra-articular IL-1-induced IL-6 challenge rat model was employed to assess in vivo pharmacodynamics. Whereas both IL-1Ra_M26 and native IL-1Ra inhibited IL-6 output when co-administered with the IL-1 challenge, only IL-1Ra_M26 inhibited when administered 1 week prior to IL-1 challenge. Collagen-binding Avimers thus represent a promising strategy for enhancing cartilage residence time of protein therapeutics. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1238-1247, 2018.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas / Sistemas de Liberación de Medicamentos / Artropatías Tipo de estudio: Evaluation_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: J Orthop Res Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas / Sistemas de Liberación de Medicamentos / Artropatías Tipo de estudio: Evaluation_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: J Orthop Res Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos