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Engineering a Low-Immunogenic Mirror-Image VHH against Vascular Endothelial Growth Factor.
Aoki, Keisuke; Higashi, Katsuaki; Oda, Sakiho; Manabe, Asako; Maeda, Kayuu; Morise, Jyoji; Oka, Shogo; Inuki, Shinsuke; Ohno, Hiroaki; Oishi, Shinya; Nonaka, Motohiro.
Afiliación
  • Aoki K; Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • Higashi K; Laboratory of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
  • Oda S; Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
  • Manabe A; Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
  • Maeda K; Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
  • Morise J; Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
  • Oka S; Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
  • Inuki S; Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
  • Ohno H; Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • Oishi S; Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • Nonaka M; Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
ACS Chem Biol ; 19(5): 1194-1205, 2024 05 17.
Article en En | MEDLINE | ID: mdl-38695546
ABSTRACT
Immunogenicity is a major caveat of protein therapeutics. In particular, the long-term administration of protein therapeutic agents leads to the generation of antidrug antibodies (ADAs), which reduce drug efficacy while eliciting adverse events. One promising solution to this issue is the use of mirror-image proteins consisting of d-amino acids, which are resistant to proteolytic degradation in immune cells. We have recently reported the chemical synthesis of the enantiomeric form of the variable domain of the antibody heavy chain (d-VHH). However, identifying mirror-image antibodies capable of binding to natural ligands remains challenging. In this study, we developed a novel screening platform to identify a d-VHH specific for vascular endothelial growth factor A (VEGF-A). We performed mirror-image screening of two newly constructed synthetic VHH libraries displayed on T7 phage and identified VHH sequences that effectively bound to the mirror-image VEGF-A target (d-VEGF-A). We subsequently synthesized a d-VHH candidate that preferentially bound the native VEGF-A (l-VEGF-A) with submicromolar affinity. Furthermore, immunization studies in mice demonstrated that this d-VHH elicited no ADAs, unlike its corresponding l-VHH. Our findings highlight the utility of this novel d-VHH screening platform in the development of protein therapeutics exhibiting both reduced immunogenicity and improved efficacy.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor A de Crecimiento Endotelial Vascular Límite: Animals / Humans Idioma: En Revista: ACS Chem Biol Año: 2024 Tipo del documento: Article País de afiliación: Japón

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor A de Crecimiento Endotelial Vascular Límite: Animals / Humans Idioma: En Revista: ACS Chem Biol Año: 2024 Tipo del documento: Article País de afiliación: Japón
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