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Journal of Biochemistry Advance Access published online on January 2, 2008
Journal of Biochemistry, doi:10.1093/jb/mvm239
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© 2008 The Japanese Biochemical Society

Immunoreactivity of Phage Library-derived Human Single-chain Antibodies to Amyloid Beta Conformers In vitro

Tomoki Yoshihara1, Sho Takiguchi1, Akifumi Kyuno1, Koichi Tanaka1, Sayaka Kuba1, Shuhei Hashiguchi1, Yuji Ito1, Tadafumi Hashimoto2, Takeshi Iwatsubo2, Shinichiro Tsuyama3, Toshihiro Nakashima4 and Kazuhisa Sugimura1

1 Department of Bioengineering, Faculty of Engineering, Kagoshima University, Korimoto 1-21-40, Kagoshima, Kagoshima 890-0065, Japan.
2 Department of Neuropathology and Neuroscinece, Tokyo University, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
3 The Second Department of Anatomy, Center of Chronic Viral Disease, Faculty of Medicine, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, Kagoshima 890-8544, Japan.
4 Chemo-Sero-Therapeutic Research Institute, Kyokushi, Kikuchi, Kumamoto 869-1298, Japan.

Corresponding author: Kazuhisa Sugimura, 1-21-40 Korimoto, Kagoshima 890-0065, Japan, Phone: +81-99-285-8345, Fax: +81-99-258-4706, E-mail address: kazu{at}be.kagoshima-u.ac.jp

Received September 29, 2007; Accepted December 11, 2007


  Abstract

The pathogenesis of Alzheimer's disease involves conformational changes of Aβ. A series of antibodies recognizing a distinct conformation of Aβ(snapshot antibody) is useful for both understanding the mechanism of molecular conversion and identifying diagnostic and therapeutic reagents. As Aβ with various conformations can be prepared in vitro under varying physicochemical conditions, snapshot antibodies can be isolated by directly binding to target molecules with antibody-displaying phages. We tested the feasibility of this idea. We show a feature of several Aβ-reactive antibodies isolated from our human single-chain Fv antibody-phage library and particularly report the characteristics of an scFv clone, B6, selected from the fibrillar Aβ1-42-coated biopanning. B6 bound to fibrillar Aβ1-42 as well as globulomer Aβ1-42 but not to soluble Aβ1-42 or Aβ1-40. B6 inhibited Aβ1-42 fibril formation with 600 nM IC50 in spite of being the monovalent scFv form. Epitope analysis suggested that the binding site might be located at the β2 sheet of the C-terminus of Aβ1-42. Although it is believed that N-terminus-recognizing antibodies tend to show the capability to inhibit Aβ1-42 fibrillation, B6 is the first human inhibitory antibody recognizing the C-terminus of Aβ1-42.

Key Words: Amyloid beta 1-42, Conformation, Human antibody, Single-chain variable fragment, scFv


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