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Engineered Antibody Fragments as Potential Therapeutics against Misfolded Proteins in Neurodegenerative Diseases

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Handbook of Neurochemistry and Molecular Neurobiology

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1 Introduction

Immunoglobulins or antibodies are powerful tools for the research, diagnosis, and treatment of human diseases due to their unique ability to identify and neutralize specific targets with high affinity. Of late, monoclonal antibodies derived from the immune system have become the gold standard for targeted drug therapies because they afford a potent combination of selective specificity and minimal immunogenicity. Consequently, antibody-based therapeutics exist for a range of human disorders, including rheumatoid arthritis and cancer, and engineered antibodies (designed and produced using recombinant technologies) represent more than 30% of biopharmaceuticals currently in clinical trials.

Targeted antibody-based therapeutics are now being investigated for the treatment of diverse “protein misfolding” disorders of the human nervous system. These disorders share a common pathogenetic mechanism in which the aggregation of specific mutant proteins is linked to the...

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Abbreviations

AAV:

adeno-associated virus

AD:

Alzheimer's disease

APP:

amyloid precursor protein

CDR:

complementarity-determining region

ER:

endoplasmic reticulum

Fab:

antigen-binding fragment

FACS:

fluorescence-activated cell sorting

Fc:

constant (crystallizable) fragment

Fv:

variable fragment

HD:

Huntington's disease

PD:

Parkinson's disease

PrP:

prion protein

PrPSc:

scrapie prion protein

scFv:

single-chain variable fragment

VH:

variable heavy chain

VL:

variable light chain

References

  • Barbas CF III, Bain JD, Hoekstra DM, Lerner RA. 1992. Semisynthetic combinatorial antibody libraries: A chemical solution to the diversity problem. Proc Natl Acad Sci USA 89: 4457–4461.

    Article  CAS  PubMed  Google Scholar 

  • Barkhordarian H, Emadi S, Schulz P, Sierks MR. 2006. Isolating recombinant antibodies against specific protein morphologies using atomic force microscopy and phage display technologies. Protein Eng Des Sel 19: 497–502.

    Article  CAS  PubMed  Google Scholar 

  • Bellotti V, Nuvolone M, Giorgetti S, Obici L, Palladini G, et al. 2007. The workings of the amyloid diseases. Ann Med 39: 200–207.

    Article  CAS  PubMed  Google Scholar 

  • Bird RE, Hardman KD, Jacobson JW, Johnson S, Kaufman BM, et al. 1988. Single-chain antigen-binding proteins. Science 242: 423–426.

    Article  CAS  PubMed  Google Scholar 

  • Boder ET, Wittrup KD. 1997. Yeast surface display for screening combinatorial polypeptide libraries. Nat Biotechnol 15: 553–557.

    Article  CAS  PubMed  Google Scholar 

  • Boldicke T. 2007. Blocking translocation of cell surface molecules from the ER to the cell surface by intracellular antibodies targeted to the ER. J Cell Mol Med 11: 54–70.

    Article  PubMed  Google Scholar 

  • Cardinale A, Filesi I, Vetrugno V, Pocchiari M, Sy MS, et al. 2005. Trapping prion protein in the endoplasmic reticulum impairs PrPC maturation and prevents PrPSc accumulation. J Biol Chem 280: 685–694.

    CAS  PubMed  Google Scholar 

  • Castellani RJ, Zhu X, Lee HG, Moreira PI, Perry G, et al. 2007. Neuropathology and treatment of Alzheimer disease: Did we lose the forest for the trees? Expert Rev Neurother 7: 473–485.

    Article  CAS  PubMed  Google Scholar 

  • Chowdhury PS, Vasmatzis G, Beers R, Lee B, Pastan I. 1998. Improved stability and yield of a Fv-toxin fusion protein by computer design and protein engineering of the Fv. J Mol Biol 281: 917–928.

    Article  CAS  PubMed  Google Scholar 

  • Colby DW, Chu Y, Cassady JP, Duennwald M, Zazulak H, et al. 2004a. Potent inhibition of huntingtin aggregation and cytotoxicity by a disulfide bond-free single-domain intracellular antibody. Proc Natl Acad Sci USA 101: 17616–17621.

    Article  CAS  Google Scholar 

  • Colby DW, Garg P, Holden T, Chao G, Webster JM, et al. 2004b. Development of a human light chain variable domain (VL) intracellular antibody specific for the amino terminus of huntingtin via yeast surface display. J Mol Biol 342: 901–912.

    Article  CAS  Google Scholar 

  • Daugherty PS, Chen G, Olsen MJ, Iverson BL, Georgiou G. 1998. Antibody affinity maturation using bacterial surface display. Protein Eng 11: 825–832.

    Article  CAS  PubMed  Google Scholar 

  • Davies J, Riechmann L. 1996. Single antibody domains as small recognition units: Design and in vitro antigen selection of camelized, human VH domains with improved protein stability. Protein Eng 9: 531–537.

    Article  CAS  PubMed  Google Scholar 

  • der Maur AA, Zahnd C, Fischer F, Spinelli S, Honegger A, et al. 2002. Direct in vivo screening of intrabody libraries constructed on a highly stable single-chain framework. J Biol Chem 277: 45075–45085.

    Article  PubMed  Google Scholar 

  • Desai UA, Pallos J, Ma AA, Stockwell BR, Thompson LM, et al. 2006. Biologically active molecules that reduce polyglutamine aggregation and toxicity. Hum Mol Genet 15: 2114–2124.

    Article  CAS  PubMed  Google Scholar 

  • Donofrio G, Heppner FL, Polymenidou M, Musahl C, Aguzzi A. 2005. Paracrine inhibition of prion propagation by anti-PrP single-chain Fv miniantibodies. J Virol 79: 8330–8338.

    Article  CAS  PubMed  Google Scholar 

  • Emadi S, Barkhordarian H, Wang MS, Schulz P, Sierks MR. 2007. Isolation of a human single chain antibody fragment against oligomeric α-synuclein that inhibits aggregation and prevents α-synuclein-induced toxicity. J Mol Biol 368: 1132–1144.

    Article  CAS  PubMed  Google Scholar 

  • Emadi S, Liu R, Yuan B, Schulz P, McAllister C, et al. 2004. Inhibiting aggregation of α-synuclein with human single chain antibody fragments. Biochemistry 43: 2871–2878.

    Article  CAS  PubMed  Google Scholar 

  • Ewert S, Honegger A, Pluckthun A. 2004. Stability improvement of antibodies for extracellular and intracellular applications: CDR grafting to stable frameworks and structure-based framework engineering. Methods 34: 184–199.

    Article  CAS  PubMed  Google Scholar 

  • Fandrich M. 2007. On the structural definition of amyloid fibrils and other polypeptide aggregates. Cell Mol Life Sci 64: 2066–2078.

    Article  CAS  PubMed  Google Scholar 

  • Ferreira ST, Vieira MNN, De Felice FG. 2007. Soluble protein oligomers as emerging toxins in alzheimer's and other amyloid diseases. IUBMB Life 59: 332–345.

    Article  CAS  PubMed  Google Scholar 

  • Filesi I, Cardinale A, Mattei S, Biocca S. 2007. Selective re-routing of prion protein to proteasomes and alteration of its vesicular secretion prevent PrPSc formation. J Neurochem 101: 1516–1526.

    Article  CAS  PubMed  Google Scholar 

  • Fukuchi K, Accavitti-Loper MA, Kim HD, Tahara K, Cao Y, et al. 2006b. Amelioration of amyloid load by anti-Aβ single-chain antibody in Alzheimer mouse model. Biochem Biophys Res Commun 344: 79–86.

    Article  CAS  Google Scholar 

  • Fukuchi K, Tahara K, Kim HD, Maxwell JA, Lewis TL, et al. 2006a. Anti-Aβ single-chain antibody delivery via adeno-associated virus for treatment of Alzheimer's disease. Neurobiol Dis 23: 502–511.

    Article  CAS  Google Scholar 

  • Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, et al. 1993. Naturally-occurring antibodies devoid of light chains. Nature 363: 446–448.

    Article  CAS  PubMed  Google Scholar 

  • He M, Taussig MJ. 2005. Ribosome display of antibodies: Expression, specificity and recovery in a eukaryotic system. J Immunol Methods 297: 73–82.

    Article  CAS  PubMed  Google Scholar 

  • Heppner FL, Musahl C, Arrighi I, Klein MA, Rulicke T, et al. 2001. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294: 178–182.

    Article  CAS  PubMed  Google Scholar 

  • Hoogenboom HR, de Bruine AP, Hufton SE, Hoet RM, Arends JW, et al. 1998. Antibody phage display technology and its applications. Immunotechnology 4: 1–20.

    Article  CAS  PubMed  Google Scholar 

  • Huston JS, Tai MS, McCartney J, Keck P, Oppermann H. 1993. Antigen recognition and targeted delivery by the single-chain Fv. Cell Biophys 22: 189–224.

    CAS  PubMed  Google Scholar 

  • Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, et al. 2003. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300: 486–489.

    Article  CAS  PubMed  Google Scholar 

  • Khoshnan A, Ko J, Patterson PH. 2002. Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc Natl Acad Sci USA 99: 1002–1007.

    Article  CAS  PubMed  Google Scholar 

  • Knappik A, Ge L, Honegger A, Pack P, Fischer M, et al. 2000. Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. J Mol Biol 296: 57–86.

    Article  CAS  PubMed  Google Scholar 

  • Lecerf JM, Shirley TL, Zhu Q, Kazantsev A, Amersdorfer P, et al. 2001. Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease. Proc Natl Acad Sci USA 98: 4764–4769.

    Article  CAS  PubMed  Google Scholar 

  • Levites Y, Jansen K, Smithson LA, Dakin R, Holloway VM, et al. 2006. Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. J Neurosci 26: 11923–11928.

    Article  CAS  PubMed  Google Scholar 

  • Li S, Li XJ. 2006. Multiple pathways contribute to the pathogenesis of Huntington disease. Mol Neurodegener 1: 19.

    Article  PubMed  Google Scholar 

  • Liu R, McAllister C, Lyubchenko Y, Sierks MR. 2004b. Proteolytic antibody light chains alter beta-amyloid aggregation and prevent cytotoxicity. Biochemistry 43: 9999–10007.

    Article  CAS  Google Scholar 

  • Liu R, Yuan B, Emadi S, Zameer A, Schulz P, et al. 2004a. Single chain variable fragments against beta-amyloid (Abeta) can inhibit Abeta aggregation and prevent Abeta-induced neurotoxicity. Biochemistry 43: 6959–6967.

    Article  CAS  Google Scholar 

  • Luginbuhl B, Kanyo Z, Jones RM, Fletterick RJ, Prusiner SB, et al. 2006. Directed evolution of an anti-prion protein scFv fragment to an affinity of 1 pM and its structural interpretation. J Mol Biol 363: 75–97.

    Article  PubMed  Google Scholar 

  • Maguire-Zeiss KA, Wang CI, Yehling E, Sullivan MA, Short DW, et al. 2006. Identification of human α-synuclein specific single chain antibodies. Biochem Biophys Res Commun 349: 1198–1205.

    Article  CAS  PubMed  Google Scholar 

  • Marks JD, Hoogenboom HR, Bonnert TP, McCafferty J, Griffiths AD, et al. 1991. By-passing immunization: Human antibodies from V-gene libraries displayed on phage. J Mol Biol 222: 581–597.

    Article  CAS  PubMed  Google Scholar 

  • Maynard J, Georgiou G. 2000. Antibody engineering. Annu Rev Biomed Eng 2: 339–376.

    Article  CAS  PubMed  Google Scholar 

  • Merk H, Stiege W, Tsumoto K, Kumagai I, Erdmann VA. 1999. Cell-free expression of two single-chain monoclonal antibodies against lysozyme: Effect of domain arrangement on the expression. J Biochem 125: 328–333.

    CAS  PubMed  Google Scholar 

  • Miller TW, Zhou C, Gines S, Mac Donald ME, Mazarakis ND, et al. 2005. A human single-chain Fv intrabody preferentially targets amino-terminal huntingtin fragments in striatal models of Huntington's disease. Neurobiol Dis 19: 47–56.

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto K, Kimura S, Nakamura N, Yokoyama T, Horiuchi H, et al. 2007. Chicken antibody against a restrictive epitope of prion protein distinguishes normal and abnormal prion proteins. Biologicals 35: 303-308.

    Google Scholar 

  • Murphy RC, Messer A. 2004. A single-chain Fv intrabody provides functional protection against the effects of mutant protein in an organotypic slice culture model of Huntington's disease. Brain Res Mol Brain Res 121: 141–145.

    Article  CAS  PubMed  Google Scholar 

  • O'Nuallain B, Wetzel R. 2002. Conformational Abs recognizing a generic amyloid fibril epitope. Proc Natl Acad Sci USA 99: 1485–1490.

    Article  PubMed  Google Scholar 

  • Orlandi R, Gussow DH, Jones PT, Winter G. 1989. Cloning immunoglobulin variable domains for expression by the polymerase chain reaction. Proc Natl Acad Sci USA 86: 3833–3837.

    Article  CAS  PubMed  Google Scholar 

  • Paganetti P, Calanca V, Galli C, Stefani M, Molinari M. 2005. beta-site specific intrabodies to decrease and prevent generation of Alzheimer's Abeta peptide. J Cell Biol 168: 863–868.

    Article  CAS  PubMed  Google Scholar 

  • Paul S, Nishiyama Y, Planque S, Taguchi H. 2006. Theory of proteolytic antibody occurrence. Immunol Lett 103: 8–16.

    Article  CAS  PubMed  Google Scholar 

  • Rangan SK, Liu R, Brune D, Planque S, Paul S, et al. 2003. Degradation of beta-amyloid by proteolytic antibody light chains. Biochemistry 42: 14328–14334.

    Article  CAS  PubMed  Google Scholar 

  • Robinson CR, Sauer RT. 1998. Optimizing the stability of single-chain proteins by linker length and composition mutagenesis. Proc Natl Acad Sci USA 95: 5929–5934.

    Article  CAS  PubMed  Google Scholar 

  • Schenk D. 2002. Amyloid-beta immunotherapy for Alzheimer's disease: The end of the beginning. Nat Rev Neurosci 3: 824–828.

    Article  CAS  PubMed  Google Scholar 

  • Solforosi L, Criado JR, McGavern DB, Wirz S, Sanchez-Alavez M, et al. 2004. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303: 1514–1516.

    Article  CAS  PubMed  Google Scholar 

  • Solomon B, Koppel R, Frankel D, Hanan-Aharon E. 1997. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci USA 94: 4109–4112.

    Article  CAS  PubMed  Google Scholar 

  • Takeda A, Hasegawa T, Matsuzaki-Kobayashi M, Sugeno N, Kikuchi A, et al. 2006. Mechanisms of neuronal death in synucleinopathy. J Biomed Biotechnol 2006: 19365.

    PubMed  Google Scholar 

  • Tanaka T, Lobato MN, Rabbitts TH. 2003. Single domain intracellular antibodies: A minimal fragment for direct in vivo selection of antigen-specific intrabodies. J Mol Biol 331: 1109–1120.

    Article  CAS  PubMed  Google Scholar 

  • Tsumoto K, Nakaoki Y, Ueda Y, Ogasahara K, Yutani K, et al. 1994. Effect of the order of antibody variable regions on the expression of the single-chain HyHEL10 Fv fragment in Escherichia coli and the thermodynamic analysis of its antigen-binding properties. Biochem Biophys Res Commun 201: 546–551.

    Article  CAS  PubMed  Google Scholar 

  • Vetrugno V, Cardinale A, Filesi I, Mattei S, Sy MS, et al. 2005. KDEL-tagged anti-prion intrabodies impair PrP lysosomal degradation and inhibit scrapie infectivity. Biochem Biophys Res Commun 338: 1791–1797.

    Article  CAS  PubMed  Google Scholar 

  • Visintin M, Settanni G, Maritan A, Graziosi S, Marks JD, et al. 2002. The intracellular antibody capture technology (IACT): Towards a consensus sequence for intracellular antibodies. J Mol Biol 317: 73–83.

    Article  CAS  PubMed  Google Scholar 

  • Visintin M, Tse E, Axelson H, Rabbitts TH, Cattaneo A. 1999. Selection of antibodies for intracellular function using a two-hybrid in vivo system. Proc Natl Acad Sci USA 96(21): 11723–11728.

    Article  CAS  PubMed  Google Scholar 

  • Westergard L, Christensen HM, Harris DA. 2007. The cellular prion protein (PrPC)): Its physiological function and role in disease. Biochim Biophys Acta 1772: 629–644.

    CAS  PubMed  Google Scholar 

  • White AR, Enever P, Tayebi M, Mushens R, Linehan J, et al. 2003. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 422: 80–83.

    Article  CAS  PubMed  Google Scholar 

  • Wolfgang WJ, Miller TW, Webster JM, Huston JS, Thompson LM, et al. 2005. Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies. Proc Natl Acad Sci USA 102: 11563–11568.

    Article  CAS  PubMed  Google Scholar 

  • Zameer A, Schulz P, Wang MS, Sierks MR. 2006. Single chain Fv antibodies against the 25–35 Abeta fragment inhibit aggregation and toxicity of Abeta42. Biochemistry 45: 11532–11539.

    Article  CAS  PubMed  Google Scholar 

  • Zhou C, Emadi S, Sierks MR, Messer A. 2004. A human single-chain Fv intrabody blocks aberrant cellular effects of overexpressed alpha-synuclein. Mol Ther 10: 1023–1031.

    Article  CAS  PubMed  Google Scholar 

  • Zuber C, Knackmuss S, Rey C, Reusch U, Rottgen P, et al. 2008. Single chain Fv antibodies directed against the 37 kDa/67 kDa laminin receptor as therapeutic tools in prion diseases. Mol Immunol 45: 144–151.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank members of the Messer lab for helpful discussions of the manuscript. Work in the Messer lab was supported in part by grants from NIH/NINDS, High Q Foundation, National Parkinson Foundation, Hereditary Disease Foundation/Cure HD Initiative, and Huntington's Disease Society of America.

Authors
  1. E. Kvam
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  2. A. Messer
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Editor information

Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 10962, 140 Old Orangeburg Road, Orangeburg, New York, USA

    Abel Lajtha (Director) (Director)

  2. Department of Neurosciences Division of Neurology, Medical University of South Carolina, 29425, 96 Jonathan Lucas Street, Suite 309, Charleston, SC, USA

    Naren Banik

  3. Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, 29209, 6439 Garners Ferry Road Building 2, Room C11, Columbia, SC, USA

    Swapan K. Ray

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Kvam, E., Messer, A. (2009). Engineered Antibody Fragments as Potential Therapeutics against Misfolded Proteins in Neurodegenerative Diseases. In: Lajtha, A., Banik, N., Ray, S.K. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30375-8_18

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