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Crystal structure reveals conservation of amyloid-β conformation recognized by 3D6 following humanization to bapineuzumab.

Feinberg H, Saldanha JW, Diep L, Goel A, Widom A, Veldman GM, Weis WI, Schenk D, Basi GS
Alzheimers Res Ther 6 31 (2014)
Cited: 25 times
EuropePMC logo PMID: 25024748

Abstract

Methods

To gain further insight into the epitope conformation, we interrogated structural details of amino-terminal epitopes in amyloid-β using x-ray crystallography of 3D6Fab:amyloid-β complexes. Humanization of 3D6 was carried out using standard procedures integrating recombinant methods, sequence informatics, and homology modeling predictions to identify important mouse framework residues for retention in the finished humanized product.

Results

Here we report the crystal structure of a recombinant Fab fragment of 3D6 in complex with amyloid-β1-7 solved at 2.0 Å resolution. The N-terminus of amyloid-β is bound to 3D6 as a 310 helix. The amino-terminal Asp residue is buried deepest in the antibody binding pocket, with the Cβ atom of residue 6 visible at the entrance to the binding pocket near the surface of the antibody. We further evaluate homology model based predictions used to guide humanization of 3D6 to bapineuzumab, with actual structure of the Fab. The structure of the Fab:amyloid-β complex validates design of the humanized antibody, and confirms the amyloid-β epitope recognized by 3D6 as previously mapped by ELISA.

Conclusion

The conformation of amyloid-β antigen recognized by 3D6 is novel and distinct from other antibodies recognizing N-terminal epitopes. Our result provides the first report demonstrating structural conservation of antigen contact residues, and conformation of antigen recognized, between the parent murine antibody and its humanized version.

Reviews - 4ong mentioned but not cited (1)

  1. Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes. Ma B, Zhao J, Nussinov R. Biochim Biophys Acta 1860 2672-2681 (2016)

Articles - 4ong mentioned but not cited (1)

  1. Crystal structure reveals conservation of amyloid-β conformation recognized by 3D6 following humanization to bapineuzumab. Feinberg H, Saldanha JW, Diep L, Goel A, Widom A, Veldman GM, Weis WI, Schenk D, Basi GS. Alzheimers Res Ther 6 31 (2014)


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  2. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease. Rajasekhar K, Govindaraju T. RSC Adv 8 23780-23804 (2018)
  3. Antibody Engineering for Optimized Immunotherapy in Alzheimer's Disease. Sumner IL, Edwards RA, Asuni AA, Teeling JL. Front Neurosci 12 254 (2018)
  4. Anti-Amyloid Immunotherapies for Alzheimer's Disease: A 2023 Clinical Update. Yadollahikhales G, Rojas JC. Neurotherapeutics 20 914-931 (2023)
  5. Structure and Function of Alzheimer's Amyloid βeta Proteins from Monomer to Fibrils: A Mini Review. Agrawal N, Skelton AA. Protein J 38 425-434 (2019)
  6. Structural biology of cell surface receptors implicated in Alzheimer's disease. Hermans SJ, Nero TL, Morton CJ, Gooi JH, Crespi GAN, Hancock NC, Gao C, Ishii K, Markulić J, Parker MW. Biophys Rev 14 233-255 (2022)

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  2. Secreted amyloid β-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity. Welzel AT, Maggio JE, Shankar GM, Walker DE, Ostaszewski BL, Li S, Klyubin I, Rowan MJ, Seubert P, Walsh DM, Selkoe DJ. Biochemistry 53 3908-3921 (2014)
  3. A highly sensitive novel immunoassay specifically detects low levels of soluble Aβ oligomers in human cerebrospinal fluid. Yang T, O'Malley TT, Kanmert D, Jerecic J, Zieske LR, Zetterberg H, Hyman BT, Walsh DM, Selkoe DJ. Alzheimers Res Ther 7 14 (2015)
  4. Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies. Crespi GA, Hermans SJ, Parker MW, Miles LA. Sci Rep 5 9649 (2015)
  5. N-Terminal Extensions Retard Aβ42 Fibril Formation but Allow Cross-Seeding and Coaggregation with Aβ42. Szczepankiewicz O, Linse B, Meisl G, Thulin E, Frohm B, Sala Frigerio C, Colvin MT, Jacavone AC, Griffin RG, Knowles T, Walsh DM, Linse S. J Am Chem Soc 137 14673-14685 (2015)
  6. Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid. Yang T, Dang Y, Ostaszewski B, Mengel D, Steffen V, Rabe C, Bittner T, Walsh DM, Selkoe DJ. Ann Neurol 86 215-224 (2019)
  7. Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N‑truncated Abeta in sporadic Alzheimer disease cases and mouse models. Bouter Y, Lopez Noguerola JS, Tucholla P, Crespi GA, Parker MW, Wiltfang J, Miles LA, Bayer TA. Acta Neuropathol 130 713-729 (2015)
  8. Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies. Zhao J, Nussinov R, Ma B. J Biol Chem 292 18325-18343 (2017)
  9. Structural and functional analyses of pyroglutamate-amyloid-β-specific antibodies as a basis for Alzheimer immunotherapy. Piechotta A, Parthier C, Kleinschmidt M, Gnoth K, Pillot T, Lues I, Demuth HU, Schilling S, Rahfeld JU, Stubbs MT. J Biol Chem 292 12713-12724 (2017)
  10. Functional detection of botulinum neurotoxin serotypes A to F by monoclonal neoepitope-specific antibodies and suspension array technology. von Berg L, Stern D, Pauly D, Mahrhold S, Weisemann J, Jentsch L, Hansbauer EM, Müller C, Avondet MA, Rummel A, Dorner MB, Dorner BG. Sci Rep 9 5531 (2019)
  11. A Brain-Targeting Bispecific-Multivalent Antibody Clears Soluble Amyloid-Beta Aggregates in Alzheimer's Disease Mice. Rofo F, Meier SR, Metzendorf NG, Morrison JI, Petrovic A, Syvänen S, Sehlin D, Hultqvist G. Neurotherapeutics 19 1588-1602 (2022)
  12. Nature-inspired design and evolution of anti-amyloid antibodies. Julian MC, Rabia LA, Desai AA, Arsiwala A, Gerson JE, Paulson HL, Kane RS, Tessier PM. J Biol Chem 294 8438-8451 (2019)
  13. A calcium-sensitive antibody isolates soluble amyloid-β aggregates and fibrils from Alzheimer's disease brain. Stern AM, Liu L, Jin S, Liu W, Meunier AL, Ericsson M, Miller MB, Batson M, Sun T, Kathuria S, Reczek D, Pradier L, Selkoe DJ. Brain 145 2528-2540 (2022)
  14. Letter Anti-Aβ antibody target engagement: a response to Siemers et al. Watt AD, Crespi GA, Down RA, Ascher DB, Gunn A, Perez KA, McLean CA, Villemagne VL, Parker MW, Barnham KJ, Miles LA. Acta Neuropathol 128 611-614 (2014)
  15. A coiled conformation of amyloid-β recognized by antibody C706. Teplyakov A, Obmolova G, Gilliland GL. Alzheimers Res Ther 9 66 (2017)
  16. Age, dose, and binding to TfR on blood cells influence brain delivery of a TfR-transported antibody. Faresjö R, Sehlin D, Syvänen S. Fluids Barriers CNS 20 34 (2023)
  17. Structural basis of an epitope tagging system derived from Haloarcula marismortui bacteriorhodopsin I D94N and its monoclonal antibody GD-26. Pao PJ, Hsu MF, Chiang MH, Chen CT, Lee CC, Wang AH. FEBS J 289 730-747 (2022)


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