Bapineuzumab captures the N-terminus of the Alzheimer's disease amyloid-beta peptide in a helical conformation

Miles, Luke A.; Crespi, Gabriela A. N.; Doughty, Larissa; Parker, Michael W.

doi:10.1038/srep01302

Cited by 107 publications

(138 citation statements)

References 29 publications

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“…Structure of 3D6 shown in purple and 4HIX [24] structure shown in green. The dotted lines indicate hydrogen bonds.…”

Section: Resultsmentioning

confidence: 99%

“…The neo-epitope specificity of 3D6 combined with conformation of the bound epitope, elucidated here at 2 Å resolution and in the structure 4HIX [24], is clearly unique among the antibodies studied to date, as well as among clinical candidates under current investigation. Gantenerumab [25] binds Aβ in a manner that overlaps the epitope recognized by 3D6 and offers an interesting comparison.…”

Section: Discussionmentioning

confidence: 99%

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

Feinberg

Saldanha²,

Diep³

et al. 2014

Alz Res Therapy

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IntroductionImmunotherapy targeting amyloid-β peptide is under active clinical investigation for treatment of Alzheimer’s disease (AD). Among the hypotheses being investigated for impact on clinical outcome are the preferred epitope or conformation of amyloid-β to target for treatment, and the mechanism of action underlying immunotherapy. Bapineuzumab (humanized 3D6), a neo-epitope specific antibody recognizing amyloid-β1-5 with strong preference for an exposed Asp residue at the N-terminus of the peptide, has undergone advanced clinical testing for treatment of AD.MethodsTo 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.ResultsHere 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.ConclusionsThe 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.

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“…Structure of 3D6 shown in purple and 4HIX [24] structure shown in green. The dotted lines indicate hydrogen bonds.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Feinberg

Saldanha²,

Diep³

et al. 2014

Alz Res Therapy

View full text Add to dashboard Cite

show abstract

“…Recent crystallization studies brought forward an ␣-helical conformation of A␤'s N terminus in complex with the 3D6-based therapeutic antibody bapineuzumab (42). Experimental evidence nevertheless suggests that N-terminal substitutions can affect A␤ aggregation (5,24,25,43).…”

Section: Discussionmentioning

confidence: 99%

The Alzheimer Disease Protective Mutation A2T Modulates Kinetic and Thermodynamic Properties of Amyloid-β (Aβ) Aggregation

Benilova

Gallardo

Ungureanu

et al. 2014

Journal of Biological Chemistry

140

150

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“…Instead, most antibodies target and bind the monomeric form of the peptide in its helical form, not its β-sheet rich diseaseassociated form. 6,7 This serves to remove the substrate from the aggregation process. In contrast, an effective peptide inhibitor should be designed based on structural signatures of the parent peptide in its disease-associated form(s).…”

Section: Targeting Aβ Structural Signatures: Monomers Vs Oligomers Vmentioning

confidence: 99%

D-amino acid-based peptide inhibitors as early or preventative therapy in Alzheimer disease

Kumar

Sim

2014

Prion

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Bapineuzumab captures the N-terminus of the Alzheimer's disease amyloid-beta peptide in a helical conformation

Cited by 107 publications

References 29 publications

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

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

The Alzheimer Disease Protective Mutation A2T Modulates Kinetic and Thermodynamic Properties of Amyloid-β (Aβ) Aggregation

D-amino acid-based peptide inhibitors as early or preventative therapy in Alzheimer disease

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