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Antibody may help fight Alzheimer’s

Claire JagodzinskiPauline FlipoJanuary 2012

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Multifactorial dementia

Memory loss (first short term)

Confusion

Apathy

Language problems

Dependance upon caregivers

2010More than 35 millions

people

Cardiovascular risk

Genetic factors

Ageing

Risk factors

Under-stimulated environment

Reitz, C. et al. Nat. Rev. Neurol. 7, 137–152 (2011)

Alzheimer’s Disease

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Mechanisms

Henry W. Querfuth, Frank M. LaFerla. Alzheimer’s Disease. New England Journal of Medicine, 2010;362(4):329-344

Misfolded proteins

Oxidative and inflammatory damage

Energy failure and synaptic dysfunction

Dementia

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Misfolded proteins : Focus on Aβ aggregates

APP = Amyloid Precursor Protein

β secretase(BACE-1)

γ secretase

Secretases lead to a pathological processing of APP

Reitz, C. et al. Nat. Rev. Neurol. 7, 137–152 (2011)

Aβ42 is toxic and associated with

Alzheimer disease

Aβ40

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Correlation

Neurotoxicity Aβ Oligomers and fibrils

Transient and hazardous

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The Aβ pathway : trials

Henry W. Querfuth, Frank M. LaFerla. Alzheimer’s Disease. New England Journal of Medicine, 2010;362(4):329-344

Vaccination (AN-1792 = AIP-001)

Phase IIa, NCT00021723

Diminution of plaquesEncephalitis

No cognitive or survival benefit

Passive immunization (bapineuzumab)

Phase II, NCT00112073

Vasogenic cerebral oedema

Ongoing

2 monoclonal antibodies against Aβ, Phase III :

Bapineuzumab, Solanezumab

Human Immune Globulin IV, Phase III

γ-secretase inhibitor (LY450139)

7http://www.fiercebiotech.com/press-releases/researchers-design-alzheimers-antibodies

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Structure of Antibody

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

CDR: Complementary Determining Region

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C-terN-ter

Motif-grafting strategy

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

Gammabodies: Grafted-Amyloid Motif Antibodies

Central Aβ motif => reactive with Aβ fibrils

C ter Aβ motif => reactive with Aβ soluble oligomers

The grafted motifs target the corresponding peptide segment within misfolded Aβ conformers

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Gammabodies: Motif-grafting strategy

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

Sequence-specific antibodies: Detection of each Aβ conformer

6E10: N-ter (Aβ 1-16)

4G8: middle region (Aβ 18-22)

9F1: C-ter (Aβ 34-39)

Conformation-specific antibodies:Specifically recognize folded conformers of amyloidogenic

proteins

OC, WO1: fibrils

A11: oligomers

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Which interactions?

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

Hypothesis : Homotypic interaction

Aβ motifsAntibody

Same Aβ motifsConformers

Competitive binding analysis

Gammabodies

Sequence-specific monoclonal antibodies against Aβ

VS

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Competitive binding analysis

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

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Neutralisation of oligomers and fibrils’ toxicity

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

Cell culture

Aβ gammabodies are nontoxic

Reduction of MTTÞ Cell survival

Sequences of grafted Aβ

peptide

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Neutralisation of oligomers and fibrils’ toxicity

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

Cell culture

Aβ gammabodies 12-21, 15-24, 18-27, 30-39 and 33-

42 inhibit the toxicity of fibrils

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Neutralisation of oligomers and fibrils’ toxicity

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

Cell culture

Aβ gammabodies 30-39 and 33-42

inhibit the toxicity of soluble oligomers

Aβ oligomers are more toxic than Aβ

fibrils

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In brief...

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

Gammabodies

Recognize aggregated Aβ isoforms in a conformation-specific manner

Neutralize the toxicity of Aβ oligomers and fibrils

Via homotypic interactions between amyloidogenic peptide motifs

Are sequence-specific

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Conclusion

Joseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. PNAS Early Edition, October 2011

Simple design strategy

Hope for Alzheimer Disease

Strategy potentially applicable to other diseases