Claire Jagodzinski                            1January 2012   Pauline Flipo
Alzheimer’s Disease                                                              2010         Multifactorial dementia     ...
Mechanisms              Misfolded proteins                Oxidative and           inflammatory damage             Energy f...
Misfolded proteins :                          Focus on Aβ aggregates                                                      ...
CorrelationNeurotoxicity                     Aβ Oligomers and fibrils                Transient and hazardous              ...
The Aβ pathway : trials           Vaccination (AN-1792 = AIP-001)                 Phase IIa, NCT00021723                  ...
7http://www.fiercebiotech.com/press-releases/researchers-design-alzheimers-antibodies
Structure of Antibody                                    CDR: Complementary Determining RegionJoseph M. Perchiacca et al. ...
Motif-grafting strategy                           N-ter                                          C-ter                    ...
Gammabodies: Motif-grafting strategy             Sequence-specific antibodies:            Detection of each Aβ conformer  ...
Which interactions?                                Hypothesis : Homotypic interaction                     Aβ motifs       ...
Competitive binding analysisJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific anti...
Neutralisation of oligomers and fibrils’                   toxicity                        Cell culture                   ...
Neutralisation of oligomers and fibrils’                   toxicity                        Cell culture                   ...
Neutralisation of oligomers and fibrils’                   toxicity                                                       ...
In brief...                 Gammabodies          Recognize aggregated Aβ isoforms in a conformation-          specific man...
Conclusion                                        Simple design strategy                                  Hope for Alzheim...
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Alzheimer Antibody

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Alzheimer Antibody

  1. 1. Claire Jagodzinski 1January 2012 Pauline Flipo
  2. 2. Alzheimer’s Disease 2010 Multifactorial dementia More than 35 millions Memory loss (first short term) people Apathy Confusion Risk factors Language problems Cardiovascular risk Dependance upon caregivers Ageing Genetic factors Under-stimulated environmentReitz, C. et al. Nat. Rev. Neurol. 7, 137–152 (2011) 2
  3. 3. Mechanisms Misfolded proteins Oxidative and inflammatory damage Energy failure and synaptic dysfunction Dementia 3Henry W. Querfuth, Frank M. LaFerla. Alzheimer’s Disease. New England Journal of Medicine, 2010;362(4):329-344
  4. 4. Misfolded proteins : Focus on Aβ aggregates APP = Amyloid Precursor Protein Aβ40 Aβ42 is toxic and associated with Alzheimer disease β secretase (BACE-1) γ secretase Secretases lead to a pathological processing of APPReitz, C. et al. Nat. Rev. Neurol. 7, 137–152 (2011) 4
  5. 5. CorrelationNeurotoxicity Aβ Oligomers and fibrils Transient and hazardous 5
  6. 6. The Aβ pathway : trials Vaccination (AN-1792 = AIP-001) Phase IIa, NCT00021723 Ongoing Diminution of plaques Encephalitis No cognitive or survival benefit 2 monoclonal antibodies against Aβ, Phase III : Bapineuzumab, Solanezumab Passive immunization (bapineuzumab) Phase II, NCT00112073 Human Immune Globulin IV, Phase III Vasogenic cerebral oedema γ-secretase inhibitor (LY450139) 6Henry W. Querfuth, Frank M. LaFerla. Alzheimer’s Disease. New England Journal of Medicine, 2010;362(4):329-344
  7. 7. 7http://www.fiercebiotech.com/press-releases/researchers-design-alzheimers-antibodies
  8. 8. Structure of Antibody CDR: Complementary Determining RegionJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. 8PNAS Early Edition, October 2011
  9. 9. Motif-grafting strategy N-ter C-ter Gammabodies: Grafted-Amyloid Motif Antibodies C ter Aβ motif => reactive with Aβ soluble oligomers Central Aβ motif => reactive with Aβ fibrils The grafted motifs target the corresponding peptide segment within misfolded Aβ conformersJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. 9PNAS Early Edition, October 2011
  10. 10. Gammabodies: Motif-grafting strategy 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: oligomersJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. 10PNAS Early Edition, October 2011
  11. 11. Which interactions? Hypothesis : Homotypic interaction Aβ motifs Same Aβ motifs Antibody Conformers Competitive binding analysis Gammabodies VS Sequence-specific monoclonal antibodies against AβJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 11β. PNAS Early Edition, October 2011
  12. 12. Competitive binding analysisJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 12β. PNAS Early Edition, October 2011
  13. 13. Neutralisation of oligomers and fibrils’ toxicity Cell culture Reduction of MTT  Cell survival Aβ gammabodies are nontoxic Sequences of grafted Aβ peptideJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 13β. PNAS Early Edition, October 2011
  14. 14. Neutralisation of oligomers and fibrils’ toxicity Cell culture Aβ gammabodies 12-21, 15-24, 18- 27, 30-39 and 33- 42 inhibit the toxicity of fibrilsJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 14β. PNAS Early Edition, October 2011
  15. 15. Neutralisation of oligomers and fibrils’ toxicity Aβ oligomers are Cell culture more toxic than Aβ fibrils Aβ gammabodies 30-39 and 33-42 inhibit the toxicity of soluble oligomersJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 15β. PNAS Early Edition, October 2011
  16. 16. In brief... Gammabodies Recognize aggregated Aβ isoforms in a conformation- specific manner Via homotypic interactions between amyloidogenic peptide motifs Are sequence-specific Neutralize the toxicity of Aβ oligomers and fibrilsJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 16β. PNAS Early Edition, October 2011
  17. 17. Conclusion Simple design strategy Hope for Alzheimer Disease Strategy potentially applicable to other diseasesJoseph M. Perchiacca et al. Structure-based design of conformation- and sequence-specific antibodies against amyloid 17β. PNAS Early Edition, October 2011

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