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Immunotherapeutic Strategies Immunotherapeutic Strategies for Alzheimer’s Diseasefor Alzheimer’s Disease
Cynthia A. Lemere, Ph.D.Center for Neurologic Diseases, Brigham &
Women's Hospital and Harvard Medical School, Boston, MA, USA
DisclosuresDisclosures
• Scientific Advisory Boards:
-- Neurophage Pharmaceuticals, Inc., Probiodrug AG, Cognition Therapeutics, Inc., Genentech, Inc.
• Consultant:
-- Baxter Healthcare, DIAN Consortium
Most common cause of dementia
Affects 5.4 mil Americans; > 30 mil worldwide
Occurs in all races and ethnic groups
No cure or effective treatment
(See www.alz.org for complete references)
Alzheimer’s Disease in 2012Alzheimer’s Disease in 2012
Alzheimer’s Disease: Hallmark LesionsAlzheimer’s Disease: Hallmark Lesions
Amyloid plaques Amyloid plaques (outside neurons): Composed of a 40-42 (outside neurons): Composed of a 40-42 amino acid peptide called amyloid -protein (A)amino acid peptide called amyloid -protein (A)
Neurofibrillary tanglesNeurofibrillary tangles (inside neurons): Composed of an (inside neurons): Composed of an altered form of a neuronal protein, taualtered form of a neuronal protein, tau
Aβ Immunotherapy for the Aβ Immunotherapy for the Prevention and/or Treatment of Prevention and/or Treatment of
Alzheimer’s DiseaseAlzheimer’s Disease
Aß proteinAß protein1 42
B cell epitope
T cell epitope
Aß1
Carrier protein
or
Active Immunization: Aß Protein Active Immunization: Aß Protein (injection, intranasal or transcutaneous)(injection, intranasal or transcutaneous)
T cellT cell
B cellB cellCellular
Release of Th1-mediated pro-inflammatory and/or Th2-mediated
anti-inflammatory cytokines depending upon antigen and adjuvant
Humoral
Imm
un
e R
esp
o nse
Passive Transfer: Aß Antibodies Passive Transfer: Aß Antibodies (i.v., s.c., or i.p. injection) (i.v., s.c., or i.p. injection)
or+ immune booster (adjuvant)
Aß-specific antibodiesAß-specific antibodies
Aß-specific antibodiesAß-specific antibodies
Aß antibodies bind Aß protein and target it for clearance
No
Imm
un
e R
esp
onse
?
Costimulatory molecules
2nd signal
Active vs. Passive ImmunizationActive vs. Passive Immunization
Pros Cons
Active: - long-lasting - immune risks- cost-effective - hard to “turn off”- large population - overlapping epitopes- fewer Dr’s visits
Passive: - does not require - monthly injections an immune response - expensive (hu mAb)- stopped easily - frequent Dr’s visits- specific targets - anti-antibodies (?)
Aβ Immunotherapy in RodentsAβ Immunotherapy in Rodents
Active Aβ immunization in AD-like Tg mice:
• Generates anti-Aβ titers
–Antibodies bind human AD plaques
–B cell epitopes within Aβ1-15
–T cell epitopes within Aβ16-42
Active and Passive Aβ Immunotherapies:
• Reduce cerebral Aβ burden
• Increase peripheral Aβ in blood; microhemorrhage?
• Improve behavior/cognition on certain tasks, especially if given early
Aβ Immunotherapy in J20 APP Tg MiceAβ Immunotherapy in J20 APP Tg Mice
J20 APP-tg mice (hAPPSw, Ind)/PDGF-promoter on a mixed C57BL/6 x DBA background (L. Mucke, UCSF)
Proposed MechanismsProposed Mechanisms
Fu et al. 2010 CNS and Neurological Disorders – Drug Targets
ELAN/Wyeth AN1792 Trial: Aβ1-42 + QS21ELAN/Wyeth AN1792 Trial: Aβ1-42 + QS21
• Phase 2a trial stopped Jan. 2002:meningoencephalitis in ~ 6% (18/300) ; anti-Aβ in 19% immunized patients
• Anti-Aβ antibodies recognize AD plaques and CAA but not soluble Aβ42 nor APP; recognize free N-terminus of Aβ
• Regionally reduced Aβ deposition in brain
• Reduced tau levels in CSF
• Transient cortical shrinkage by MRI in antibody responders
• Some slowing of cognitive decline, even 4.5 yr later (DAD)
• However, 2 patients who came to autopsy had few plaques and yet had severe dementia -- too little, too late????
Note: Living patients still show cognitive benefit.
AN1792 cleared plaques but did not slow AD AN1792 cleared plaques but did not slow AD
Holmes et al., Lancet 2008
• Possible causes for adverse events? T cell response to self-antigen, strong Th1 adjuvant, or possibly, a formulation change to include polysorbate 80 for vaccine stability
Next Steps….
• Passive immunotherapy: Monthly injections of anti-Aβ humanized monoclonal antibodies (mAb) targeting different binding sites and conformations of Aβ protein
• Second-generation active Aß vaccines: target B cell epitope in Aβ N-terminus and avoid T cell epitope; target Aβ oligomers; mimotopes; use Aβ-conjugates, DNA, phage, VLP, and AAV vaccines
ELAN/Wyeth AN1792 Clinical Trial:ELAN/Wyeth AN1792 Clinical Trial:
Passive Aβ IT in Mice: N-terminal Aβ mAbPassive Aβ IT in Mice: N-terminal Aβ mAb
• 3D6 Antibody gets into brain and induces Fc-receptor mediated phagocytosis of Aβ deposits
• Binds free N-terminus of Aβ; binds plaques
• Precursor to Bapineuzumab
Bard et al., Nature Med, 2000
Passive Aβ IT in Mice: N-terminal Aβ mAbPassive Aβ IT in Mice: N-terminal Aβ mAb
Science 2002
• mAb against Aβ3-6
• APP23 mice with CAA
• 21 mo-old mice treated for 5 mo
• Plaque lowering
• Significant increase in hemorrhage
PNAS 2001
• m266 increased plasma Aβ levels; reduced plaque burden
Dodart et al., Nature Neurosci, 2002:
• 6 wk chronic Tx reversed cognitive deficits in 2 yo PDAPP mice
• Single i.p. injection improved cognition within 24 hr
• Cerebral Aβ unchanged in both studies; plasma Aβ increased
• m266 is the precursor to Solanezumab
Passive Aβ IT in Mice: mid-region Aβ mAbPassive Aβ IT in Mice: mid-region Aβ mAb
J Neuroinflammation 2004
Passive Aβ IT in Mice: C-terminal Aβ mAbPassive Aβ IT in Mice: C-terminal Aβ mAb
• Bapineuzumab Phase III (Janssen/Pfizer)
• Solanezumab Phase III (Eli Lilly)
• MABT5102A Phase II (Genentech/AC Immune)
• Gantenerumab Phase II (Hoffmann-LaRoche)
• GSK933776 Phase II (GSK)
• Ponezumab Phase II (Pfizer/Rhinat) discontinued
• BAN2401 Phase I (Esai/BioArtic)
• Gammagard 10% IGIV Phase III (Baxter HC)
• Octagam 10% IVIG Phase II (OctaPharma) completed
• NewGam 10% IVIG Phase II (Sutter Health)
Passive Aβ Immunotherapy in HumansPassive Aβ Immunotherapy in Humans
Bapineuzumab: Aβ N-term IgG1 mAbBapineuzumab: Aβ N-term IgG1 mAbPhase II (2009; n=234): ELAN/Wyeth
• Signs of efficacy in “completers”, APOE ε4 non-carriers
• ε4 non-carriers had reduced brain volume loss
• ε4 carriers had ventricular enlargement
• Vasogenic edema in 12 ε4 carriers
• Reduced cortical 11C-PiB PET
retention compared to baseline
Phase III (ongoing): Janssen/Pfizer
• over 4,000 AD patients
• divided ε4 carrier/non-carriers
• Primary endpoints include efficacy and safety
• Trials will be completed 2012-2014
Rinne Lancet Neurol 2010
• Eli Lilly
• Recognizes full-length and N-term truncated soluble Aβ; prevents aggregation; increases plasma Aβ; cognitive efficacy in mice
Phase II:
• 52 AD pts, 16 healthy volunteers
• Safe; no signs of VE or microhemorrhage
• Increased plasma Aβ, incl. pyroglu3 Aβ; No cognitive efficacy
Phase III (ongoing):
• 2,000 AD pts Tx every 4 wk for 80 wk – completion Aug 2012
• 1,275 AD pts (Open label extension) – completion July 2014
• Efficacy and safety
Solanezumab: Aβ mid-region IgG1 mAbSolanezumab: Aβ mid-region IgG1 mAb
• Crenezumab; Genentech/AC Immune
• humanized IgG4 Aβ mAb; binds soluble, oligomeric and fibrillar Aβ; inhibits aggregration; disaggregates fibrillar Aβ
Phase I (completed in 2010):
• Safe; no vasogenic edema; 56 AD pts
Phase II (ongoing):
• 372 AD pts; i.v. and s.c.
• Primary endpoint: cognitive and global function
• Completion date: September 2014
Prevention Trial (new):
• 300 Colombian PS1 E280A FAD Kindred
MABT5102A: Aβ IgG4 mAbMABT5102A: Aβ IgG4 mAb
• Hoffmann-LaRoche
• Conformation-specific IgG1 hu mAb; binds N-term then mid-Aβ epitopes; high affinity for fibrillar Aβ
Phase I ended in Sep 2010; 60 AD pts
• PET sub-study showed plaque lowering; MRI VE
Phase II (ongoing):
• 360 prodromal AD pts; subcutaneous injection
• Primary endpoints: CDR-SOB, PET imaging
• Secondary endpoints: ADAS-Cog, safety, pharm
• Completion date is April 2015
Gantenerumab: fully humanized Aβ mAbGantenerumab: fully humanized Aβ mAb
Other Passive Aβ/IVIG IT Clinical TrialsOther Passive Aβ/IVIG IT Clinical Trials
• GSK933776: Phase I complete; Phase I in 35 pt with mild AD or MCI; CSF Aβ w/single dose; Dec 2011; Phase II trial in geographic atrophy secondary to AMD in 162 patients; completion date Mar 2014
• BAN2401: Esai/BioArtic, humanized mAb against Aβ protofibrils; Phase I for safety/tolerability in 80 AD pts; Oct 2012
• Gammagard: Baxter Healthcare; 10% IGIV; Phase III in 390 AD pts; cognitive and global function; Jan 2013
• NewGam: Sutter Healthcare; 10% IVIG; Phase II in 50 MCI pts; Jan 2013
Other IT Therapeutic Targets?Other IT Therapeutic Targets?
• Pyroglutamate-3 Amyloid-β• BACE-1 enzyme• Pathological Tau
What is PyroGlutamate-3 Aβ? What is PyroGlutamate-3 Aβ?
Gunn et al.,Intl J Biochem & Cell Biol, 2010
R1 2
8 2A
ßp
E3
AD: 78 yr male DS: 47 yr male aCtrl: 74 yr male
AβpE3 vs. General Aβ in Human Brain:AβpE3 vs. General Aβ in Human Brain:Frontal Cortex
12/12 AD (ave. 84 yr) 3/3 DS (ave. 49 yr) 7/10 aCtrl (ave. 71 yr)
Mandler et al., J Alz Dis 2011
PyroGlu-3 Aβ in PSD in Early ADPyroGlu-3 Aβ in PSD in Early AD
APPswe/PS1dE9: 14 moAPPswe/PS1dE9: 14 mo
Pilot Study: AβpE3 Passive Pilot Study: AβpE3 Passive Immunization Prevention Trial in MiceImmunization Prevention Trial in Mice
• APPswe/PS1dE9 (C57BL/6) mice
• Start: 6 mo
• End: 14 mo
• Weekly intraperitoneal injections of 200 μg AβpE3-x mAb [n=6 (3M, 3F)] or PBS [n=3 (1M, 2F)]
• Duration: 32 weeks
Frost et al., Neurodegen Dis, 2012
Passive Aβ IT in Mice: PyroGlu-3Aβ mAbPassive Aβ IT in Mice: PyroGlu-3Aβ mAb
Passive IT against BACE1 -VIB, Lilly, J&JPassive IT against BACE1 -VIB, Lilly, J&J
• mAb 1A11 inhibited BACE1 in vitro and in vivo
• Intra HC injection• APPDutch Tg mice
JBC 2011
Passive IT against BACE1 (Genentech)Passive IT against BACE1 (Genentech)
Sci Transl Med, 2011
• High-affinity, phage-derived BACE1 mAb
• Reduces Aβ production in vitro
• Lowers peripheral and CNS Aβ levels in vivo in mice and NHPs
• Highly selective; does not recognize BACE2 or Cathepsin D
Passive Tau IT in Tau Tg Mice (Lilly)Passive Tau IT in Tau Tg Mice (Lilly)
Chai et al., JBC, in press
• PHF-1 and MCI mAbs; prevention in JNPL3 and P301S Tg mice• reduced tau pathology and axonal degeneration• slowed disease progression
Hurdles: Passive IT for ADHurdles: Passive IT for AD
• Frequent dosing & doctor visits; expensive
• Vasogenic edema and MH (Aβ); ~ 40-65% of AD = APO E4
• Getting enough mAb into brain
• BBB integrity
• Anti-idiotypic Ab secondary response
• Which type or conformation? Aβ, tau
• Targeting intracellular proteins (e.g., tau)
• Off-target binding (e.g., anti-oligomer mAb, anti-BACE1)
• Will any of this make a difference in AD pts with established neurodegeneration?
Perrin et al., Nature October 2009
AD Pathogenesis: Amyloid plaque accrual precedes NFTs and cognitive decline
ConclusionsConclusionsCurrent Immunotherapeutic Strategies for AD:• Passive vaccination against Aβ, BACE 1, or Tau
-- avoids immune response-- repeated iv injections monthly; expensive-- evidence for Aβ clearance; microbleeds-- awaiting the results of Phase III clinical trials
• Active vaccination against Aβ-- adverse effects due to T cell response to self-protein-- second generation vaccines include B cell epitopes, DNA vaccines, different routes of administration-- long-lasting; fewer doses; cost-effective for large
at- risk population; need biomarkers -- Currently in Phase I and II trials in humans
• For both: the earlier, the better!
AcknowledgementsAcknowledgements
Center for Neurologic Diseases
J Frost Q ShiB Liu S MatousekK Le J Kenison
Former Lab/CND Members:H FuY PengL JiangJ Sun
Supported by NIH RO1 AG20159 and philanthropic funds.
Probiodrug AG*H DemuthS SchillingM Kleinschmidt
* We are grateful to Probiodrug for providing us with the AβpE3-x mAb