Session 4 part 4

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  • www.dana.org/news/publications/detail.aspx?id=4270www.alzheimers.org/clinicaltrials/fullrec.asp?PrimaryKey=308http://www.medscape.com/viewarticle/733407
  • The time point was 14 days post one injection of tracer level of 3D6 in PDAPP mice.
  • Title pages of key papers in AD, PD, etc.
  • Degradation of Tau via endosomal/lysosomal pathway“Confocal microscopy analysis showed that the FITClabeled anti-tau antibody co-stained withphosphorylatedtau,had a perinuclear appearance and co-localized with markers of the endosomal/lysosomalpathway. Additionally, tau and FITC–IgG were found together in an enriched lysosome fraction.”Bomiel: “The level of the lysosomal proteases, cathepsins D and L, was affected in the immunized mice suggesting the possible involvement of the lysosomal system in the decrease of NFTs.
  • TfRMediates transcytosis of ligand from bloodstream into brain parenchyma
  • Google success rates of mAbsvs Small molecules

Transcript

  • 1. Neurotrophins Promises  Neuroprotection, Neuro-restoration  NGF, BDNF, Nerturin Limitations  Poor bio-availability in target organ following systemic peripheral delivery  Undesirable side effects from non-targeted central delivery, e.g. generalized sprouting promoting inappropriate connections, neuralgia Solutions  Localized (chronic) central delivery to affected region(s)  Surgical implants for localized infusion (GDNF)  Targeted delivery  Gene therapy (Tuczyinski 2004) via implantation of genetically modified fibroblasts;  CERE-110 – viral delivery of NGF (recruiting P2, n=50 end May 2012)  CERE-120 (AAV2-Neurturin) - P2 (Dec 2008): Failed on 1o endpoint (efficacy in motor function at 12 mo), may have benefit at 18 mo. OLE in progress
  • 2. Immunotherapy targeting Ab for AD Ab peptide active immunizationFormerly theexclusivedomain ofsmall moleculePotential ofbiologics for RxofNeurodegenerative disease Anti-Ab mAb passivePhagocytosis immunizationof plaquetriggered byantibodyopsonization ofamyloid
  • 3. Initial Results of Immunotherapy: Active &Passive Immunotherapy targeting Ab Preclinical Observations  Induces clearance of plaques, improvement in synaptic density, reduces gliosis  Efficacy in behavioral testing  Multiple potential mechanisms: antibody induced plaque phagocytosis, peripheral sink Clinical observations with AN1792  Plaque clearance and reduced plaque associated neuropathology  Significant effect on NTB  P2 trial halted due to meningioencephalitis in subset of patients  Attributable to T-cell epitopes in full length Ab peptide  Epitope mapping of responders combined with pre-clinical studies suggests safer follow-on approaches
  • 4. Antibody Response in AN1792 treated AD Patients is Specific to the Amino Terminus of Ab • No reaction to APP • Binds to plaques • Adsorbable by linear peptideM. Lee et al, Ann Neurol 2005
  • 5. Preclinical Endpoints Effected By Immunotherapy with3D6, the Murine Precursor of BapineuzumabNeuritic  3D6: Very similar to AN1792-induceddystrophy antibodies  Binds amino-terminus of Ab, but not APPAstrogliosis  Recognizes both plaques and soluble forms of AbNeutralizatio  Chronic efficacy testing in PDAPP mousen of model of ADneurotoxic  Treatment and prevention models, followingAb species chronic therapyVascular  Positive on broad spectrum of efficacy end-pointsAmyloid
  • 6. Principles of Drug Development Exemplified inAb Targeted Immunotherapy Access to target organ  CNS:Plasma exposure of drug Target engagement  Biological readout of drug activity Translational medicine  Preclinical clinical observation
  • 7. Access of drug to target organ 10000 7500 cpm/gm tissue• Peak accumulation of binding occurred ~14 d post injection and remains stable up to 27 5000 days 2500• Accumulation continues even as antibody serum levels drop over two weeks 0  The 125I-3D6 tHippocampus in Cortexbrain than in the serum Cerebellum 1/2 is longer 2 7 the 14 21 27 2 7 14 21 27 2 7 14 21 27 Day post-injection Bard et al., 2010“Unique Brain PK Properties of 3D6 and Bapineuzumab Depend on Cerebral Amyloid Load in PDAPP Transgenic Mice” P4-406, ICAD 2010
  • 8. Target Engagement Elevation of plasma Ab via prolongation of t1/2  Seubert et al (2007), Neurodegenerative Dis. 5:65-71;  Gray et al. (2007) Neuroreport 18: 293 Mobilization of deposited central Ab  Pre-clinical: dose dependent increased vascular Ab, microhemorrhage  Wilcock 2004) J Neuroinflammation 1:24  Racke (2005)J Neurosci 25:629  Schroeter (2008) J Neurosci 28:6787  Clinical: Vasogenic edema/ ARIA  Sperling (2012) The Lancet: DOI 10.1016/S1474-4422(12)70015-7
  • 9. Clinical translation of pre-clinicalObservations 1. Ab ImmunizedReductio PDAPP Micen of Ab  Schenk, D. (1999) Nature 400:173amyloid 2. AN 1792 (A-beta)pathology Immunized patients Nicoll, J et al. (2006) J. Exp. Neurol. &in brain  Exp. Neur. 65:1040 3. Bapineuzumab Treated patient  Rinne, JO (2010) Lancet Neurol. 9:363
  • 10. A proliferation of biologics in preclinical discovery for neurodegenerative disease Immunotherapy Engineered BiologicsImmunotherap (mAbs, Fc-Fusions, etc.)y AD (Ab Tau, BACE); PD (a-Syn);TargetedDelivery viaEngineeredBiologics
  • 11. Tau ImmunotherapyEfficacy on taupathology andbehavior end-points followingactive andpassive Rxtargeting PHFtau epitope inFTD mousemodelSub-cellularlocalization ofinternalizedAntibody inbrain slicemodel
  • 12. “Prionoid” agents inNeurodegenerative DiseaseTransmissablepathogenicelement, e.g.tau, supportsrationale forimmuno-therapy withantibodyantagonist
  • 13. Case by case opportunities employing TargetedDelivery Antagonist antibody targeting BACE, a traditional small molecule target
  • 14. Anti-BACE immunotherapyAnti-BACEmAb IC50 ~3 nMCentralreduction ofAb followingperipheraladministration in mice(brain) andprimate(CSF) at 30or 100 mg/Kg Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y, Heise CE, Hoyte K, Luk W, Lu Y et al. 2011. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Science translational medicine 3: 84ra43.
  • 15. Brain:Plasma of non-targeted anti- BACEAtwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y, Heise CE, Hoyte K, Luk W, Lu Y et al. 2011. A therapeuticantibody targeting BACE1 inhibits amyloid-beta production in vivo. Science translational medicine 3: 84ra43.
  • 16. Leveraging Transferrin Receptorfor Brain Delivery of CargoTfR expressed onbrain endothelialcellsBi-specific anti-TfR/BACE mAbImproved brainaccumulation cfparent anti-BACE2X improvement inefficacy (25mg/Kgvs 50 mg/Kg) forlowering brain Ab Yu et al., (2011) Science Translational Med. 3: 84ra44
  • 17. Pharmacokinetics considerations oftargeted delivery of antibodiesCNS and • Order of magnitude dropperipheral in plasma concentrationexpression ofcarrier of drug by 2h following IVmediated administration attributabletransport to uptake via peripheraltargets e.g. TfR insulin receptorand InsRcontributes to • mAb Volume ofrapid clearance distribution ~ plasmaof mAb from volumecirculation, witht1/2 ~ small • Transport receptormolecules targeted mAb volume of Boado, R.J., Hui, E. K. W., Lu,J. Z., and Pardridge, W. M. (2009b). AGT- 181: Expressionin CHO cells and pharmacokinetics, safety, and plasma distribution ~ small iduronidase enzyme activity in Rhesus monkeys.). Biotechnol. 144, 135-141. molecule
  • 18. Challenges Associated with TargetedDelivery for CNS indications Advantages of Traditional mAbs  Bi-specific targeting modalities, e.g.  Long t1/2 BACE  IV-transfusion, infrequent dosing  Scalable manufacture of bi-specific (monthly) mAb PK Advantages Negated by transport  Cost of Goods: receptor targeted delivery  Hu eq dose BACE/TfR = 1.75g/70kg; More Frequent dosing depending  Tysabri: 300 mg IV, q4 wks upon:  Humira: 40-160 mg IV, qw – q4 wk  Target:Ligand stoichiometry demands  Dosing interval BACE/TfR? for desired pharmacologic outcome  Monthly = 21g/person/yr  Pharmacodynamic effect if target engagement may allow less frequent  Bimonthly = 42g/person/yr dosing  300 person 1 yr P2 trial = 12.6 kg drug product
  • 19. Antibody TechnologiesCMC, timeline to IND, and cost considerations
  • 20. Growth of Antibody TherapeuticsNelson AL, Dhimolea E, Reichert JM. 2010. Development trends for human monoclonal antibody therapeutics.Nature reviews Drug discovery 9: 767-774.