Session 4 part 4


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  • 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
  • Session 4 part 4

    1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 11. Tau ImmunotherapyEfficacy on taupathology andbehavior end-points followingactive andpassive Rxtargeting PHFtau epitope inFTD mousemodelSub-cellularlocalization ofinternalizedAntibody inbrain slicemodel
    12. 12. “Prionoid” agents inNeurodegenerative DiseaseTransmissablepathogenicelement, e.g.tau, supportsrationale forimmuno-therapy withantibodyantagonist
    13. 13. Case by case opportunities employing TargetedDelivery Antagonist antibody targeting BACE, a traditional small molecule target
    14. 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. 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. 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. 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. 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. 19. Antibody TechnologiesCMC, timeline to IND, and cost considerations
    20. 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.