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
Immunotherapy targeting Ab for AD
Formerly the exclusive domain of small molecule
Potential of biologics for Rx of Neurodegenerative disease
Phagocytosis of plaque triggered by antibody opsonization of amyloid
Ab peptide active immunization
Anti-Ab mAb passive
immunization
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
M. Lee et al, Ann Neurol 2005
• No reaction to APP
• Binds to plaques
• Adsorbable by linear peptide
Antibody Response in AN1792 treated AD Patients is
Specific to the Amino Terminus of Ab
Preclinical Endpoints Effected By Immunotherapy with
3D6, the Murine Precursor of Bapineuzumab
Neuriticdystrophy
Astrogliosis
Neutralization of neurotoxic Ab species
Vascular Amyloid
3D6: Very similar to AN1792-induced antibodies Binds amino-terminus of Ab, but not APP
Recognizes both plaques and soluble forms of Ab
Chronic efficacy testing in PDAPP mouse model of AD Treatment and prevention models, following
chronic therapy
Positive on broad spectrum of efficacy end-points
Principles of Drug Development Exemplified in
Ab Targeted Immunotherapy
Access to target organ
CNS:Plasma exposure of drug
Target engagement
Biological readout of drug activity
Translational medicine
Preclinical clinical observation
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
2 7 14 21 27 2 7 14 21 27 2 7 14 21 270
2500
5000
7500
10000
Cerebellum CortexHippocampus
Day post-injection
cpm
/gm
tis
sue
2 7 14 21 271000
10000
100000
1000000
Day post-injection
cpm
/ gm
tis
sue Serum
Hippocampus
140x65x
15x
6x4x• Peak accumulation of binding occurred ~14 d post injection and remains stable up to 27
days• Accumulation continues even as antibody serum levels drop over two weeks
The 125I-3D6 t1/2 is longer in the brain than in the serum
Access of drug to target organ
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
Clinical translation of pre-clinical
Observations
Reductio
n of Ab
amyloid
pathology
in brain
1. Ab Immunized PDAPP Mice Schenk, D. (1999) Nature 400:173
2. AN 1792 (A-beta) Immunized patients Nicoll, J et al. (2006) J. Exp. Neurol. &
Exp. Neur. 65:1040
3. BapineuzumabTreated patient
Rinne, JO (2010) Lancet Neurol. 9:363
A proliferation of biologics in preclinical
discovery for neurodegenerative disease
Immunotherap
y
AD (Ab
Tau, BACE);
PD (a-Syn);
Targeted
Delivery via
Engineered
Biologics
Immunotherapy Engineered Biologics (mAbs, Fc-Fusions, etc.)
Tau Immunotherapy
Efficacy on tau pathology and behavior end-points following active and passive Rx targeting PHF tau epitope in FTD mouse model
Sub-cellular localization of internalized Antibody in brain slice model
“Prionoid” agents in
Neurodegenerative Disease
Transmissab
le
pathogenic
element, e.g.
tau, supports
rationale for
immuno-
therapy with
antibody
antagonist
Antagonist antibody targeting BACE, a
traditional small molecule target
Case by case opportunities employing Targeted
Delivery
Anti-BACE immunotherapy
Anti-BACE mAb IC50 ~ 3 nM
Central reduction of Ab following peripheral administration in mice (brain) and primate (CSF) at 30 or 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.
Brain:Plasma of non-targeted anti-
BACE
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.
Leveraging Transferrin Receptor
for Brain Delivery of Cargo
TfR expressed on
brain endothelial
cells
Bi-specific anti-
TfR/BACE mAb
Improved brain
accumulation cf
parent anti-BACE
2X improvement in
efficacy (25mg/Kg
vs 50 mg/Kg) for
lowering brain Ab
Yu et al., (2011) Science Translational Med. 3: 84ra44
Pharmacokinetics considerations of
targeted delivery of antibodies
CNS and peripheral expression of carrier mediated transport targets e.g. TfRand InsRcontributes to rapid clearance of mAb from circulation, with t1/2 ~ small molecules
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
iduronidase enzyme activity in Rhesus monkeys.). Biotechnol. 144, 135-141.
• Order of magnitude drop
in plasma concentration
of drug by 2h following IV
administration attributable
to uptake via peripheral
insulin receptor
• mAb Volume of
distribution ~ plasma
volume
• Transport receptor
targeted mAb volume of
distribution ~ small
molecule
Challenges Associated with Targeted
Delivery for CNS indications
Bi-specific targeting modalities, e.g. BACE
Scalable manufacture of bi-specific mAb
Cost of Goods:
Hu eq dose BACE/TfR = 1.75g/70kg;
Tysabri: 300 mg IV, q4 wks
Humira: 40-160 mg IV, qw – q4 wk
Dosing interval BACE/TfR?
Monthly = 21g/person/yr
Bimonthly = 42g/person/yr
300 person 1 yr P2 trial = 12.6 kg drug product
Advantages of Traditional mAbs
Long t1/2
IV-transfusion, infrequent dosing (monthly)
PK Advantages Negated by transport receptor targeted delivery
More Frequent dosing depending upon:
Target:Ligand stoichiometry demands for desired pharmacologic outcome
Pharmacodynamic effect if target engagement may allow less frequent dosing
CMC, timeline to IND, and cost
considerations
Antibody Technologies
Growth of Antibody Therapeutics
Nelson AL, Dhimolea E, Reichert JM. 2010. Development trends for human monoclonal antibody therapeutics.
Nature reviews Drug discovery 9: 767-774.
Top Related