TrustArc Webinar - Unlock the Power of AI-Driven Data Discovery
Session 4 part 4
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 immunization
Formerly the
exclusive
domain of
small molecule
Potential of
biologics for Rx
of
Neurodegener
ative disease
Anti-Ab mAb passive
Phagocytosis immunization
of plaque
triggered by
antibody
opsonization of
amyloid
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 peptide
M. Lee et al, Ann Neurol 2005
5. Preclinical Endpoints Effected By Immunotherapy with
3D6, the Murine Precursor of Bapineuzumab
Neuritic
3D6: Very similar to AN1792-induced
dystrophy antibodies
Binds amino-terminus of Ab, but not APP
Astrogliosis Recognizes both plaques and soluble forms of Ab
Neutralizatio Chronic efficacy testing in PDAPP mouse
n of model of AD
neurotoxic Treatment and prevention models, following
Ab species chronic therapy
Vascular Positive on broad spectrum of efficacy end-points
Amyloid
6. 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
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-clinical
Observations
1. Ab Immunized
Reductio PDAPP Mice
n of Ab Schenk, D. (1999) Nature 400:173
amyloid 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 Biologics
Immunotherap (mAbs, Fc-Fusions, etc.)
y
AD (Ab
Tau, BACE);
PD (a-Syn);
Targeted
Delivery via
Engineered
Biologics
11. 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
12. “Prionoid” agents in
Neurodegenerative Disease
Transmissab
le
pathogenic
element, e.g.
tau, supports
rationale for
immuno-
therapy with
antibody
antagonist
13. Case by case opportunities employing Targeted
Delivery
Antagonist antibody targeting BACE, a
traditional small molecule target
14. Anti-BACE immunotherapy
Anti-BACE
mAb IC50 ~
3 nM
Central
reduction of
Ab following
peripheral
administratio
n 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.
15. 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.
16. 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
17. Pharmacokinetics considerations of
targeted delivery of antibodies
CNS and • Order of magnitude drop
peripheral in plasma concentration
expression of
carrier of drug by 2h following IV
mediated administration attributable
transport to uptake via peripheral
targets e.g. TfR insulin receptor
and InsR
contributes to • mAb Volume of
rapid clearance distribution ~ plasma
of mAb from
volume
circulation, with
t1/2 ~ small • Transport receptor
molecules
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 Targeted
Delivery 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
20. 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.
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