1. 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

2. 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

3. Antibody Technologies
CMC, timeline to IND, and cost
considerations

4. 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.

5. Upfront considerations with antibody
therapeutics
 Advantages:
 Excellent target selectivity (safety), Ka
 Predictable PK, metabolism, and elimination
 Cross reactive with antigen in humans and in preclinical model
 Straight forward path to clinical development with pre-clinically active agent
 Humanized or Human mAb via appropriate technology
 Neutralizing agent in preclinical model does not recognize Hu antigen, or with less activity (e.g. Ka)
 Ab discovery to identify lead with equipotent activity against Hu Ag
 Demonstrate bio-equivalence of anti-Hu mAb with pre-clinically active lead
 Confirm activity of hu mAb in pre-clinical model of disease
 Primates
 Rodents
 Acute (target engagement) vs chronic (treatment) paradigm
 Induce tolerance to huAb in rodent model

6. Antibody Technologies
Mouse – Human
• CDR Grafted
• Humanized
Fully Human
• Hu
Hybridomas
• Phage
Display
• Tg Mouse
• Direct
cloning from Brekke, O. H. and I. Sandlie (2003). "Therapeutic antibodies for human diseases at the dawn of
Patient/Dono the twenty-first century." Nat Rev Drug Discov 2(1): 52-62.
r B-cells

7. Antibody Humanization
Humanized
Mouse Hybridoma VL + VH
VH-C 1 rDNA
VL-C
VL C
Sequence informatics
VH C 1 +
Molecular Modeling
Transfected Cell
VH-C 1
VL-C
Murine mAb Chimeric mAb

8. CM&C: Biologics v small molecules
 Terminology, jargon, and lexicon
 Upstream: scale up production of composition of matter/drug substance
 Downstream: Purification, formulation, stability of drug product
 Drug substance – Comp of matter, pre formulation to post formulation (i.e. incl. excipients
stability, buffers etc.) bulk substance
 Drug Product – Final formulation of DP in labeled vial, pills, or capsules, as it will be
administered to patients
 Sm Molecule – customized mfg for ea candidate dictated by composition of matter
 Biologic – Platform process, upstream & downstream
 Composition of matter – rDNA technology, vectors
 Cell based production, scalable bioreactor technology + process improvements = Titers≥1g/L
 Downstream
 Extensive list of QA/QC tests for DP

9. Manufacturing timeline and $ for typical mAb
(„whaddya mean no IND this year?)
Months 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Stage Cell Line Dev. PD & Tox GMP (Clinic)
Material Supplied RCB MCB 500g Tox 1.5Kg Clinic
Vector Generation
Cell Line Development
CLD: $1.5M
Upstream Development
Downstream Development
Formulation and Analytical Dev DS Mfg: $6.2M
MCB and WCB Generation
Tech Xfer / Tox / GMP runs
Fill / Analysis /Release
DP Mfg: $0.8M

10. “Caveat Entrepreneur(?)”
“The first one out the
door gets all the
arrows in his back” *
*Michael West, Geron
CEO, Nature 479: 459
Steinmetz & Spack, BMC Neurology 2009, 9(Suppl 1):S2
doi:10.1186/1471-2377-9-S1-S2

11. Summary
 Opportunities for biologics in Neurodegenerative
disease
 Apply & Exercise Sound Principles of Drug
Discovery
 Targeted delivery poses challenges from
perspective of drug development
 Antibody therapeutics offer robust, scalable
platform with proven market value, at a cost