Pharmacokinetics considerations oftargeted delivery of antibodiesCNS and                                                  ...
Challenges Associated with TargetedDelivery for CNS indications   Advantages of Traditional mAbs               Bi-specif...
Antibody TechnologiesCMC, timeline to IND, and cost considerations
Growth of Antibody TherapeuticsNelson AL, Dhimolea E, Reichert JM. 2010. Development trends for human monoclonal antibody ...
Upfront considerations with antibodytherapeutics   Advantages:       Excellent target selectivity (safety), Ka       Pr...
Antibody TechnologiesMouse – Human•   CDR Grafted•   HumanizedFully Human•   Hu    Hybridomas•   Phage    Display•   Tg Mo...
Antibody Humanization                                                HumanizedMouse Hybridoma          VL    +     VH     ...
CM&C: Biologics v small molecules   Terminology, jargon, and lexicon       Upstream: scale up production of composition ...
Manufacturing timeline and $ for typical mAb                                   („whaddya mean no IND this year?)          ...
“Caveat Entrepreneur(?)”                                                       “The first one out the                     ...
Summary   Opportunities for biologics in Neurodegenerative    disease   Apply & Exercise Sound Principles of Drug    Dis...
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Session 4 part 5

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  • Google success rates of mAbsvs Small molecules
  • Apredica Poster
  • Accompany slide with PR of JNJ/Pfizer mergers
  • Session 4 part 5

    1. 1. 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
    2. 2. 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
    3. 3. Antibody TechnologiesCMC, timeline to IND, and cost considerations
    4. 4. Growth of Antibody TherapeuticsNelson AL, Dhimolea E, Reichert JM. 2010. Development trends for human monoclonal antibody therapeutics.Nature reviews Drug discovery 9: 767-774.
    5. 5. Upfront considerations with antibodytherapeutics 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. 6. Antibody TechnologiesMouse – Human• CDR Grafted• HumanizedFully 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. 7. Antibody Humanization HumanizedMouse 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. 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. 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 DevelopmentFormulation and Analytical Dev DS Mfg: $6.2M MCB and WCB Generation Tech Xfer / Tox / GMP runs Fill / Analysis /Release DP Mfg: $0.8M
    10. 10. “Caveat Entrepreneur(?)” “The first one out the door gets all the arrows in his back” * *Michael West, Geron CEO, Nature 479: 459Steinmetz & Spack, BMC Neurology 2009, 9(Suppl 1):S2doi:10.1186/1471-2377-9-S1-S2
    11. 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

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