formation & delivery issues of therapeutic proteins
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Formation & DeliveryFormation & DeliveryIssues of TherapeuticIssues of Therapeutic
ProteinsProteinsMahvash AnsariMahvash Ansari
M-Phil (Pharmaceutics)M-Phil (Pharmaceutics)
Roll # 02Roll # 02Session 2008-2010Session 2008-2010
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IntroductionIntroduction
Pharmaceuticals based on natural and recombinant proteins have provenPharmaceuticals based on natural and recombinant proteins have proven
their therapeutic value. Whether for hormone or enzyme replacementtheir therapeutic value. Whether for hormone or enzyme replacement
therapies or to block or inhibit other protein signals, pharmaceuticaltherapies or to block or inhibit other protein signals, pharmaceutical
proteins exhibit exquisite selectivity and specificity in their targets. Overproteins exhibit exquisite selectivity and specificity in their targets. Over
100 proteins have been approved by U.S. Food and Drug Administration100 proteins have been approved by U.S. Food and Drug Administration
since their inception and many more are currently in various phases ofsince their inception and many more are currently in various phases of
development. Despite their potency, many issues hinder the widespreaddevelopment. Despite their potency, many issues hinder the widespreaduse of protein pharmaceuticals. Proteins require special (expensive)use of protein pharmaceuticals. Proteins require special (expensive)
preparation techniques, usually recombinant engineering and expressing inpreparation techniques, usually recombinant engineering and expressing in
cell culture followed by lengthy and costly purifications. They must becell culture followed by lengthy and costly purifications. They must be
stored and shipped under special conditions as they are susceptible tostored and shipped under special conditions as they are susceptible to
denaturation and degradation by proteolysis. The barriers to easy oraldenaturation and degradation by proteolysis. The barriers to easy oral
administration and bioavailability are formidable, as the body has manyadministration and bioavailability are formidable, as the body has many
natural defenses to exogenous proteins. Nevertheless, although there arenatural defenses to exogenous proteins. Nevertheless, although there are
many hurdles to be overcome, protein biopharmaceuticals are certain tomany hurdles to be overcome, protein biopharmaceuticals are certain to
see continued rapid development and growth because their potential forsee continued rapid development and growth because their potential for
providing a more specific and potent therapeutic approach is unparalleled.providing a more specific and potent therapeutic approach is unparalleled.
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IntroductionIntroduction
o Recombinant DNA TechnologyRecombinant DNA Technology
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IntroductionIntroduction
o Specificity and PotencySpecificity and Potency
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IntroductionIntroduction
o Molecular MedicineMolecular Medicine
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IntroductionIntroduction
o Therapeutic, Subunit VacinesTherapeutic, Subunit Vacines
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Stability of TherapeuticStability of Therapeutic
ProteinsProteins
o Chemical InstabilityChemical InstabilityDeamidationDeamidation
OxidationOxidation
Beta EliminationBeta Elimination
Incorrect Disulfide FormationIncorrect Disulfide Formation
RacemizationRacemization
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Chemical InstabilityChemical Instability
Chemical Instability Physical Instability
Hydrolysis
Deamidation (Gin & Asn)
Oxidation (His, Met, Cys, Trp &Tyr)
Proteolysis
Incorrect disulfide formation(Cysteine)
Racemization
Beta climination
Denaturation
Adsorption to surface
Aggregation
Precipitation
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Stability of TherapeuticStability of Therapeutic
ProteinsProteins
o Physical InstabilityPhysical Instability
DenaturationDenaturationAggregationAggregation
PrecipitationPrecipitation
Surface AdsorptionSurface Adsorption
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Stability of TherapeuticStability of Therapeutic
ProteinsProteins
o Formulation & DeliveryFormulation & Delivery
Approaches to OvercomeApproaches to Overcome
InstabilityInstability
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Immunological Properties ofImmunological Properties of
Protein TherapeuticsProtein Therapeutics
o
Immunogenicity of ProteinsImmunogenicity of Proteins
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Immunogenicity of ProteinsImmunogenicity of ProteinsTherapeutic Protein Detected Incidence of
Anti-product AntibodyOKT3
Remicade
Roferon
Proleukin (interleukin-2)
Betaferon
Advate
Bone morphogenic protein-7
Enbrel (TNF receptor/anti-TNF
IgG)Thrombopoietin
PEGylated-MGDF
-80%
10-57%
20-50%
47-74%
44%
15-30%
13-38%
16%
10%
0.5-1.6%
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Immunological Properties ofImmunological Properties of
Protein TherapeuticsProtein Therapeutics
o Formulation & DeliveryFormulation & Delivery
Considerations to ReduceConsiderations to Reduce
ImmunogenicityImmunogenicity
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Pharmacokinetics andPharmacokinetics and
PharmacodynamicsPharmacodynamics
o Formulation and Delivery Approaches toFormulation and Delivery Approaches to
Overcome PK IssuesOvercome PK Issues
PEGylationPEGylationLipid Structures as Drug DeliveryLipid Structures as Drug Delivery
VehiclesVehicles
PLGA Micro SpheresPLGA Micro Spheres