Formation & Delivery Issues of Therapeutic Proteins

8/14/2019 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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o Recombinant DNA TechnologyRecombinant DNA Technology


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o Specificity and PotencySpecificity and Potency


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o Molecular MedicineMolecular Medicine


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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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ProteinsProteins

o Physical InstabilityPhysical Instability

DenaturationDenaturationAggregationAggregation

PrecipitationPrecipitation

Surface AdsorptionSurface Adsorption


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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

Documents

Formation & Delivery Issues of Therapeutic Proteins