Agriculture Reference
In-Depth Information
m onoclonal a ntIbodIeS
Monoclonal. antibodies. (mAbs). have. a. wide. range. of. important. pharmaceutical.
applications.. MAb. market. was. projected. to. reach. $16.7. billion. by. 2010,. account-
ing.for.over.a.quarter.of.the.total.protein.therapeutics.market. 37,38 .As.a.result,.new.
expression. systems. have. to. demonstrate. their. effectiveness. in. producing. mAbs. in.
order.to.be.considered.seriously.as.contenders.for.commercial.production.of.pharma-
ceutical.proteins..MAbs.are.extremely.expensive.to.produce.in.mammalian.culture.
system.and,.therefore,.are.costly.to.patients.and.health.care.systems..Development.
of. new. production. platforms. is. indeed. necessary. to. reduce. the. cost. and. increase.
the. scalability. of. mAb. manufacture.. MAbs. have. been. successfully. expressed. in.
stable.transgenic.plants.since.the.early.stage.of.PMP.development,.despite.they.are.
complex. heterotetrameric. glycoproteins. 5 . Since. then,. a. variety. of. mAbs. and. their.
derivatives,.such.as.secretory.IgAs,.single-domain.fragments,.single-chain.variable.
fragment.(scFv),.and.diabodies.and,.more.recently,.recombinant.immune.complexes.
(RICs),.have.been.successfully.produced.in.many.host.plant.species,.with.increas-
ing.number.and.type.of.mAb.being.produced.each.year.(Table.4.1). 39-62 .Our.group.
recently.published.the.irst.report.that.demonstrated.the.eficacy.of.a.plant-produced.
mAb.against.a.potentially.lethal.infection.several.days.after.exposure.in.an.animal.
challenge.model. 58 .Several.mAbs.have.been.selected.for.clinical.evaluation.with.two.
having.reached.Phase.II.clinical.studies.(Table.4.2). 63,64 .For.example,.a.TMV-based.
vector.was.demonstrated.to.be.an.eficient.vector.to.express.a.human.scFv.for.the.
treatment. of. non-Hodgkin's. lymphoma. (NHL). in. tobacco. plants. 65,66 . The. tobacco-
produced. scFv. is. an. effective. anti-idiotype. vaccine. candidate. in. a. murine. NHL.
tumor. challenge. model. and. has. been. further. evaluated. in. human. clinical. trials. 67 .
This. patient-speciic. anti-idiotype.vaccine. requires. a. speedy.system. for.rapid. pro-
duction. and. patient. treatment. evaluation.. In. contrast. to. mammalian. cell. cultures,.
the.TMV-based.plant.expression.system.has.successfully.provided.such.speedy.and.
versatile.production.platform.
Similar.to.stable.transgenic.plants,.transient.expression.systems.have.been.very.
successful.in.producing.single.subunit.therapeutics.such.as.scFvs. 68,69 .However,.until.
recently,.viral.vector-based.transient.expression.systems.are.incapable.of.producing.
full-length.mAbs.or.any. other.heterooligomeric.proteins.eficiently..This.is.due.to.
the.fact.that.viral.vectors.built.on.the.same.virus.backbone.are.typically.“competing”.
with.each.other,.resulting.in.early.segregation.and.subsequent.preferential.ampliica-
tion.of.one.of.the.vectors.in.one.cell. 23,70-72 .The.MagnICON™.system.composed.of.
two. sets. of. noncompeting. vectors.(TMV.and. PVX). has.successfully.resolved. this.
problem. 22,73 . TMV. and. PVX. do. not. compete. with,. nor. dominate. over,. each. other,.
because.they.interact.with.different.host.factors.for.their.movement.and.replication..
As.a.result,.the.eficient.co-expression.of.light.chain.and.heavy.chain.of.mAb.in.the.
same.cells.occurs.when.two.vectors.harboring.the.two.mAb.genes.are.co-delivered.
into. plants. 23 . Extensive. studies. have. shown. that. this. transient. system. can. rapidly.
(within. 10. days. of. vector. delivery). produce. fully. assembled. mAbs. in. high. levels,.
reaching.up.to.0.8.g.mAb/kg.of.fresh.tissue.weight.(FW). 23,58 .Therefore,.MagnICON.
system.provides.a.potential.large-scale.production.platform.for.rapid.manufacturing.
of.mAbs.and.other.oligomeric.proteins.
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