Biomedical Engineering Reference
In-Depth Information
subfamily. of. four. closely. related. receptor. tyrosine. kinases:. EGFR. (ErbB-1),. HER2/c-neu.
(ErbB-2),. HER3. (ErbB-3),. and. HER4. (ErbB-4).. Mutations. affecting. EGFR. expression. or.
activity.could.result.in.cancer..EGFR.exists.on.the.cell.surface.and.is.activated.by.binding.
of.its.speciic.ligands,.including.epidermal.growth.factor.and.transforming.growth.factor.
α.(TGFα)..Overexpression.of.EGFR.has.been.associated.with.a.poor.prognosis.in.a.variety.
of.solid.tumors,.and.thus.represents.an.attractive.therapeutic.target.
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8.3.1.2 Monoclonal Antibody
Monoclonal.antibodies.(mAbs).were.irst.described.in.1975.by.Kohler.and.Milstein,.who.
shared.the.Nobel.Prize.in.Physiology.or.Medicine.in.1984.for.the.discovery..Monoclonal.
antibodies.target.speciic.molecules.and.are.used.as.passive.immunotherapy.to.treat.vari-
ous.diseases,.including.certain.types.of.cancer..These.mAbs.selectively.target.tumor.tis-
sues. and. have. been. safely. administered. in. cancer. patients.. It. was. in. the. 1980s. that. the.
development.of.blocking.mAbs.to.EGFR.as.a.cancer.therapy.was.proposed.by.Mendelsohn.
for.the.irst.time.
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.Since.then,.various.antibodies.have.become.valuable.therapeutic.agents.
for.targeting.of.extracellular.proteins.in.various.diseases,.including.cancer,.autoimmunity,.
and.cardiovascular.disorders.
Development.of.mAbs.of.human.origin.has.proven.to.be.a.hard.task..The.irst.genera-
tion.of.humanized.mAbs.was.simply.chimeric.antibodies,.in.which.the.variable.regions.of.
murine.mAbs.were.linked.to.the.constant.region.of.a.human.immunoglobulin.(Ig).G.
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.As.
expected,.these.humanized.molecules.should.lack.the.immunogenicity.of.a.murine.mAb.
and.interact.more.eficiently.with.the.human.immune.system.
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.The.second.generation.of.
humanized.mAbs.was.the.reshaped.antibodies,.in.which.the.antigen-binding.loops.of.the.
murine.mAbs.were.built.into.a.human.IgG..The.main.problem.was.related.to.the.speciic-
ity..It.is.usually.not.enough.to.maintain.the.original.binding.speciicity.by.combining.the.
complementarity-determining.regions.(CDRs).from.the.murine.mAb.with.the.framework.
of.a.human.IgG,.since.several.speciic.residues.in.the.original.murine.framework.contrib-
ute.to.maintaining.the.CDR.conformations..Molecular.modeling.techniques.allowed.this.
problem. to. be. resolved,. and. thus. reshaped. antibodies. have. successfully. been. produced.
and.used.for.clinical.purposes.
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The.differences.between.mAbs.and.small.molecule.drugs.lie.in.several.pharmacologi-
cal.properties..Antibodies.are.administered.intravenously.and.act.only.on.the.receptors.
expressed.on.the.cell.surface.
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.Small.molecule.tyrosine.kinase.inhibitors.are.orally.avail-
able.small,.membrane-permeable.synthetic.compounds.that.block.or.compete.with.adenos-
ine. triphosphate. (ATP). binding,. thus. inhibiting. the. intracellular,. downstream. signaling.
cascade.stimulated.by.a.receptor.or.several.receptors..The.half-life.of.many.tyrosine.kinase.
inhibitors,.such.as.geitinib,.is.approximately.24-48.h,.whereas.the.half-life.of.monoclonal.
antibodies.such.as.bevacizumab.is.about.3-4.weeks..mAbs.cannot.cross.the.blood-brain.
barrier. eficiently. due. to. their. large. size,. whereas. current. evidence. suggests. that. small.
molecule.drugs.can.successfully.cross.the.blood-brain.barrier.
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.Small.molecules.are.gen-
erally.less.speciic.than.therapeutic.monoclonal.antibodies.and,.therefore,.a.higher.risk.of.
toxicity.potential.comes.along.with.small.molecule.drugs.
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8.3.2 Trastuzumab-Conjugated Nanoparticles
8.3.2.1 HER2-Targeted Therapy
The.EGFR.family.is.thought.to.play.a.primary.role.in.the.control.of.epithelial.cell.prolif-
eration.and.mutations.affecting.EGFR.expression.or.activities.that.could.result.in.cancer..
