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THE SCRIPPS RESEARCH INSTITUTE
I 0 6 6 6 N O R T H T O R R E Y P I N E SR O A D
LA JOLLA, CALIFORNIA 920]7
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For information:
Robin B. Goldsmith
(619)5s4-8134
# 043093
Embargoed by Proceedingsof the National Academy of Sciences:
Friday, April 30, 1993, 3:00 p.m. Pacific Time
Scripps ScientistsDevelop Procedurefor Isolating Human Monoclonal Antibodies to
Fight Infectious Diseases
La Jolla, CA. April 30, 1993-- A novel and powerful strategyfor isolatinghuman
monoclonalarrtibodiesreactiveagainstvirnrally any infectiousorganismhasbeen
developedby investigatorsat The ScrippsResearchInstitutein La Jolla, California.
With this technique,scientistsand physicianscan now pursuethe long-soughtgoal of
using humanmonoclonalantibodiesas pharmacologicagentsto combatinfectious
diseases,especiallythosecausedby viruses,for which almostno suchtreatments
currently exist. Conventionalmonoclonalantibodytechnology-so successfulin the
mouse-works poorly and unreliablyin the humansystem;few humanmonoclonals
have beenproduced. Also, the effectiveness
of mousemonoclonalantibodiesin treating
humandiseaseis limited.
A descriptionof the methodwas publishedin today's issueof the Proceedingsof the
National Academyof Sciencesby Drs. R. Anthony Williamson, RobertoBurioni, PietroPaolo Sanna,Lynda J. Partridge,CarlosF. Barbasand DennisR. Burton.
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Scripps ScientistsDevelopProcedurefor Isolating Human Monoclonal
Antibodies
To illusffate the potentialof this new technology,the Scrippsscientistspreparedfrom
just two humandonorsmonoclonalantibodiesthat bind stronglyand selectivelyto a
variety of pathogenichumanviruses, including humanimmunodeficiencyvirus (the cause
of AIDS), respiratorysyncytialvirus (severelower respiratorytract illnessin young
children), cytomegalovirus(deafnessand mentalretardation),herpessimplexvirus (cold
sores,genitalherpes),varicella-zostervirus (chickenpox, shingles),rubella virus
(Germanmeasles,birth defects),and Epstein-Barrvirus (mononucleosis,lymphomas).
Many of theseantibodiesefficiently neutralizetheir target virus in laboratory test
systems.
"Currently, drugseffectiveagainstmost viral infectionssimply do not exist," noted
Burton, in whoselaboratorymost of the work was conducted. "We have relied on the
power of our immunesystemsto counteractinfectiousdiseases.Unfortunately,a disease
suchas AIDS has demonstrated
the necessityof finding other ways to combatviruses
with suchdevastatingconsequences.
"
The new procedureis an extensionof the combinatorialantibody library technology
pioneeredat Scrippsduring the pastthreeyears.In contrastto conventionalmonoclonal
antibodytechnique,which involvesthe isolationand culnrringof individual antibodyproducingcells, here humanantibody-producing
cells serveonly as the sourceof the
genesthat code for the vast array of different antibodiesin humansor other animals.
Onceextracted,the antibodygenesare inserted,in randomcombinations,into individual
particles(bacteriophage,
bacteriophage
or phagefor short, are virusesthat infect
bacteria).
In this way, eachphageparticle becomesthe carrier of the geneticinformationneededto
make a particularantibodyprotein, and a bacteriacell infectedby that phagebecomesin
effect a minute factory for manufacturingcopiesof that protein. Each of the infected
bacterialcells can then be individually grown into large populations,or clones,from
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Scripps ScientistsDevelopProcedurefor Isolating Human Monoclonal
Antibodies
which substantialamountsof the identical(i.e., monoclonal)antibodiescan be extracted.
A major technicaladvancedescribedin the paperpubtishedtoday was the demonstration
that antibodiesagainstvirtually any virus can be derivedby "panning"sucha library,
providedthe donor from whom the library was derivedhad contactwith the virus(es)in
question. Further, they can be isolatedquickly and inexpensively,and the numbersof
different antibodiesroutinely obtainedmakesit possibleto selectthe best amongmany.
A wide rangeof different monoclonalscan be extractedfrom a singlelibrary, and the
libraries themselvescan be preservedindefinitelyand exploitedmany times. Burton
explainedthat with the ability to easilygeneratehumanantibodiesagainstspecific
virusesat will, researchers
will be able to begin to assess
their therapeuticvalue.
It has long beenknown that specificantibodiesfrom one individual can benefit another.
Decadesago researchers
provedthat "immune" serumfrom a personwho had recovered
from an infectiousdisease,could, upon transfusioninto anotherperson,provide some
protectionagainstthe samedisease. Natureitself usesthis strategy;in all mammals,
specific antibodiesagainsta rangeof infectiousagentsare passedfrom motherto
newbornto provide immuneprotectionuntil lhe newborn'sown immunesystembecomes
fully functional.
However, early efforts to use immuneseraor antibodyextractsclinically proved to be
marginally effectiveand potentiallydangerous.Not only was the amountof specific
antibodycontainedin a serumor extractoften too small or too weak to be effective,but
the risk of transmittingserum-bornediseasessuchas hepatitisfar outweighedany
potentialbenefit. Animal antibodyextractswere alsotried but thesetoo provedto be
unacceptablyhazardous.
With the introductionof the monoclonalantibodytechnologydevelopedin the 1970s,it
appearedthat the major problemsassociated
with the use of antibodiesas prophylacticor
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Scripps ScientistsDevelopProcedurefor Isolating Human Monoclonal
Antibodies
therapeuticagentsmight havebeensolved.Sincepreparationswould consistentirely of
antibodymoleculesagainstthe targetin questionpreparedand purified under laboratory
conditions,there would be little or no dangerof contamination.
While monoclonalantibodieswere shownto havegreatpotentialas pharmacologic
agents,it was also soondiscoveredthat antibodiesderivedfrom mousecells would not
be suitablefor use in humans.The immunesystemsof humansinjectedwith thesemouse
antibodiesquickly producedtheir own antibodiesin responseto the foreign mouse
protein and neutralizedthem.
Accordingly, many investigatorsturnedtheir efforts to makinghumanmonoclonal
antibodies,which, they reasoned,would be toleratedby the humanimmunesystem.
Unfortunately,efforts to dateto adaptconventionalmonoclonalantibodytechnologyto
humancells have beendisappointing. A few humanmonoclonalsagainstpathogenshave
beenproducedand shownto haveclinical potential,but thesepreparationsexist largely
in laboratoriesand it is difficult or impossible-andvery expensive-to producethem in
therapeuticamounts. The researchersnote th4t the combinatoriallibrary approach
devisedat Scrippswould appearto solvemost or all of theseproblems.
It shouldbe notedthat authorBurioni is at Scrippson leavefrom the Universita
Cattolicain Rome, Italy, and Partridgeis a faculty memberat the University of Sheffield
in Sheffield, England.
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