lMl NlAl D NEW5s:';';frc
National
Institute
ofAllergy
. National
andInfectious
Disease
Institutes
of Health
EMBARGOEDFOR RELEASE
Monday,Feb.14, 1994
6 p.m.,EasternTime
MAID: MarionE. Glick at (301) 402-1663
TSRI: RobinGoldsmithat (619) 554-8134
Antibody FragmentOffers PossibleNew Therapy for SeriousViral Respiratorylllnesses
Antibody fragmentsintroduceddirectly to the lungshavecleareda seriousviral respiratory
infectionin mice,suggesting
that a similartherapymay proveusefulfor suchdiseases
in humans,
reportscientistsfrom the NationalInstituteof Allergy andInfectiousDiseases
(NIAID) andThe
ScrippsResearch
Insdnrte(TSRI)in the Feb.15 Proceedings
of theNationalAcademyof
Sciences.
"The therapy'ssuccess
may signalthe beginningof an era of immunotherapy
for
infectionsby virusesthat anackandgrow in the liningsof airwaysandlungs,suchas respiratory
syncytialvirus (RSV) aswell asinfluenzaandparainlluenza
viruses,"saysJamesE. Crowe,Jr.,
M.D., leadauthorof the studyanda fellow in the NIAID Laboratoryof InfectiousDiseases.
In the study,the scientistscuredRSV infectionin miceusingtailor-madepiecesof human
antibody,knownas antibodybindingfragments(Fabs),derivedandproducedusingrecombinant
DNA technologyin bacteria.The investigators
deliveredthe Fabsdirectlyinto the lower
respiratorytractsof the RSV-infectedmice.
"This is the first time that a studyhasdemonstrated
the successful
useof recombinant
Fabsin a therapyfor a viral infectionin an animal,"sayscoauthorDennisR. Burton,Ph.D.,
professorat TRSI's Departrnents
of MolecularBiology andof Immunology."This is particularly
importantbecause
Fabsareinexpensive
andeasyto producein bacteria."
"Our studysuggests
that Fabsmay proveeffectivefor treatingseriousRSV diseasein the
lower respiratorytractsof normalinfants or the elderly as well as individualsof any ageat high
risk" addsDr. Crowe.
(more)
2
RSVis theleadingcauseof earlychildhood
viralpneumonia
andbronchiolitis--wheezy
bronchitis--inthe UnitedStates.Moreover,RSV-related
illnessesare responsible
for 90,000U.S.
hospitalizations
annually. Worldwideeachyear,RSV causesaboutI million deathsamong
infantsandyoungchildren,primarilyin developingcountries.
At greatestrisk for deathor long-termillnessassociated
with RSV and similarrespiratory
viral infectionsareinfantswith congenitatheartdiseaseor bronchopulmonary
dysplasi4a chronic
diseasefrequentlyseenin prematureinfantswho requiresupportfrom a ventilatorto breatheat
the time of binh.
In addition,olderchildrenand adultswith respiratoryor cardiacanomalieshavea high
risk of developingseriousRSV disease.Individualswith suppressed
immunesystemsresulting
from HIV infectionor from receivingtherapyfor canceror organtransplantation
areat greatrisk
as well.
The mostrecentlydevelopedexperimental
therapyfor RSV diseaserelieson intravenous
deliveryof onetype of wholeantibody,a proteinknownas immunoglobulinG (IgG). This type
of therapycontainsonly a smallproportionof RSV-specificantibodies.However,the arnountof
IgG neededin the therapycanbe reducedby a substantial
amountby usinghumanmonoclonal
IgG antibodiesthat aredirectedsolelyat RSV. Furthermore,
IgG therapycanbe made80 to 160
timesmoreeffective,previousstudieshaveshown,whendeliveredby aerosol,which carriesthe
antibodiesdirectlyto the lung tissuethat RSV infects.
However,onty limited amountsof IgG canbe safelyandefficientlyintroducedinto the
lungsby an aerosol.By substitutingthe humanmonoclonalFabs,fragmentsof IgG, the NIAID
and TSRI scientistshavereducedthe quantityof proteinneededto fight RSV by 2,000to 8,000fold.
"The successof the Fabsin micehasshownthat RSV therapycanbe improvedusing
thesefragments,"saysDr. Burton. "If provensafeandeffectivefor usein humans,Fabtherapy
couldbecomeimportantin the clinic in the management
of respiratoryviral infectionsin general."
(more)
3
Fabtherapyfor RSV offersseveraladvantages
overusingwholeIgG, notesDr. Crowe.
Fabscanbe madecheaplyandeasilyin largeamountsusingbacteria,suchu Escherichiacoli,
whereasIgG mustbe madeby morecomplicated'methods
usinganimalcells.
In addition,Fabslack structures
commonto IgG. IgG is shapedlike a Y, with a Fab
occupyingthe tip of eacharm of the fork. An individualFabhasonly onebindingsitethatjoins
to RSV. In contrast,IgGs havetwo bindingsites,permittingthe antibodiesto tink up with
severalvirusesinto a chainlike immunecomplex. Suchcomplexescan accumulateand cause
damaginginflammation.Also, individualFabslack the IgG's tail that is capableof triggeringa
cascadeof harmfulinflammatoryreactions.
"Becauseof their simplicity,Fabsmay be saferto usethanwholeIgG antibodieswhen
treatingRSV infections,"sayscoauthorRobertM. Chanock,M.D., chief of MAID's Laboratory
of InfectiousDiseases."Theuseof Fabsprecludesa numberof adverseeffectswholeantibody
moleculescancause."
For the study,scientistsscreened
manyFabsand foundthat in tissueculturesFab 19 could
neutralizeRSV very efficientlyby bindingto a regionof the virus. The investigators
placed
dropletscontainingFab 19 into the lungsof anesthetized
micethreeor four daysaftertheir
infectionwith RSV, a time whenthe virus replicatesmostactively. In four separate
experiments,
the investigalorsfoundthat very smalldoses,up to 50 microgramsper mouse,could reducethe
amountof RSV in the lungs5,000to 12,000fold.
Moreover,the researchers
couldsustainthe'reductionandclearRSV if they gavethe mice
a daily doseof Fab 19 for threedays. In contrast,the scientistscoulddetectactiveRSV from
untreatedmice infectedfor the samelengthof time.
Fab-resistant
strainsof RSV couldnot be detectedin the treatedmice. However,to
preventresistance
to RSV Fabtherapyfrom developingin humans,the investigarors
suggest
therapyshouldinclude one or moreadditionalFabsthat can bind to otherpartsof the virus
distinctfrom the regiontargetedby Fab 19.
(more)
4
Othercoauthorson the studyincludeBrian R. Murphy,M.D., at MAID, R. Anthony
Williarnson,Ph.D.,researchfellow in TSRI's Department
of Immunology,andCarlosF. Barbas
m, Ph.D.,assistantprofessorin TSRI's Department
of MolecularBiology.
NIAID, a componentof the NationalInstitutesof Health,supportsinvestigators
and
scientificstudiesat universities,medicalschools,hospitalsandresearch
institutionsin the United
Stuesand abroadaimedat preventing,diagnosingandtreatingsuchillnessesas AIDS,
tuberculosisand asthmaas well as allergies. NIH is an agencyof the U.S. Departmentof Health
andHumanServices.
r
TSRI is the nation'slargestnon-profitbiomedicalresearchfacility not affiliatedwith a
university. Sinceits establishment
in 1961,the Institutehasbecomeinternationallyrenownedfor
its basicresearchinto immunology,autoimmune
diseases,
neurosciences,
molecularbiology,
chemistryandsyntheticvaccinedevelopment.TSRI is dividedinto eight departments:cell
biology,chemistry,immunology,molecularbiology,molecularandexperimental
medicine,
neurobiology,neuropharmacology
andvascularbiology.
ttttt