Q N A BIOTEK

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CHAPTER 71.What are the structural diferences between the veimmunolobulin classes!". #a$ What are %e& diferences in P'(P) between*A+s and small molecule drus!#b$ Wh& do ,-s t&icall& show nonlinear P' in the

lower lasma #serum$ concentration rane!/. What is a surroate *A+ and how can it otentiall&be used in the dru develoment rocess o0 *A+s!. Which other modes o0 actions aart 0rom A)CC 2antibod& deendent cellular c&toto3icit& are %nown0or *A+s! What are the %e& stes o0 A)CC!4. Wh& do ,-s have a loner in vivo hal05li0e comaredwith other ,s!6. What are the develoment hases 0or antibod& theraeutics!What maor activities are involved in theeach hase!

8awaban

The 0ollowin structural roerties distinuish*A+s9: The molecular 0orm can be diferent 0or the 4immunolobulin classes9 ,-; ,); and ,E aremonomer< ,* aears as entamer or he3amer;and ,A are either monomer or dimer.: Conse=uentl&; the molecular weiht o0 thediferent ,s is diferent #,- 14>216? %); ,A16>2/>> %); ,) 174 %); ,E 1?>; ,* ?4> %)$.". #a$ ,. *etabolism o0 *A+s aears to be simler

than 0or small molecules. ,n contrast to smallmolecule drus; the t&ical metabolic en@&mesand transorter roteins such as c&tochromeP4>; multidru resistance #*)R$ e u3 umsare not involved in the disosition o0 *A+s. There0ore; dru2dru interaction studies 0orthose disosition rocesses are onl& art o0 thestandard sa0et& assessment 0or small moleculesand not 0or *A+s. *onoclonal antibodies;which have a rotein structure; are metaboli@edb& roteases. These en@&mes are ubi=uitousl&available in mammalian oranisms. ,n contrast;small molecule drus are rimaril& metaboli@ed

in the liver.,,. +ecause o0 the lare molecular weiht; intact*A+s are t&icall& not cleared b& the renalelimination route in the %idne&s. However;renal clearance rocesses can la& a maor rolein the elimination o0 small molecule drus.,,,. Pharmaco%inetics o0 *A+s usuall& is deendenton the bindin to the harmacoloicaltaret rotein and shows nonlinear behavioras conse=uence o0 its saturation %inetics.,B. ,n eneral; *A+s have a loner hal05li0e #inthe order o0 da&s and wee%s$ than small moleculedrus #t&icall& in the order o0 hours$.

B. The distribution o0 *A+s is ver& restricted#volume o0 distribution in the rane o0 >.1 (


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%$. As a conse=uence; *A+s do have limitedaccess to tissue comartments as otential taretsites via assive; ener&5indeendent distributionrocesses onl& #e..; brain$.#b$ At lower concentrations; *A+s enerall& shownonlinear harmaco%inetics due to recetormediated

clearance rocesses; which are characteri@edb& small caacit& o0 the clearanceathwa& and hih aD nit& to the taret rotein.Conse=uentl& at these low concentrations; *A+se3hibit t&icall& shorter hal05li0e. With increasindoses; these recetors become saturated; and theclearance as well as elimination hal05li0e decreasesuntil it becomes constant. The clearance in thehiher concentration rane; which is dominatedb& linear; nontaret5 related clearance rocesses;is there0ore also called nonseci c clearance incontrast to the taret5 related; seci c clearance./. A surroate *A+ has similar antien seci cit& and

aD nit& in e3erimental animals #e..; mice and rats$comared to those o0 the corresondin humanantibod& in humans. ,t is =uite common that theantien seci cit& limits A)*E studies o0 humani@edmonoclonal antibodies in rodents. tudiesusin surroate antibodies miht lead to imortantin0ormation reardin sa0et&; mechanism o0 action;disosition o0 the dru; tissue distribution; andrecetor harmacolo& in the resective animal secies;which miht be too cumbersome and e3ensiveto be conducted in nonhuman rimates.urroate *A+s #0rom mouse or rat$ rovide ameans to ain %nowlede o0 A)*E and P) in reclinicalrodent models and miht 0acilitate the doseselection 0or clinical studies.. Aart 0rom A)CC; monoclonal antibodies can e3ertharmacoloical efects b& multile mechanismsthat include direct modulation o0 the taret antien;comlement5deendent c&toto3icit& #C)C$ andaotosis. The %e& stes o0 A)CC are #1$ osoni@ation o0 thetareted cells; #"$ reconition o0 antibod&5coated taretedcells b& Fc recetors on the sur0ace o0 monoc&tes;macrohaes; natural %iller cells; and othercells; and #/$ destruction o0 the osoni@ed tarets b&

haoc&tosis o0 the osoni@ed tarets and(or b&to3ic substances released a0ter activation o0 monoc&tes;macrohaes; natural %iller cells; and othercells.4. ,- can bind to neonatal Fc recetor #FcRn$ in theendosome; which rotects ,- 0rom catabolism viaroteol&tic deradation. This rotection results intoa slower clearance and thus loner lasma hal05li0eo0 ,-s. Conse=uentl&; chanin the FcRn aD nit&allows to adust the clearance o0 *A+s #hiher aD nit&2 lower clearance$; which can be emlo&ed totailor the harmaco%inetics o0 these molecules.6. Pre5,G); hase ,; ,,; ,,,; and ,B are the maor develoment

hases 0or antibod& theraies. a0et& harmacolo&;to3ico%inetics; to3icolo&; tissue cross


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reactivit&; local tolerance; P' suort 0or moleculesselection; assa& suort 0or P'(P); and P'(P)suort 0or dose(route(reimen are maor activitiesin the re5,G) hase. -eneral to3icit&; reroductiveto3icit&; carcinoenicit&; immunoenicit&; characteri@ationo0 dose2concentration2efect relationshi;

material comarabilit& studies; mechanistic modelinaroach; and oulation harmaco%inetics(

CHAPTER 171. From the name tositumomab and 1/1, tositumomab;I

what can one in0er about the t&e o0 druand oriin!". The eidermal rowth 0actor recetor inhibitorshave a uni=ue side efect ro le which ma& alsodemonstrate a harmacod&namic efect. )escribethe ro le and what develoment o0 this side efectma& mean in terms o0 treatment efectiveness./. )escribe the theor& o0 anioenesis and how vascular

endothelial rowth 0actor inhibitors ma& counteractthis imortant mechanism o0 cancerdeveloment.. +evaci@umab is an anioenesis inhibitor. ist whatis %nown about bevaci@umab in terms o0 thromboticand bleedin concerns. Are there an& uidelines onduration o0 time between bevaci@umab use a0termaor surer&! What are the&!4. )escribe the clinical literature that suorted theF)A aroval o0 anitumumab! What indicationdoes it currentl& have!6. 'eein ritu3imabJs mechanism o0 action in mind;which o0 the 0ollowin disease states would ritu3imabli%el& not show an& bene t and wh&!#a$ Autoimmune hemol&tic anemia#b$ Cutaneous T5cell l&mhoma#c$ ,mmune thromboc&toenic urura#d$ Rheumatoid arthritis7. Which o0 the eidermal rowth 0actor inhibitorsre=uire that atients test ositive 0or the 'RAwild5t&e!K. Trastu@umab and ertu@umab re=uire a ositive test0or the e3ression o0 which recetor!?. ist the three blac% bo3 warnins associated withritu3imab use.

Answers1. From the name tositumomab and 1/1, tositumomab;Ione can in0er several characteristics o0 thisdru. First; it is a monoclonal antibod& o0 murineoriin; as desinated b& its suD 3 o0 omab.I econd;the dru is conuated or radiolabeled since thedru name contains a second word containin oneo0 the eriodic elements.". The eidermal rowth 0actor recetors #E-FR$ inhibitorsall share a common side efect ro le that is dermatoloic

in oriin. -enerall&; atients will resentwith an acnei0orm rash that cannot be success0ull&


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treated with over5the5counter acne aents. This rashis due to the 0act that E-FR is overe3ressed in man&cancers as well as normal s%in and hair 0ollicles. There0ore; in some cases; the develoment o0 a rashma& be associated with clinical eD cac& o0 the dru

/. For tumors to row larer than " mm / ; the& mustbein to row their own blood sul&; both to rovideo3&en and carr& awa& wastes; a rocess%nown as anioenesis. everal rowth 0actors arenecessar& to stimulate anioenesis< one o0 the mostotent is vascular endothelial rowth 0actor #BE-F$.+evaci@ umab is a BE-F inhibitor that reventsBE-F 0rom bindin to recetors; which subse=uentl&revents anioenesis and tumor rowth.*an& thin% that BE-F inhibitors will be ver& success0ulin earl& stae disease where the& can reventlare tumor rowth; althouh bevaci@umab is currentl&used more in a metastatic and late stae

settin.. Evidence suests that at least "K da&s must elasebetween a maor surer& and subse=uent bevaci@umabadministration. This is because antianioenesisinhibitors are associated with vascular d&s0unctionb& their mechanism o0 action. There have been woundhealin concerns; e3cessive bleedin; and even clottinconcerns with the use o0 bevaci@umab in clinicaltrials. Concomitant use o0 war0arin was shown to besa0e in one recent clinical trial.4. Panitumumab is currentl& indicated 0or the treatmento0 atients with E-FR5e3ressin; metastaticcolorectal carcinoma with disease roression on or0ollowin L uoro&rimidine5; o3alilatin5; andirinotecan5 containin chemothera& reimensI #i.e.;third5 or 0ourth5line use$. This aroval was basedon a hase ,,, trial # n M 6/$ that randomi@ed atientsto receive anitumumab monothera& or best suortivecare. The mean roression50ree survival was?6 da&s 0or the anitumumab rou and 6> da&s 0orthe +C alone rou. Eiht ercent o0 atients in thetreatment arm e3hibited a artial resonse and noobservable resonse was detected in the control arm.6. Cutaneous T5cell l&mhoma. This is because ritu3imabis a chimeric monoclonal antibod& that binds

to the antien C)"> #cluster o0 diferentiation ">$;which is 0ound on + l&mhoc&tes #+ cells$.7. ,n the treatment o0 colorectal cancer; both anitumumaband cetu3imab are rendered inefective b&the activatin 'RA mutation. There0ore; tumor tissueshould be tested 0or 'RA and onl& thoseatients with a wild5t&e 'RA are li%el& to bene t0rom E-FR inhibitor *A+ thera&.K. Nse o0 trastu@umab and ertu@umab re=uires a ositivetest 0or the HER5"(neu rotein #i.e.; a ositiveresult either on L uorescence in situ h&bridi@ation#F,H$ or immunohistochemistr& #,HC$ "O$ as clinicaleD cac& in the ivotal aroval trials was related

to overe3ression o0 this rotein.?. Fatal in0usion reactions; tumor l&sis s&ndrome


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#T$; and severe mucocutaneous reactions.

CHAPTER 1?

1. *onoclonal antibodies are used 0or several reasonsin solid oran translantation. What bene t do the&rovide over ol&clonal antibodies!". The rational develoment and use o0 monoclonalantibodies in solid oran translantation is 0ocusedon the revention o0 host reconition o0 donor tissue#reection$. What are the two wa&s in which the hostimmune s&stem reconi@es donor tissue and ma&cause tissue damae!/. What are the molecular tarets 0or monoclonalantibodies currentl& used in solid orantranslantation!. *onoclonal antibodies are used at various times in

solid oran translantation. )escribe the reasonswh& a monoclonal antibod& would be administeredbe0ore translant; at the time o0 translant; or 0ollowintranslant!4. There are several imortant harmaco%ineticarameters that must be considered when administerinmonoclonal antibodies to solid oran translantreciients. What are these harmaco%ineticarameters!6. *uromonab has a characteristic in0usion5relatedreaction. Wh& does this reaction occur and how canit be attenuated!

7. )acli@umab and basili3imab are two monoclonalantibodies directed aainst the alha subunit o0 theinterleu%in5" recetor. What is the diferencebetween these two antibodies!K. There are several bene ts; as well as several ris%sassociated with the use o0 monoclonal antibodies insolid oran translantation. What are these bene tsand ris%s!

Answers

1. *onoclonal antibodies rovide tareted immunosuression. The advantae monoclonal antibodiesofer over ol&clonal antibodies is that the recetortaret is %nown. Pol&clonal antibod& develomentinvolves the introduction o0 human l&mhoc&tesinto an animal host immune s&stem. The animal willthen develo ol&clonal antibodies directed aainsthuman l&mhoc&te cell sur0ace tarets. As a conse=uence;each inter5batch variabilit& and otenc&ma& var&. Althouh sini cant outcome data e3istswith the use o0 ol&clonal antibodies; monoclonalantibodies have a %nown taret allowin 0or in vivoand in vitro harmaco%inetic and harmacod&namic

data to aid incororation into novel immunosuressionreimens.


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". The two wa&s in which the host immune s&stem reconi@esdonor tissue. Comlement5deendentantibod&5 mediated reection occurs when the host#reciient$ develos or has re0ormed antibodiesaainst the donor tissue. Pre0ormed antibodies willareate to the imlanted tissue and initiate the comlement

cascade; which 0acilitates cell l&sis. The maorit&o these antibodies are usuall& directed aainst themaor histocomatibilit& comle3es #*HC$ located onthe sur0ace o0 the donor tissue. An absolute contraindicationto translantation is the resence o0 re0ormedantibodies aainst *HC comle3 ,; which is locatedon the sur0ace o0 all nucleated cells. The second wa& inwhich the host immune s&stem attac%s donor tissue isthrouh T5cell5mediated reection. This occurs whenthe donor tissue is reconi@ed as 0orein b& host antienresentin cells. Antien resentin cells resentdonor tissue antiens to the T cells which stimulates T5cell roli0eration and ra0t in ltration leadin to

inL ammation and arteritis./. Alemtu@umab #Camath51H $ tarets the C)4"recetor; located on eriheral blood l&mhoc&tes;natural %iller cells; monoc&tes; macrohaes; andth&moc&tes.)acli@umab #Qenaa3 $ tarets the C)"4 alhasubunit o0 the ,5" recetor; located on activated Tl&mhoc&tes.+asili3imab #imulect $ tarets the C)"4 alhasubunit o0 the ,5" recetor; located on activated Tl&mhoc&tes.

*uromonab5'T/ #rthoclone5'T/ $ taretsthe C)/ recetor located on C)"5; C)5; and C)K5ositive l&mhoc&tes.Ritu3imab #Ritu3an $ tarets the C)"> recetorlocated on + l&mhoc&tes.Eculi@umab #oliris $ tarets C4 in the comlementathwa&.. The administration o0 monoclonal antibodies riorto translant is called desensiti@ation. This strate&is reserved 0or hihl& sensiti@edI atients; meaninthe& have hih titers o0 circulatin antibodiesaainst donor5seci c antiens. *onoclonal antibodiesthat taret cells which roduce these antibodies

are emlo&ed; in conunction withlasmaheresis and ooled human immune lobulins.Removal o0 these antibodies ma& 0acilitate success0ultranslantation across this immunoloicbarrier.*onoclonal antibodies administered at the timeo0 translant are called induction. ,nduction is rovidedat the time o0 translant to decrease the abilit&o0 the host immune s&stem to resond to imlantationo0 0orein tissue. ,n addition; monoclonal antibodieswhich rovide ro0ound T5cell deletioniven at the time o0 translant ma& 0acilitate theneed 0or certain maintenance immunosuressants.

Followin translantation; monoclonal antibodiesma& be used to treat cell5mediated or antibod&mediated


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reection. Cell and antibod& in ltrates0ound in bios& secimens in correlation with theclinical status o0 the atient will dictate the t&e;dose; and duration o0 the monoclonal antibod&chosen 4. The volume o0 distribution; bioloical hal05li0e; andtotal5bod& clearance can difer sini cantl& between

solid oran translant reciients. Care0ul considerationo0 these harmaco%inetic arameters must beemlo&ed to ma3imi@e the eD cac& and minimi@e theto3icit& associated with administration o0 theseaents. For e3amle; weiht5based dosin in obeseatients must be care0ull& considered; and bioloicalmar%ers o0 eD cac& should be evaluated to determinethe aroriate dose and dosin schedule. ,n addition;monoclonal antibodies are also removed b&lasma e3chane rocedures; such as lasmaheresis;which ma& be er0ormed durin the erioerativeeriod. There0ore; it would be rudent to administerthe monoclonal antibod& 0ollowin the lasma

e3chane rescrition to avoid removal o0 the druand avoid a ossible decrease in eD cac&.6. *uromonabJs in0usion5related reaction occursbecause when the molecule binds to the C)/ recetor.,t actuall& activates the cell rior to inducinaotosis. T5cell activation leads to increased roductiono0 inL ammator& c&to%ines and when the cell underoes aotosis these c&to%ines arereleasedcausin a c&to%ine release s&ndrome.I This c&to%inerelease s&ndrome is characteri@ed b& 0ever;chills; riors; diarrhea; and otentiall& caillar& lea%leadin to ulmonar& edema. 0ten times this reactionis the worst when the larest number o0 cells areresent; namel&; the rst dose. However; this reactioncan occur a0ter several da&s o0 dosin. Thisreaction can be attenuated b& administration o0 corticosteroids;histamine bloc%ers; and c&cloo3&enaseantaonists. Pharmacothera& aimed at reducinthe roduction or the interaction o0 c&to%ines withtheir recetors ma& decrease the severit& o0 the c&to%inerelease s&ndrome.7. Structure activity relationship 9 )acli@umab has a bindincaacit& o0 / S 1> ? * 1 versus basili3imab whichhas a bindin caacit& o0 1 S 1> 1> * 1 . There0ore;basili3imab is three times more otent than

[email protected]. Dosing 9 )acli@umab is dosed based on weiht; whilebasili3imab is iven as a "> m dose. The dosinschedule varies based on the t&e o0 solid orantranslanted as well as concomitant immunosuressioniven. These aents; however; are onl&aroved 0or revention o0 acute reection in %idne&translant reciients.?. +ene ts include tareted immunosuression; nobatch variabilit&; and low antienicit& in humani@edroducts. The ris%s associated with an& t&e o0 immunosuression include an increased ris% 0orin0ection; as well as malinanc&. Patients who

receive monoclonal antibodies which seci call&taret a cell line; such as muromonab; are associated


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with a sini cantl& increased ris% o0 osttranslantl&mhoroli0erative disease. Aroriate antimicrobialroh&la3is and viilant screenin 0or osttranslantmalinanc& ma& allow 0or sa0e andefective use o0 these monoclonal antibodies in solidoran translantation.

CHAPTER ">

Questions1. Are tareted bioloic theraies 0or autoimmune diseasesonl& to be used once drus li%e corticosteroidsand methotre3ate have had an ade=uate trial o0 useand have 0ailed to control the atientJs s&mtoms!". What is the rimar& clinical concern with the immunoenicit&o0 bioloic theraies!/. What is the most li%el& e3lanation 0or wh& a atient

who receives a dose o0 omali@umab miht have anincrease in their total serum ,E level 0or man&wee%s a0ter the rst dose!. Wh& do some cell subsets in the eriheral bloodincrease a0ter dosin with natali@umab!4. ,0 a trial reorts an ACR7> o0 "> U on active dru;what does that mean!6. What does PA, 74 mean!7. -iven that there are currentl& ve anti5TGFV biotheraeuticaents on the mar%et; how would &oucomare and contrast them!K. What are the %e& diferences in the indication 0or useo0 ritu3imab vs. abatacet in RA!?. What is the mechanism o0 action 0or uste%inumab intreatin la=ue soriasis!

Answers1. Thouh the standard o0 care in diseases li%e RA isstill to start with older )*AR)s li%e methotre3ate;the decision o0 when to start or switch theraies iscomle3 and imacted b& individual issues lin%edto clinical resonse li%e tolerance(adherence to aarticular theraeutic reimen; severit& and courseo0 disease and its roression; and concomitantmedications and medical issues. ,t is li%el& that the

standard o0 care will continue to chane and incororateearlier use o0 bioloic theraies that can modi0&the disease course with 0ewer enerali@ed sideefects.". ,0 a bioloic thera& is hihl& immunoenic; there isa concern that an increasin number o0 atientse3osed to the dru; articularl& uon reeatede3osure a0ter a hiatus; because their antidru antibodiescould sometimes neutrali@e the maorit& o0 the dru and the& would not li%el& et the 0ull doseor efect. Thouh less li%el& there are also rare e3amleso0 antidru antibodies resultin in an autoimmuneor alleric5t&e reaction.

/. Theraeutic monoclonal antibodies that taret solublemolecules li%e ,E 0orm comle3es. Thouh


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immune comle3es are t&icall& cleared 0rom theblood more =uic%l& than monomeric ,-; solubletaret molecules t&icall& have a shorter serum halLi0ethan ,-. o an assa& detectin the soluble taret#in this case ,E$ that can detect taret even when itis bound to the dru #which is t&icall& an lonerlived

,-$ will show more taret resent in theserum ost5dosin as comared to baseline. This iscalled a carrier efect. Assumin the dru neutrali@edthe bound taret; the test detectin the taretcan be misleadin; because the taret; thouh resent;is efectivel& inactive.. Gatali@umab is a monoclonal antibod& that bloc%sl&mhoc&te movement between the blood and tissues#traD c%inI$< when this movement is efectivel&bloc%ed in one direction #0rom the blood intothe tissues$; an aarent increase in the eriherall&mhoc&te oulation will be evident on assessmentb& L ow c&tometr& #or erhas even on a C+C

with diferential$ ost5dosin.4. An ACR7> o0 "> U means the "> U o0 the atientshad a 7> U imrovement in their RA disease.6. The PA, score stands 0or Psoriasis Area and everit&,nde3. This tool allows researchers and dermatoloiststo ut an obective number on what would otherwisebe a ver& subective idea9 how bad is aersonJs soriasis. The PA, evaluates the deree o0 er&thema; thic%ness; and scalin o0 soriatic la=uesand estimates the e3tent o0 involvement o0 each o0 these comonents in 0our searate bod& areas #head;trun%; uer; and lower e3tremities$.

,0 in a clinical stud& a certain roortion o0 atientse3erienced a 74 U reduction in their PA, scores; itis reorted as a ercentae o0 eole achievinPA, 74.I7. Althouh the ve anti5TGFV bioloics have broadl&similar eD cac& and sa0et& ro les in RA; there aresini cant diferences in the ve anti5TGFV aentsarticularl& with resect to dosin characteristicsand also in the details o0 the aroved indications0or use.,nL i3imab is the onl& anti5TGFV aent ivenintravenousl&; has the lonest dosin interval; and

is the rst F)A5aroved anti5TGFV aent 0or ,+)indication. All the other anti5TGFV aents areadministered b& subcutaneous administration. ,t isa chimeric monoclonal antibod& that neutrali@es TGF5V and has arovals in the most indications#rheumatoid arthritis; soriatic arthritis; an%&losinsond&litis; adult and ediatric ulcerativecolitis; adult and ediatric CrohnJs disease; andsoriasis$.Etanercet is a dimeric soluble 0usion rotein andhas arovals 0or use in several indications #rheumatoidarthritis; ol&articular uvenile rheumatoidarthritis; soriatic arthritis; an%&losin sond&litis;

and soriasis$. ,t is used as wee%l& inection.Adalimumab is a human monoclonal antibod&


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that neutrali@es TGF5V and has F)A arovals 0oruse in atients with rheumatoid arthritis; soriaticarthritis; an%&losin sond&litis; soriasis; andCrohnJs disease. ,t is used at a 0re=uenc& o0 ever&wee% or ever& other wee%.-olimumab is a human monoclonal antibod&

that neutrali@es TGF5V and has F)A arovals 0oruse in atients with rheumatoid arthritis; soriaticarthritis; and an%&losin sond&litis. ,t is used at a0re=uenc& o0 ever& month.Certoli@umab eol is a recombinant; humani@edantibod& Fab 0rament; with seci cit& 0or humantumor necrosis 0actor alha #TGFV$; conuated toan aro3imatel& >5%)a ol&eth&lene l&col#PE-"*A>'$. ,t has been aroved b& F)A 0orthe treatment o0 rheumatoid arthritis and CrohnJsdisease.K. Ritu3imab in combination with methotre3ate isindicated 0or the treatment o0 adult atients with

moderate to severe rheumatoid arthritis who havehad an inade=uate resonse to one or more TGFantaonist theraies. Abatacet is indicated 0or useas monothera& or in combination with )*AR)in atients with moderate to severe active rheumatoidarthritis who have had an inade=uate resonseto )*AR)s or TGF antaonists.?. ,51" and ,5"/ are naturall& occurrin c&to%inesthat are involved in inL ammator& and immuneresonses; such as natural %iller cell #G'$ activationand C)O T5cell diferentiation and activation.Nste%inumab; a human ,-1 monoclonal antibod&that binds with hih aD nit& and seci cit& to the> rotein subunit used b& both the ,51" and,5"/; can revent human ,51" and ,5"/ 0rombindin to the ,51"RX1 recetor chain o0 ,51"#,51"RX1(X"$ and ,5"/ #,51"RX1("/R$ recrecetorcomle3es on the sur0ace o0 G' and T cells.

CHAPTER "

Questions1. What was the disease taret 0or the rst ene thera&

clinical trial! What vector was selected 0or enetrans0er!". ,denti0& and describe ve transcrition reulator&elements #TRE$ discussed in the chater./. everal clinical trials involve ene trans0er 0or treatinmalinant lioma. ne aroach involves the useo0 a recombinant retrovirus e3ressin the HB5t%transene. Another involves the use o0 a recombinantadenovirus e3ressin the 4/ transene.#A$ Which o0 the ve current strateies to treatcancer b& viral ene thera& does each o0 thesetrials emlo&! )escribe the rincile behindeach strate&.

#+$ ist " advantaes and " disadvantaes associatedwith the vector used in each o0 these


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trials.#C$ utline otential drawbac%s to the use o0 eacho0 these strateies 0or cancer thera&.#)$ What other aroaches could have beenselected to revent the rowth and sread o0 malinant tissue! E3lain the rincile behind

each.. What is the urose o0 the ac%ain cell line durinthe roduction o0 recombinant viral vectors 0orene trans0er! What is the ris% associated with usinac%ain cell lines 0or vector roduction!4. Provide two e3amles o0 how ene thera& is usedto modulate the immune s&stem to ht in0ection.6. )escribe one clinical trial 0or retrovirus5based enethera& and adenovirus5based ene thera&; andidenti0& the most sini cant adverse efects thathave been reorted 0or each trial.7. ,denti0& the three mar%eted ene thera& roductsin the world and describe the mechanism o0 actions

o0 each roduct.

Questions1. What was the disease taret 0or the rst ene thera&clinical trial! What vector was selected 0or enetrans0er!". ,denti0& and describe ve transcrition reulator&elements #TRE$ discussed in the chater./. everal clinical trials involve ene trans0er 0or treatinmalinant lioma. ne aroach involves the useo0 a recombinant retrovirus e3ressin the HB5t%transene. Another involves the use o0 a recombinantadenovirus e3ressin the 4/ transene.#A$ Which o0 the ve current strateies to treatcancer b& viral ene thera& does each o0 thesetrials emlo&! )escribe the rincile behindeach strate&.#+$ ist " advantaes and " disadvantaes associatedwith the vector used in each o0 thesetrials.#C$ utline otential drawbac%s to the use o0 eacho0 these strateies 0or cancer thera&.#)$ What other aroaches could have been

selected to revent the rowth and sread o0 malinant tissue! E3lain the rincile behindeach.. What is the urose o0 the ac%ain cell line durinthe roduction o0 recombinant viral vectors 0orene trans0er! What is the ris% associated with usinac%ain cell lines 0or vector roduction!4. Provide two e3amles o0 how ene thera& is usedto modulate the immune s&stem to ht in0ection.6. )escribe one clinical trial 0or retrovirus5based enethera& and adenovirus5based ene thera&; andidenti0& the most sini cant adverse efects thathave been reorted 0or each trial.

7. ,denti0& the three mar%eted ene thera& roductsin the world and describe the mechanism o0 actions


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