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CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y

m T OR Inhibitors

nan nan

Ev e ro lim us i s a l so i nd i ca t ed f o r s ub e p e ndy mal g ia n t cell astr o c y t o ma (SEGA) assoc i a t ed w it h t ube r ou s scler o sis c o m p le x (TSC) , re n al a ng i o m yo li po m a w it h TS C, p r og ressi v e n e u r o e ndo cri n e t u m o rs o f p a n c r eati c o ri g i n, and advanc e d ho rm on e rece p t o r- po siti v e , HER 2 - n e g a tive br east c ance r i n co m b i na ti on wit h e x emesta n e . T h e m o st c o mm on a dv e r se r eac ti ons we r e s t o m a titis , i n fecti on s , ast h e n ia , fati gu e , c ough, a nd d ia rrh ea . T he m os t co mm on g ra d e 3 / 4 a dv erse reacti on s were i n fecti on s, dy s pn ea , f a ti gue, s t o m a titi s, d e hyd rati on, pn e u m on itis , a bdo mi n al p ai n, and ast h e n ia . Bo t h t e m s ir o lim us and e v er o lim u s are c u rre n tl y b ei ng e v al u ate d in ph ase I thr ough III s t ud i es o f v ari ou s ca n cer t yp es . B y do w n re gu lati ng H I F - 1 i n t h e t u m o r ce ll , m T OR i nh i b it o rs ma y c o m p leme n t t h e e f fects o f TKI s at t h e le ve l o f t he E C ; t hus, t he c o m b i n ati on o f mTOR i nh i b it o rs wit h o t he r

CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y

m T OR Inhibitors

nan nan

ta r g ete d agen t s such as bevac iz u ma b o r s o rafe n i b /s un iti n i b are als o b ei ng i nv esti g at ed.

CLINICAL U T I L ITY O F APPROVED ANTIANGI OGE NIC A GE NTS I N CANCER T HE RA P Y

On the Horizon: Anti-VEGFR2 Monoclonal Antibody

nan nan

On the Horizon: Anti-VEGFR2 Monoclonal Antibody

COMBIN A TI O N THERAPIES

nan nan

COMBIN A TI O N THERAPIES

COMBIN A TI O N THERAPIES

nan nan

T u m or a ng i ogenes i s i s a h i gh l y c o m p le x p r o cess i nvo l v i ng m u lti p le g r owth f act or s and t he ir r ecep t o r s i gn ali ng p at h wa y s . Base d on c u rre n t e v i d e n ce , w it h a few excep ti ons, e f f ec ti v e t h era py will p r ob a b l y rel y on a c o m b i na t o ri a l app r oach t ha t i nvo l v es tar g eti ng m u lti p le p at h wa y s

COMBIN A TI O N THERAPIES

nan nan

sim u lta neous l y . Howeve r , a r e ce n t st udy h as d em on strate d t h at sim u lta neous i nh i b iti on o f t he VEGF a nd EGF p at h wa y s i n c o m b i n ati on w it h c he m o t he r apy sho rt ens rat h er t h a n p r o l ong s PFS as c o m p are d t o i nh i b iti o n o f t he V E G F pa t h wa y al on e i n c o m b i n ati on wit h c h em o t he r ap y . Whe t he r o t h er ta r g ete d a g e n ts e xh i b it b e n eficial e f fect s wh e n c omb i ned w it h V E G F i nh i b it o rs remai n s t o b e i nv esti g ate d. M or e ove r , a nu m be r o f s t ud i es h a v e s ho w n t h at a n tia ng i og e n ic a g e n ts i n c o m b i na ti on w it h che m o t he r apy o r ra d i o t h era py res u lt i n a dd iti v e o r s yn e r g is t i c e f f ec t s. S eve r a l m od els h a v e b ee n p r opo se d t o e xp lai n t h e mec h a n ism r espons i b l e f o r t h is po te n tiati on, k e y i ng i n on t h e c h em o s ens iti z i ng e f f ec t s o f an tia ng i og e n ic t h era p y . O n e hypo t h esis is t hat a n tia ng i ogen i c t he r apy m ay no rmalize t h e t u m o r v asc u lat u re , t hu s res u lt ing i n im pr o ved oxygena ti on, be t t er b l ood p erf u si on, a nd c on se qu e n tl y , im prov e d de li ve r y o f che m o t h era p e u tic d r ug s . A sec ond m od el s ugg e sts t h at c h e mo t he r apy de li ve r ed a t l o w do ses a nd at cl o se , re gu lar i n ter v als w it h no ex t ended d r ug -fr ee b r e a k p eri od s p refere n tiall y d ama g es ECs i n the t u m or neovascu l a t u r e and s upp resses circ u lati ng e ndo t h elial prog e n it o r ce ll s . T h i s r eg ime n, als o calle d metr ono mic c h em o t h era p y , s u stai n s an ti ang i ogen i c ac ti v it y a nd re du ces ac u te t ox icit y . T hu s , t h e e f f icac y o f m e tr ono mi c che m o t h era py ma y i n crease w h e n a d mi n istere d i n c o m b i na ti on w it h spec ifi c an tia ng i og e n ic d r ug s . A no t h er m od el a dd ress es t h e u se o f an ti ang i ogen i c d r ug s t o sl o w do w n t u m o r cell re popu lati on b et w ee n success i ve cyc l es o f cy t o t ox ic c h em o t h era p y . T h is m od el und e r sc o r es t he im po rt ance o f timi ng a nd se qu e n ce i n ac h ie v i ng t h e ma x imal t he r apeu ti c bene fit f ro m c o m b i n ati on t h era p ies . I n fact , a pr ecli n i ca l s t udy i n m u ri ne t u m o r m od els d em on strate d t h at t h e a d mi n is t r a ti on o f sun iti n i b m a r k e d l y re du ce d c h em o t h era py -i ndu ce d bone ma rrow tox i c it y , sugges ti ng that t h e se qu e n tial treatme n t re g ime n ( d eli ve r y of a n tia ng i ogen i cs f o ll owed by c h em o t h era py ) s ho we d s up eri o r s u r v i v al b e n e f its co m pa r ed w it h t he s im u lta n e ou s a d mi n istrati on o f tw o d r ug s .

COMBIN A TI O N THERAPIES

nan nan

COMBIN A TI O N THERAPIES

nan nan

Fi n all y , o t he r m echan i s m s t ha t mi gh t als o c on tri bu te t o t h e s yn er g ism i n cl ud e ang i ogenes i s i nh i b it o r – i ndu ce d t u m o r b l ood v essel re g ressi on, t he pr e v e n ti on o f t u m o r coop ti ng o f v essels fr o m s u rr ound i ng h ealt hy tiss u es ,

COMBIN A TI O N THERAPIES

nan nan

a nd t h e fo rm a ti on o f abno rm al v essels i n t h e t u m o r micr o e nv ir on me n t .

COMBIN A TI O N THERAPIES

nan nan

COMBIN A TI O N THERAPIES

nan nan

N e v e r t he l ess, it r e m a i ns a cha lle ng e t o d etermi n e w hy b e v aciz u ma b h as prov e d la r ge l y i ne f f ec ti ve as a si ng le a g e n t , w h ereas VEGF R TK i nh i b it o r s h a v e r ep ea t ed l y f a il ed i n r ando mize d ph ase III trials w h e n u se d i n c o m b i na ti on w it h che m o t he r ap y . F u rt h erm o re , a n a dd iti on al c h alle ng e i s to d ete r mi ne t he op tim a l dose and du rati on o f a n tia ng i og e n ic d r ug s as well as t h e im pac t o f d r ug sequenc i ng i n c o m b i n ati on re g ime n s . St ud ies are w a rr a n t ed t o de li nea t e t he d i sc re p a n c y o f b e v aciz u ma b ’ s e f ficac y i n t h e mac ro m e t as t a ti c ve r sus mi c r o metastatic d isease setti ng s .

BIOMARKERS OF AN T IANG I OGENIC T HE RA P Y

nan nan

BIOMARKERS OF AN T IANG I OGENIC T HE RA P Y

BIOMARKERS OF AN T IANG I OGENIC T HE RA P Y

nan nan

VEG FR 1 exp r ess i on and poor b e v aciz u ma b treatme n t ou tc o mes .

BIOMARKERS OF AN T IANG I OGENIC T HE RA P Y

nan nan

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

D es p ite a decade o f tri a l s w it h a ng i og e n esis i nh i b it o rs , cli n ical e xp erie n c e r e v eals t ha t V E G F-t a r ge t ed thera py o fte n p r o l ong s t h e s u r v i v al o f ca n cer p atie n ts b y on l y m on t hs becau se t u m o rs elicit e v asi v e resista n ce .

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

Resista n c e t o V E G F i nh i b it o r s ma y b e ob ser v e d i n late-sta g e t u m o rs w hen t u m or s reg r ow du ri ng tr ea tme n t after a n i n itial p eri od o f g r o wt h s uppr es s i on fr o m t hese an ti ang i og e n ic a g e n ts . T h is resista n ce i nvo l v es t he r eacti v a t i on o f t u m o r ang i ogen esis a nd i n crease d e xp ressi on o f o t h er pro a ng i ogen i c f ac t o r s. As t he d isease p r og resses , it is po ssi b le t h at r e dund a n t pa t hways mi gh t be im p licate d, wit h VEGF b ei ng re p lace d by o t h e r a ng i ogen i c pa t hways, wa rra n ti ng t h e a dd iti on o f a sec ond a ng i og e nes i s i nh i b it o r t ha t wou l d ta r g et t h ese sec ond ar y g r o wt h fact o rs a nd / or t he ir ac ti va t ed r ecep t o r p at h wa y s , o r t h e u se o f a m u ltita r g ete d T K I a n tia ng i ogen i c d r ug ( e.g., sun iti n i b, s o rafe n i b ) . H o we v e r , resista n ce t o t hese drug s e ven t ua ll y occu r s, im p l i cati ng t h e e x iste n ce o f a dd iti on al p at h wa ys me d iati ng r es i s t ance t o an ti ang i og e n ic t h era p ies . M o re ov e r , t u m o r cells b ea r i ng gene ti c a lt e r a ti ons o f th e p53 g e n e ma y d is p la y a l o wer a pop t o si s r ate unde r hypox i c cond iti ons, w h ic h mi gh t re du ce t h eir relia n ce on v asc u la r supp l y and, t he r e f o re , t h eir res pon si v e n ess t o a n tia ng i og e n ic t h e r a p y T he se l ec ti on and ov e r g r o wt h o f t u m o r - v aria n t cells t h at are hypox ia r es i s t an t and, t hus, l es s d e p e nd e n t on a ng i og e n esis a nd v asc u lat u r e r e m ode li ng, r esu l t i ng i n v essel sta b ilizati on , c ou l d als o e xp lai n t he r es i s t ance t o an ti a n g i og e n ic d r ug s . Ot h er po ssi b le mec h a n is ms for ac qu ir ed r es i s t ance i nc l ud e t u m o r v essels b ec o mi ng less se n siti v e t o a n tia ng i ogen i c agen t s, t u m o r r e g r o wt h v ia re bound re v asc u larizati on, a nd v essel c oop ti on . – P e r haps on e o f t h e m o st i n tri gu i ng fi nd i ng s is t h at , alt hough E Cs a r e assu m ed t o b e g e n eticall y sta b le , t h e y ma y und er s o m e ci r c u ms tances ha r bo r gene ti c abno rmalities a nd t hu s ac qu ire resista n ce as w ell

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

Rece n t s t ud i es r epo rt t ha t V EGF-ta r g ete d t h era p ies no t on l y i ndu ce pr ima ry t u m o r sh ri nkage and inh i b it t u m o r p r og ressi on, bu t ca n als o i n iti ate mec h a n ism s t ha t i nc r ease m a li gn a n c y t o p r o m o te t u m o r i nv asi v e n ess a nd metasta s i s . T hese m ech a n isms o f resista n ce t o a n tia ng i og e n ic t h e r a py i nvo l ve t u m o r - and ho st-me d iate d p at h wa y s a nd ma y all o w f o r d i f f e r e n ti a l e f fi cacy i n d i f f e r en t sta g es o f d isease p r og ressi on .

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

S p eci f ic a ll y , an ti ang i ogen i c d r ug– resista n ce mec h a n isms i nvo l v e p at h wa ys me d iated by t he t u m o r , whe t h er i n tri n sic o r ac qu ire d i n res pon se t o t h er apy or by t he hos t , wh i ch i s e it he r res pond i ng d irectl y t o t h era py o r i nd irectl y to t u m or al cues. T aken t oge t he r , a n tia ng i og e n ic t h era py ca n e nh a n ce t u m o r i nv asi v e ness and m e t as t as i s t o facilitate a nd / o r accelerate d isease i n mic ro sco p i c t u m o r s and, hen ce , re du ce OS b e n efit . U nd ersta nd i ng t h e mec h a n ism s o f r es i s t ance, whe t h er i n tri n sic o r ac qu ire d, after e xpo s u re t o a n tia ng i ogen i c d r ug tr ea tm en t is esse n tial f o r d e v el op i ng strate g ies t h at will all ow fo r op tim a l exp l o it a ti on o f VEGF i nh i b it o rs . It is e qu all y im po rtan t to i d e n ti fy b i o m a r ke r s o f d r ug resista n ce a nd fact o rs me d iati ng t h is resistan ce b eca u se t he deve l op m en t o f r e lia b le b i o mar k ers ca n b e i nv al u a b le t o m on it or t he deve l op m en t o f ev asi v e resista n ce t o a ng i og e n esis i nh i b it o r s.

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

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Hanahan D, W einbe r g RA. Hallmarks of cancer: the next generation. Cell 20 1 1;144:646–674. Ide AG, Baker NH, W arren SL. V ascularization of the Brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamge r . Am J Roentgenol 1939;42:891–899. Algire GH, Chalkley H W , Legallais F Y , et al. V ascular reactions of normal and malignant tissues in vivo. I. V ascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 1945;6:73–85. Folkman J, Merler E, Abernathy C, et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971;133:275–288. Folkman J. T umor angiogenesis: therapeutic implications. N Engl J Med 1971;285: 1 182– 1 186. Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 2002;282:C947–C970. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–364. Black WC, W elch HG. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therap y . N Engl J Med 1993;328:1237–1243. Folkman J, Kalluri R. Cancer without disease. Natu r e 2004;427:787.

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

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W eidner N, Semple J P , W elch WR, et al. T umor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 1991;324:1–8. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995;1:149–153. Naumov GN, Bender E, Zurakowski D, et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst 2006;98:316–325. Udagawa T , Fernandez A, Achilles EG, et al. Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormanc y . Faseb J 2002;16:1361– 1370. Holash J, Maisonpierre PC, Compton D, et al. V essel cooption, regression, and growth in tumors mediated by angiopoietins and VEG F . Science 1999;284:1994–1998. Relf M, LeJeune S, Scott P A, et al. Expression of the angiogenic factors vascular endothelial cell growth facto r , acidic and basic fibroblast growth facto r , tumor growth factor beta-1, platelet-derived endothelial cell growth facto r , placenta growth facto r , and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 1997;57:963–969. Carmeliet P , Dor Y , Herbert JM, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Natu r e 1998;394:485–490. Folkman J. Endogenous angiogenesis inhibitors. Apmis 2004; 1 12:496–507. Nybe r g P , Xie L, Kalluri R. Endogenous inhibitors of angiogenesis. Cancer Res 2005;65:3967–3979. Rak J, Y u JL. Oncogenes and tumor angiogenesis: the question of vascular “supply” and vascular “demand”. Semin Cancer Biol 2004;14:93–104. Bottos A, Bardelli A. Oncogenes and angiogenesis: a way to personalize anti-angiogenic therapy? Cell Mol Life Sci 2013;70:4131–4140. Rak J, Y u JL, Klement G, et al. Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Investig Dermatol Symp P r oc 2000;5:24–33. Langer R, Brem H, Falterman K, et al. Isolations of a cartilage factor that inhibits tumor neovascularization. Science 1976;193:70–72. Langer R, Conn H, V acanti J, et al. Control of tumor growth in animals by infusion of an angiogenesis inhibito r . P r oc Natl Acad Sci U S A 1980;77:4331–4335. Ribatti D. Endogenous inhibitors of angiogenesis: a historical revie w . Leuk Res 2009;33:638–644. Folkman J. Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Exp Cell Res 2006;312:594–607. Karamouzis M V , Moschos SJ. The use of endostatin in the treatment of solid tumors. Expert Opin Biol Ther 2009;9:641–648. Lawler J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med 2002;6:1–12. Maeshima Y , Manfredi M, Reimer C, et al. Identification of the anti-angiogenic site within vascular basement membrane-derived tumstatin. J Biol Chem 2001;276:15240–15248. Kerbel RS. V asohibin: the feedback on a new inhibitor of angiogenesis. J Clin Invest 2004; 1 14:884– 886. Sato Y . The vasohibin family: a novel family for angiogenesis regulation. J Biochem 2013;153:5– 1 1. Noguera- T roise I, Daly C, Papadopoulos NJ, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Natu r e 2006;444:1032–1037. Ridgway J, Zhang G, W u Y , et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Natu r e 2006;444:1083–1087.

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

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Kuhnert F , Kirshner JR, Thurston G. Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. V asc Cell 20 1 1;3:20. Sund M, Hamano Y , Sugimoto H, et al. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. P r oc Natl Acad Sci U S A 2005;102:2934–2939. Dameron KM, V olpert O V , T ainsky MA, et al. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994;265:1582–1584. Zhang L, Y u D, Hu M, et al. W ild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res 2000;60:3655–3661. Sherif ZA, Nakai S, Pirollo K F , et al. Downmodulation of bFGF-binding protein expression following restoration of p53 function. Cancer Gene Ther 2001;8:771–782. Ravi R, Mookerjee B, Bhujwalla ZM, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 2000;14:34–44. Farhang Ghahremani M, Goossens S, Nittner D, et al. p53 promotes VEGF expression and angiogenesis in the absence of an intact p21-Rb pathwa y . Cell Death Differ 2013;20:888–897. T eodoro JG, Parker AE, Zhu X, et al. p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science 2006;313:968–971. Folkman J. T umor suppression by p53 is mediated in part by the antiangiogenic activity of endostatin and tumstatin. Sci STKE 2006;2006:pe35. Brouty-Boye D, Zetter BR. Inhibition of cell motility by interferon. Science 1980;208:516–518. Dvorak H F , Gresser I. Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumors in mice. J Natl Cancer Inst 1989;81:497–502. Sidky Y A, Borden EC. Inhibition of angiogenesis by interferons: effects on tumo r - and lymphocyte-induced vascular responses. Cancer Res 1987;47:5155–5161. T aylor S, Folkman J. Protamine is an inhibitor of angiogenesis. Natu r e 1982;297:307–312. Crum R, Szabo S, Folkman J. A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment. Science 1985;230:1375–1378. Ingber D, Fujita T , Kishimoto S, et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Natu r e 1990;348:555–557. Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 1991;13:31–36. Folkman J. Angiogenesis: an o r ganizing principle for drug discovery? Nat Rev Drug Discov 2007;6:273–286. D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. P r oc Natl Acad Sci U S A 1994;91:4082–4085. Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol 1998;55:1827–1834. Figg WD. The 2005 Leon I. Goldbe r g Y oung Investigator A ward Lecture: development of thalidomide as an angiogenesis inhibitor for the treatment of androgen-independent prostate cance r . Clin Pharmacol Ther 2006;79:1–8. Kenyon BM, Browne F , D’Amato RJ. E f fects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997;64:971–978. Price DK, Ando Y , Kruger EA, et al. 5’-OH-thalidomide, a metabolite of thalidomide, inhibits angiogenesis. Ther Drug Monit 2002;24:104– 1 10.

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

Dredge K, Marriott JB, Macdonald CD, et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 2002;87: 1 166– 1 172. Gupta D, T reon S P , Shima Y , et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001;15:1950–1961. Ng SS, Gutschow M, W eiss M, et al. Antiangiogenic activity of N-substituted and tetrafluorinated thalidomide analogues. Cancer Res 2003;63:3189–3194. Zhang H, V akil V , Braunstein M, et al. Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood 2005;105:3286–3294. De Sanctis JB, Mijares M, Suarez A, et al. Pharmacological properties of thalidomide and its analogues. Recent Pat Inflamm Alle r gy Drug Discov 2010;4:144–148. Ferrara N, Gerber H P , LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–676. Lindahl P , Johansson BR, Leveen P , et al. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997;277:242–245. Oliner J, Min H, Leal J, et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 2004;6:507–516. Fingleton B. MMPs as therapeutic targets—still a viable option? Semin Cell Dev Biol 2008;19:61–68. Roy R, Y ang J, Moses MA. Matrix metalloproteinases as novel biomarkers and potential therapeutic ta r gets in human cance r . J Clin Oncol 2009;27:5287–5297. Shi ZG, Li J P , Shi LL, et al. An updated patent therapeutic agents ta r geting MMPs. Recent Pat Anticancer Drug Discov 2012;7:74–101. Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological ta r geting. FEBS J 20 1 1;278:16–27. Nikolopoulos SN, Blaikie P , Y oshioka T , et al. Integrin beta4 signaling promotes tumor angiogenesis. Cancer Cell 2004;6:471–483. Bradley DA, Daignault S, R yan CJ, et al. Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium. Invest New Drugs 20 1 1;29:1432–1440. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010;10:9–22. Hersey P , Sosman J, O’Day S, et al. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or − dacarbazine in patients with stage IV metastatic melanoma. Cancer 2010; 1 16:1526–1534. Heidenreich A, Rawal SK, Szkarlat K, et al. A randomized, double-blind, multicente r , phase 2 study of a human monoclonal antibody to human alphanu integrins (intetumumab) in combination with docetaxel and prednisone for the first-line treatment of patients with metastatic castration-resistant prostate cance r . Ann Oncol 2013;24:329–336. O’Day S, Pavlick A, Loquai C, et al. A randomised, phase II study of intetumumab, an anti-alphav-integrin mAb, alone and with dacarbazine in stage IV melanoma. Br J Cancer 20 1 1;105:346–352. Stupp R, Hegi M, Gorlia T , et al. Standard chemoradiotherapy ± cilengitide in newly diagnosed glioblastoma (GBM): updated results and subgroup analyses of the international randomized phase III CENTRIC trial (EO R TC trial #26071-22072/Canadian Brain T umor Consortium). Program and abstracts presented at: 2013 European Cancer Congress; 2013; Amsterdam. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activit y . Nat Rev Cancer 2008;8:579–591.

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

Jain RK, Duda DG, W illett CG, et al. Biomarkers of response and resistance to antiangiogenic therap y . Nat Rev Clin Oncol 2009;6:327–338. Murukesh N, Dive C, Jayson GC. Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer 2010;102:8–18. Davis D W , McConkey DJ, Abbruzzese JL, et al. Surrogate markers in antiangiogenesis clinical trials. Br J Cancer 2003;89:8–14. W ehland M, Bauer J, Magnusson NE, et al. Biomarkers for anti-angiogenic therapy in cance r . Int J Mol Sci 2013;14:9338–9364. Lambrechts D, Lenz HJ, de Haas S, et al. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol 2013;31:1219–1230. Lambrechts D, Claes B, Delmar P , et al. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the A V i T A and A VOREN randomised trials. Lancet Oncol 2012;13:724–733. Schneider B P , W ang M, Radovich M, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 2008;26:4672–4678. Hurwitz HI, Douglas PS, Middleton J P , et al. Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies. Oncologist 2013;18:273–280. Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet 2009;41:677–687. Batchelor T T , Sorensen AG, di T omaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibito r , normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007; 1 1:83–95. Sennino B, McDonald DM. Controlling escape from angiogenesis inhibitors. Nat Rev Cancer 2012;12:699–709. Y u JL, Rak J W , Coomber BL, et al. E f fect of p53 status on tumor response to antiangiogenic therap y . Science 2002;295:1526–1528. Glade Bender J, Cooney EM, Kandel JJ, et al. V ascular remodeling and clinical resistance to antiangiogenic cancer therap y . Drug Resist Updat 2004;7:289–300. Be r gers G, Hanahan D. Modes of resistance to anti-angiogenic therap y . Nat Rev Cancer 2008;8:592– 603. Crawford Y , Ferrara N. T umor and stromal pathways mediating refractoriness/resistance to anti-angiogenic therapies. T r ends Pharmacol Sci 2009;30:624–630. Ebos JM, Lee CR, Kerbel RS. T umor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therap y . Clin Cancer Res 2009;15:5020–5025. Kerbel RS, Y u J, T ran J, et al. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev 2001;20:79–86. Shojaei F , Ferrara N. Role of the microenvironment in tumor growth and in refractoriness/resistance to anti-angiogenic therapies. Drug Resist Updat 2008; 1 1:219–230. Sweeney CJ, Miller KD, Sledge GW J r . Resistance in the anti-angiogenic era: nay-saying or a word of caution? T r ends Mol Med 2003;9:24–29. Hida K, Hida Y , Amin DN, et al. T umo r -associated endothelial cells with cytogenetic abnormalities. Cancer Res 2004;64:8249–8255.

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

nan nan

Streubel B, Chott A, Huber D, et al. L ymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N Engl J Med 2004;351:250–259. Loges S, Mazzone M, Hohensinner P , et al. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 2009;15:167–170.

RES I S T ANCE T O AN T IANG I OGENIC T HE RA P Y

Monoclon a l Antibod i es

nan nan

Monoclon a l Antibod i es

IN T RODUCTION

nan nan

An ti body - based t he r apeu ti cs a re im po rta n t c o m pon e n ts o f t h e ca n cer t h e r a p euti c a rm a m en t a ri u m . Earl y a n ti body t h era py st ud ies attem p te d t o e xp licitl y t a r ge t cance r s based on t h e str u ct u ral a nd b i o l og ic p r op erties t hat d isti ngu i sh neop l as ti c ce ll s fr o m t h eir no rmal c oun ter p arts . T h e imm unogen i c it y and i ne f fi c i en t e f fect o r f un cti on s o f t h e first- g e n erati on m ur i n e monoc l ona l an ti bod i e s (MA b ) t h at were e v al u ate d i n cli n ical tria ls limite d t he ir e f f ec ti veness. Patie n ts d e v el op e d hu ma n a n tim ou se a n ti body (HA M A) r esponses aga i ns t t h e t h era p e u tic a g e n ts t h at ra p i d l y cleare d it fro m t he body and limit ed t he nu m b er o f times t h e t h era py c ou l d b e a d mi n is te r ed. T he deve l op m en t o f e ng i n eere d c h imeric , hu ma n ize d, a nd fu ll y hu m an MAbs has i den tifie d a nu m b er o f im po rta n t a nd u sef u l a pp licat ions f o r an ti body - bas e d ca n cer t h era p y . C u rre n tl y , t h e U . S . F ood a nd Drug Ad mi n i s tr a ti on (F D A) h as a pp r ov e d 14 MA b s a nd MA b -c on j ug a tes f o r t he tr ea tm en t o f ca n cer ( ) a nd ma ny m o re are und e r e va l ua ti on i n l a t e - s t age cli n ical trials . A n ti bod ies p r ov i d e a n im por ta n t m eans by wh i ch t o exp l o it t h e imm un e s y stem by s p ecificall y r ec ogn i z i ng and d ir ec ti ng an t i t u m o r res pon ses .

IMMUNOGLOBU L IN STRUC T URE

nan nan

IMMUNOGLOBU L IN STRUC T URE

IMMUNOGLOBU L IN STRUC T URE

Structural and Functional Domains

nan nan

An IgG m o l ecu l e i s t yp i ca ll y di v i d e d i n t o t h ree do mai n s c on sisti ng o f t wo i d e n tica l an ti gen - b i nd i ng (F ab ) do mai n s c onn ecte d t o a n effect o r o r Fc do mai n by a fl ex i b l e h i nge sequ e n ce . s ho ws t h e str u ct u re o f an IgG m o le cu l e. I gG an ti bod i es are c o m p rise d o f tw o i d e n tical li gh t c h ai ns a nd t wo i den ti ca l heavy cha i ns, wit h t h e c h ai n s j o i n e d by d is u lfi d e bonds, r es u lti ng i n a b il a t e r a ll y sy m m etrical c o m p le x. T h e Fa b do mai n s me d iat e t h e b i nd i ng o f I gG m o l ecu l es t o t h eir c ogn ate a n ti g e n s a nd are c o m po se d o f a n i n tac t li gh t cha i n and ha lf o f a h ea vy c h ai n. Eac h c h ai n i n t h e Fa b do mai n i s f u rt he r d i v i ded i n t o v aria b le a nd c on sta n t re g i on s , wit h t h e v a r ia b le r eg i on con t a i n i ng hy per v aria b le , o r c o m p leme n tarit y d etermi n i ng r e g i on s ( CDR ) i n wh i ch t he a nti g e n -c on tact resi du es resi d e . T h e li gh t a nd h ea vy c ha i n va ri ab l e r eg i ons eac h c on tai n t h ree CDRs (CDR 1, CDR 2, a nd C D R 3). A ll s i x CDRs f o rm the a n ti g e n - b i nd i ng po c k et a nd are c o llecti v e ly d e f i n e d i n imm uno l og i c t e rm s as t h e i d i o t yp e o f t h e a n ti bod y . I n t h e maj or it y o f cases, t he va ri ab l e h ea vy c h ai n CDR 3 p la y s a do mi n a n t r o le in b i nd i ng.

IMMUNOGLOBU L IN STRUC T URE

Structural and Functional Domains

nan nan

Th e d i f f e r en t i so t ypes o f imm unog l obu li n s are d efi n e d by t h e str u ct u r e a nd func ti on o f t he ir F c do m ain s . T h e Fc do mai n, c o m po se d o f t h e CH 2 a nd C H 3 r eg i ons o f t he an ti b o dy ’ s h ea vy c h ai n s , is t h e critical d etermi n a nt of how an an ti body m ed i a t es e f fect o r f un cti on s , tra n s po rts acr o ss cell u lar b a rr ie r s , and pe r s i s t s i n c ir cu lati on .

MO D I F IED AN T IBOD Y -BASED MOL E CUL E S

nan nan

MO D I F IED AN T IBOD Y -BASED MOL E CUL E S

MO D I F IED AN T IBOD Y -BASED MOL E CUL E S

nan nan

Adv a n ce s i n an ti body eng i ne eri ng a nd m o lec u lar b i o l ogy h a v e facilitated t h e d e v e lop m en t o f m any nov el a n ti body - b ase d str u ct u res wit h un i qu e phy sical and pha rm acok i ne ti c p r op erties (see ) . T h ese i n cl ud e c h ime r i c hu m an -m u ri ne an ti bod ies wit h hu ma n -c on sta n t re g i on s a nd m ur i n e -va ri ab l e r eg i ons hu ma n ize d a n ti bod ies i n w h ic h m u ri n e CDR se qu e n c es have been g r a ft ed int o hu ma n I g G m o lec u les , a nd e n tirel y hu m an a n ti bod i es de ri ved fr o m hu ma n hyb ri do mas a nd, m o re rece n tl y , fr o m t r a n s g e n i c mi ce exp r ess i ng h uma n imm unog l obu li n g e n es . A n acce p te d n ami ng sche m e based on “s t em s” was d e v el op e d by t h e W o rl d Healt h

MO D I F IED AN T IBOD Y -BASED MOL E CUL E S

nan nan

O r g a n izati on ’ s I n t e r na ti ona l Nonp r op rietar y Names (INN) f o r ph a r ma ceu ti ca l s and i s e m p l oy e d i n t h e U n ite d States ( . Eng i n eeri ng has a l so f ac ilit a te d t h e d e v el op me n t o f a n ti body - b ase d fr a g me n t s. I n add iti on t o t he c lassic , e n z y maticall y d eri v e d Fa b a nd F(a b′ ) 2 m o lec u l es, a p l e t ho r a o f p r om isi ng I g G- d eri v ati v es h a v e b ee n d e v el op e d t h at r etai n an ti gen - b i nd i ng p r op erties o f i n tact a n ti bod ies (see f o r r e v ie w s ee Rob i nson e t a l . . T h e b asic bu il d i ng b l o c k f o r t h ese m o lec ules is t h e 25 kDa, m onova l en t s i ng le-c h ai n F v (scF v ) t h at is c o m p rise d o f t he v a r ia b le do m a i ns ( V H and V L ) o f a n a n ti body f u se d t og et h er wit h a s ho rt p e p ti d e li nke r . Nove l , b i spec i f ic a n ti body - b ase d str u ct u res ca n facilitate b i nd i ng t o t wo t u m o r an ti gen s o r b ri dg e t u m o r cells wit h imm un e e f fect o r cells t o f ocus an ti body - depend e n t cell-me d iate d c y t o t ox icit y (ADCC) o r k illi ng b y T ce ll s. An exa m p le o f t h e f o rmer is MM- 1 1 1, a b is p ecific g e ne - fu se d m o l ecu l e co m posed o f a n a n ti-HER 2 scF v c onn ecte d t o a n a n ti-H E R 3 scF v v ia a m od ifi ed f o rm o f hu ma n ser u m al bu mi n E x am p les o f t h e la tte r mec h a n ism i nc l ude s m a ll sc F v - b ase d b is p ecific T -cell e ng a g ers (BiTE) s u c h as the an ti- CD3 / an ti- CD19 m o lec u le b li n at u m o ma b a nd la r g er M Ab - b ase d a n ti bod i es such as ca t u ma xo ma b, a rat/m ou se a n ti-CD 3 /E p CAM b is p eci f i c MAb p r oduced v i a qu a d r o ma tec hno l og y B o t h classes o f b is p eci f i cs endow se l ec ti v it y and tar g eti ng p r op erties t h at are no t ob tai nable w it h n at u r a l an ti body f o rm a t s.

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

nan nan

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

Antibody Size

nan nan

Nonun i fo rm d i s tri bu ti on o f sy stemicall y a d mi n istere d a n ti body is g e n era lly ob se rv e d i n b i ops i ed spec im e ns o f s o li d t u m o rs . Heter og e n e ou s t u m o r b l ood su pp l y limit s un if o rm an ti body d eli v er y t o t u m o rs , a nd ele v ate d i n te r stiti a l p r essu r es i n t he ce nter o f t u m o rs oppo se i n war d d iff u si on T his h i gh i n ter s titi a l p r essu r e s l ow s t h e d i f f u si on o f m o lec u les fr o m t h eir v asc u la r ex tr avasa ti on s it e i n a size- d e p e nd e n t ma nn e r . T h e relati v ely la r g e t r a nspo rt d i s t ances i n t he t u m o r i n terstiti u m als o s ub sta n tiall y i n cr ease t h e time r equ ir ed f o r l a r ge I gG macr o m o lec u les t o reac h ta r g et cells .

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

T umor Antigens

nan nan

T umor Antigens

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

T umor Antigens

nan nan

A ccess to t he t a r ge t an ti gen i s undoub te d l y a critical d etermi n a n t o f t h e r a p euti c e f f ec t o f an ti body - b ase d a pp licati on s . S u c h access is re gu lat ed

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

T umor Antigens

nan nan

by t h e he t e r ogene it y o f an ti gen e xp ressi on by t u m o r cells . S h e d a n ti g e n in t h e se ru m , t u m o r mi c r oenv ir o nme n t , o r bo t h ma y sat u rate t h e a n ti body ’ s b i nd i ng s it es and p r even t b i nd i ng t o t h e cell s u rface . Alter n ati v el y , a ra pid i n te rn ali za ti on o f an an ti body/ a n ti g e n c o m p le x, alt hough critical f o r a n ti body–d r ug con j uga t es ( AD C) , ma y d e p lete t h e qu a n tit y o f cell s u rfa ce M Ab ca pab l e o f i n iti a ti ng A DCC o r c y t o t ox ic si gn al tra n s du cti on e v e n t s. Fi n all y , t a r ge t an ti gens a r e no rmall y t u m o r a ss o ci a te d rat h er t h a n t u m o r s p ecifi c . T u m o r - spec ifi c an ti g e n s are bo t h h i gh l y d esira b le a nd rare . T yp icall y , such an ti gens a ri se as a res u lt o f un i qu e t u m o r - b ase d g e n etic r ec o m b i na ti ons, such as c l ona l imm unog l obu li n i d i o t yp es e xp resse d on the s urf ace o f B - ce ll l y m pho m as An ti body a f fi n it y f o r it s t a r g et a n ti g e n h as c o m p le x e f fects on t u m o r ta r g eti ng. T he b i nd i ng - s it e bar rier hypo t h esis po st u lates t h at a n ti bod ies w it h e x tr e m e l y h i gh a f fi n it y f o r ta r g et a n ti g e n w ou l d b i nd irre v ersi b l y t o the f i r st a n tig en encoun t e r ed upon e n teri ng t h e t u m o r , w h ic h w ou l d limit t he d i f fu si on o f t he an ti body i n t o t h e t u m o r a nd acc u m u late i n stea d i n re g i ons s urround i ng t he t u m o r vascu lat u re . Similarl y , i n t u m o r s ph er o i d s , t h e in v it ro p e ne tr a ti on o f eng i nee r e d a n ti bod ies is p rimaril y limite d by i n te rn ali za ti on and deg r ada ti on T h e v ale n ce o f a n a n ti body m o lec u le c an i n c r ease t he f unc ti ona l a f fi n it y o f t h e a n ti body t h r ough a n a v i d it y e f fect

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

Half-Life/Clearance Rate

nan nan

Half-Life/Clearance Rate

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

Glycosylation

nan nan

Glycosylation

F AC T ORS REGU L A TING ANTIBOD Y -BA S ED TUMOR T AR GET ING

Glycosylation

nan nan

IgG s unde r go N -li nked g l yco s y lati on at t h e c on ser v e d As n resi du e at po siti on 297 w it h i n t he C H 2 do mai n o f t h e c on sta n t re g i on. Gl y c o s y lati on stat u s of t he r es i due has l ong b ee n kno w n t o im p act t h e a b ilit y o f I g Gs t o b i nd e f f e c t o r li gands such as FcγR a nd C 1q, w h ic h, i n t u r n, a f fects t h eir a b ilit y t o pa rti c i pa t e i n F c -m ed iate d f un cti on s s u c h as ADCC a nd c o m p lem en t- dependen t cy t o t ox icit y (CDC) . T h e g l y c o s y lati on o f M Abs ca n b e alt e r ed t o i nc r ease ADC C by p r odu ci ng t h em i n a cell li n e e ng i n ee red t o exp r ess β( 1,4 )-N-acet y l g l u c o sami ny ltra n sferase III (G n TIII) , t h e e n z yme r equ ir ed t o add t h e b isecti ng GlcNAc resi du es . Def u c o s y la tion of a n ti body F c do m a i ns i s a l s o ass o ciate d wit h e nh a n ce d ADCC , a nd i n a r ece n tl y co m p l e t ed m u lti cen ter ph ase II trial o f a d ef u c o s y late d a n ti-CC c h em okine r ecep t o r 4 ( CCR4), MA b was ass o ciate d wit h mea n i ng f u l a n tit u m o r ac ti v it y , i nc l ud i ng c o m p lete res pon ses a nd e nh a n ce d p r og ressi on - fr ee s urv i va l (PFS) .

UNC O NJUG A TED ANTIBODIES

nan nan

UNC O NJUG A TED ANTIBODIES

UNC O NJUG A TED ANTIBODIES

nan nan

Th e maj o rit y o f m onoc l ona l an ti bod ies a pp r ov e d f o r cli n ical u se d is p la y i n t r i n sic an tit u m o r e f f ec t s t hat are me d iate d by on e o r m o re o f t h e f o ll owing mec h a n ism s.

UNC O NJUG A TED ANTIBODIES

Cell-Mediated Cytotoxicity

nan nan

A s c o mp onen t s o f t he imm un e s y stem , e f fect o r cells s u c h as n at u ral k ill e r (NK) cell s and m onocy t es /macr oph a g es re p rese n t n at u ral li n es o f d efe nse a g ai n st onco l og i ca ll y tr ans f o r m e d cells . T h ese effect o r cells e xp ress Fcγ r ece p t ors (F cγR ) on t he ir ce ll s u rfaces , w h ic h i n teract wit h t h e Fc do mai n o f IgG m o le cu l es. T h i s f a mil y i s c o m p rise d o f t h ree classes (t yp e I , II , a nd III) t h at a r e fu rt he r d i v i ded i n t o sub classes (IIa/II b a nd IIIa/III b ) . Rec ogn it ion of t r a n s f orm ed ce ll s by imm un e e f fect o r cells lea d s t o cell-me d iate d k ill ing

UNC O NJUG A TED ANTIBODIES

Cell-Mediated Cytotoxicity

nan nan

ca p a b le o f b i nd i ng t o m ono meric I g G , o r FcγRII (CD 32 ) a nd FcγRIII ( C D16), wh i ch a r e l ow a f fi n it y rece p t o rs t h at p refere n tiall y b i nd m u ltim e r ic c o m p le xes o f I gG. Si gna li ng th r ough t yp e I , IIa , a nd IIIa rece p t o rs res u lt s in t h e activ a ti on o f e f f ec t o r ce ll s du e t o ass o ciate d imm uno rece p t o r t y r o si n e- b ase d a c ti va ti on m o tif s (I T AM ) , w h ereas t h e e ng a g eme n t o f t yp e II b r ece p t ors i nh i b it s ce ll ac ti va ti on t h r ough ass o ciate d imm uno rece p t o r t yro si n e -based i nh i b it o r y m o t i fs (ITIM) . Cli n ical res u lts s uppo rt t h e i d e a t h at ADCC can p l ay a r o l e i n t h e e f ficac y o f a n ti body - b ase d t h era p ies . N at ur all y occu rri ng po l y m o r ph isms i n FcγRs alter t h eir affi n it y f o r hu m an IgG1 a nd have been li nked t o cli n ical res pon se . A po l y m o r ph ism i n th e FC G R 3A gene r esu lt s i n e it h er a v ali n e o r ph e ny lala n i n e at po siti on 158 o f FcγR IIIa. Hu m an I gG1 b i nds m o re str ong l y t o FcγRIIIa- 158 V t h a n FcγR IIIa - 158 F , and li kew i se to NK cells fr o m i nd i v i du als t h at are eit h er ho m o z ygous f o r 158 F o r he t e r o z ygou s f o r t h is po l y m o r ph ism T h e FcγR IIIa - 158v was a p r ed i c t o r o f earl y res pon se a nd was ass o ciate d wit h im prov e d PFS . A second po l y m o r ph ism , FcγRIIa- 131 H/R , d i d no t p re d i ct ea r l y r es ponse bu t was an i nd e p e nd e n t p re d ict o r o f time t o p r og ressi on (TT P ). T aken t oge t he r , t hese d ata s ugg est t h at m odu lati ng t h e a f fi n it y o f M Ab s f or F cγR III a, F cγR II a, o r bo t h ma y i n crease t h e efficac y o f t h e r a p euti c MAbs.

UNC O NJUG A TED ANTIBODIES

Cell-Mediated Cytotoxicity

nan nan

E ac h c l ass o f F cγR exh i b its a c h aracteristic s p ecificit y f o r I g G s ub class es . Many g r oups hav e f o c u se d on m od if y i ng t h e Fc do mai n o f IgG s t o op timi ze t he engage me n t o f s ub classes o f FcγR a nd t h e i ndu cti on o f AD CC , based on t he fi nd i ngs o f S h iel d s et al . , w ho p erf o rme d a series o f m u ta g e nes i s expe rim en t s t o ma p t h e resi du es re qu ire d f o r I g G 1 -FcγR i n te r acti on. An ti bod i es such as o creliz u ma b, a hu ma n ize d v ersi on o f r it ux ima b, have i nc r eased b i nd i ng t o l o w a f fi n it y FcγRIIIa v aria n ts a nd a r e now i n c li n i ca l tri a l s. An alt e r na ti ve t o m od if y i ng t h e Fc re g i on o f MA b s is t o create b is p ec i f ic a n ti bod i es ( bsAbs ) t ha t r ecogn ize bo t h a t u m o r -ass o ciate d a n ti g e n a nd a tri gg er an ti gen p r esen t on t he s u rface o f a n imm un e e f fect o r cell .

UNC O NJUG A TED ANTIBODIES

Cell-Mediated Cytotoxicity

nan nan

Sim u lta neous engage m en t o f bo t h a n ti g e n s ca n re d irect t h e c y t o t ox ic po te n tial o f t he e f f ec t o r ce ll ag ai n st t h e t u m o r S u c h a n ti bod ies are ca p a b le o f e li c iti ng e f f ec t o r fu n cti on a g ai n st t u m o r cell li n es i n v itr o a nd in a n imal m ode l s. T wo H E R - 2 directe d b is p ecific a n ti bod ies , 2 B 1 a nd MD X - H210, have been t es t ed i n pha se I cli n ical trials .

UNC O NJUG A TED ANTIBODIES

Cell-Mediated Cytotoxicity

nan nan

Bis pec ifi c an ti bod i es have a nu m b er o f d isti n cti v e p r op erties , i n cl ud i ng f le x i b le cho i ces o f cy t o t ox i c tri gg er m o lec u les , recr u itme n t o f e f fect o r fun cti on i n t he p r esence o f ex cess I g G , a nd c u st o m tail o ri ng o f t h e a f fi nity of t h e bsAb t o m a t ch e f f ec t o r cell c h aracteristics . T h ese a dv a n ta g es h a ve b ee n f acilit a t ed by im p r oved met hod s o f b sA b p r odu cti on . BiTE a n ti bod i es r ep r esen t a nove l c lass o f b is p ecific , si ng le-c h ai n F v a n ti bod i es .

UNC O NJUG A TED ANTIBODIES

Cell-Mediated Cytotoxicity

nan nan

P ro misi ng r esu lt s have been s ee n i n earl y ph ase cli n ical trials wit h at lea st t wo Bi T E an ti bod i es, one o f w h ic h, b li n at u m o ma b, tar g ets CD 19 /CD 3

UNC O NJUG A TED ANTIBODIES

Cell-Mediated Cytotoxicity

nan nan

P ro misi ng phase I r esu lt s have als o b ee n re po rte d i n a n i n terim a n al y sis o f a n a n ti - E pCAM / an ti- CD3 M T 1 10 BiTE i n t h e setti ng o f a dv a n ce d l ung a nd g ast ro i n t es ti na l t u m o r s

UNC O NJUG A TED ANTIBODIES

Complement-Dependent Cytotoxicity

nan nan

In a dd iti on t o ce ll-m ed i a t ed k illi ng (see p re v i ou s) , MA b s ca n recr u it t h e c o m p lem en t cascade t o k ill ce lls v ia CDC . Alt hough I g M is t h e m o st e f f ecti ve i so t ype f o r co m p l e me n t acti v ati on, it is no t wi d el y u se d i n cli n ic al on c o l og y . Simil a r t o ADCC, the hu ma n I g G s ub class u se d t o c on str u ct a t h e r a p euti c MAb d i c t a t es it s ab ilit y t o elicit CDC; I g G 1 is e x tremel y e f f icie n t a t fi x i ng co m p l e m en t , i n c on trast t o I g G 2 a nd I g G 4 A n ti bod ie s acti v ate co m p l e m en t t h r ough th e classical p at h wa y , by e ng a g i ng m u lti p l e C 1q t o tri gge r ac ti va ti on o f a casca d e o f ser u m p r o teases , w h ic h k ill t h e a n ti body - bound ce ll s . T he a n ti-CD 20 MA b rit ux ima b h as b ee n f ound to d e p e nd in pa rt on CDC f o r it s i n viv o e f ficac y . A n ti body e ng i n eeri ng a ppro ach es have i den tifi ed r es i du es i n t h e C H 2 do mai n o f t h e Fc re g i on t hat eit h e r su pp r ess o r enhance t h e a b ilit y o f rit ux ima b t o b i nd C 1q a nd acti vate C D C . T he ab ilit y t o m an i pul ate c o m p leme n t fi x ati on t h r ough e ng i n eeri ng a ppro ach es wa rr an t s i n v i vo testi ng t o d etermi n e t h e im p act o f t h ese c h a ng es on t he e f fi cacy and t ox icit y o f MA b s .

A L TERING S I G NAL TRANSDUC T ION

nan nan

A L TERING S I G NAL TRANSDUC T ION

A L TERING S I G NAL TRANSDUC T ION

nan nan

Grow t h f ac t o r r ecep t o r s r ep r e se n t a well-esta b lis h e d class o f ta r g ets f o r t h e r a p euti c i n t e r ven ti on. No r m al si gn ali ng t h r ough t h ese rece p t o rs o fte n lea d s t o mit ogen i c and p r osu r v i v al res pon ses . U n re gu late d si gn ali ng, as see n i n a nu m be r o f co mm on c a n cers du e t o rece p t o r ov ere xp ressi on, pro m o te s t u m o r ce ll g r ow t h and i n se n siti v it y t o c h em o t h era p e u tic a g e n t s. Cli n ical ly r e l evan t MAbs can m odu late si gn ali ng t h r ough t h eir ta r g et r ece p t ors t o no rm a li ze ce ll g r o wt h rates a nd se n sitize t u m o r cells t o c y t o t ox i c agen t s. T he b i nd i ng o f cet ux ima b o r p a n it u m u ma b t o t h e e p i d e r m a l g r ow t h f ac t o r r ece pt o r (EGFR) phy sicall y b l o c k s li g a nd b i nd i n g

A L TERING S I G NAL TRANSDUC T ION

nan nan

A L TERING S I G NAL TRANSDUC T ION

nan nan

a nd pr e ven t s t he r ecep t o r fr o m ass u mi ng t h e e x te nd e d c on f o rmati on r e qu i r e d f o r d im e ri za ti on . Pert u z u ma b b i nd s t o t h e d imerizati on do main o f HE R -2, t he r eby s t e ri ca ll y i nh i b iti ng s ub se qu e n t rece p t o r h eter od imeriza tion w it h o t he r li gand - bound f a mil y mem b ers Alter n ati v el y , si gn ali ng t h r ough grow t h f ac t o r r ecep t o r s can b e i nd irectl y m od ifie d by MA b s t h at b i nd t o acti v atin g li gands, as i s seen w it h t h e a n ti –v asc u lar e ndo t h elial g r o wt h f act or (V E G F) MAb, bevac i zu ma b .

IMMUNOCONJ U G A TES

nan nan

IMMUNOCONJ U G A TES

IMMUNOCONJ U G A TES

nan nan

imm unocon j uga t e s tr a t eg i es . Alt hough t h ere are p r o misi ng p recli n ical st ud ies f ew success f u l c li n ical trials h a v e b ee n re po rte d u si ng t h is a ppro ach . I n a phase I c li n i cal trial i n h air y cell le uk emia p atie n ts w ho we r e r esista n t t o c l ad ri b i ne, 1 1 o f 16 p atie n ts e xh i b ite d c o m p lete remissi on s with mi n imal s i de e f f ec t s w it h an a n ti-CD 22 imm uno t ox i n wit h a tr un cate d f o r m of P se udomonas exo t ox i n Cli n ical trials wit h o t h er imm uno t ox i n s h a ve b ee n ass oc i a t ed w it h unaccept a b le n e u r o t ox icit y a nd life-t h reate n i ng v asc u la r l eak synd r o m e I mmu nocy t ok i ne f us i ons ha v e als o b ee n i nv esti g ate d as a n a pp r o ac h t o d i r ect t he pa ti en t ’ s imm une r e s pon se t o h is o r h er o w n t u m o r A nu m be r o f c y t ok i nes have been i nco r po r a te d i n t o a n ti body - b ase d c on str u cts , i n cl uding i n te r le uk i n - 2 (IL- 2 ) , i n t e rf e r on γ (IFN-γ) , t u m o r n ecr o sis fact o r α (T F N-α ) , V E G F and IL- 12

IMMUNOCONJ U G A TES

Antibody–Drug Conjugates

nan nan

Antibody–Drug Conjugates

IMMUNOCONJ U G A TES

Antibody–Drug Conjugates

nan nan

Th e f i r s t ADC, ge mt uzu m ab o z og amici n (M y l o tar g ) , was a pp r ov e d by t he F DA i n 2000 f o r t he tr ea tm ent o f p atie n ts wit h rela p se d CD 33 - po siti v e ac u te my e l o i d l euke mi a, bu t w as vo l un taril y wit hd raw n fr o m t h e US mar ket by its m anu f ac t u r e r i n 2010 af ter a c on firmat o r y ph ase III trial (SWOG S 0106) reco mm ended, based on res u lts o f a p la nn e d i n terim a n al y sis , t hat M y l o ta r g r ando mi za ti ons be t e rmi n ate d du e t o a lac k o f efficac y i n t h e pr ese n c e o f enhanced t ox i c it y . Alt hough tw o a dd iti on al ra ndo mize d t r ials sugges t ed t ha t so m e p atie n t popu lati on s ma y b e n efit fr o m M y l o ta r g t he r ap y , t he d r ug r e mai n s o f f t h e mar k et i n t h e U n ite d States . Th e m a j o rit y o f ADCs und er d e v el op me n t em p l oy po te n t c y t o t ox ic a g e n ts t ha t b l ock t he po l y m e r i zati on o f t ubu li n (e .g., a u ristati n s o r ma y ta n si nes ) o r da m age DN A (e .g., calic h eamici n s o r pyrro l obenzod i azep i nes ) by e m p l oy i ng a v ariet y o f li nk ers a nd c on j ug ati on st r ate g ie s A v ari e t y o f ADCs spec ific f o r a wi d e ra ng e o f on c o l ogy tar g ets are c urr e n tly i n c li n i ca l eva l ua ti on, wit h t h e maj o rit y o f t h e m o re a dv a n ce d a g e n ts be i ng t es t ed i n t he se tti ng o f d iff u se mali gn a n cies . T h e maj o rit y o f

IMMUNOCONJ U G A TES

Antibody–Drug Conjugates

nan nan

t h ese em p l oy au ri s t a ti ns o r m ay ta n si n es as t h eir p a y l o a d s . Earl y ob se rv ati ons sugges t t ha t cumu lati v e , do se-relate d p eri ph eral se n s o r y n e urop a thy can r esu lt when au ristati n s are c on j ug ate d t o a n a n ti body v ia a clea v a b l e li nke r , and dose -limiti ng t h r o m bo c y t op e n ia ca n res u lt w h e n a ur istatin s and m ay t ans i no i ds are c on j ug ate d t o t h e a n ti body v ia a n un clea v a b l e li nke r . T wo ADCs a r e now app r ov e d f o r u se i n cli n ical p ractice . A do -t r ast u z u m ab e mt ans i ne ( T - D M 1, Ka d c y la) , a n ADC c o m po se d o f t h e a nti - HE R 2 MAb tr as t uzu m ab li nk e d t o DM 1 is no w a pp r ov e d f o r t h e t r eatme n t o f pa ti en t s w it h r e fr a ct o r y HER 2 / n e u e xp ressi ng b reast ca n cer s. Th e o t h e r , b r en t ux im ab vedo ti n (SGN- 35, A d cetris) , is a n ADC c on sist i ng of t h e a n ti- CD30 ch im e ri c MAb cAC 10 t h at is li nk e d t o t h ree t o fi v e m o lec u l es o f t he mi c r o t ubu l e-d isr up ti ng a g e n t M ono met hy l a u ristati n E . At t h is po i n t , t h i s d r ug i s app r ov e d f o r u se i n p atie n ts wit h rec u rre n t s y stem ic a n a p lasti c l a r ge ce ll l y m phom a . T h e cli n ical d ata ass o ciate d wit h bo t h o f t h ese ADCs w ill be d i scussed i n s ub se qu e n t secti on s o f t h is c h a p te r . An ti bod i es a l so can be used t o ta r g et li po s o me-e n ca p s u late d d r ug and o t h e r c y t o t ox i c agen t s, such a s a n tise n se RN A o r ra d i onu cli d es t o t u m o r s.

IMMUNOCONJ U G A TES

Radioimmunoconjugates

nan nan

T wo a n ti- CD20 r ad i o imm unocon j ug ates h a v e b ee n FDA a pp r ov e d f o r r a d i o imm uno t he r apy ( R IT) o f non -H odgk i n l y m pho ma (NHL) . Ibr it u m o m ab (Z eva li n ) and t o sit u m o ma b (Be xx ar) are m u ri n e MA b s la b ele d wit h y ttri u m- 90 ( 90 Y ) a nd i od i n e- 131 ( 131 I) , res p ecti v el y . B o t h ar e ass o ciate d w it h im p r ess i ve c li n ical efficac y . Alt hough t h ese r a d i o imm unocon j uga t es a r e e f fecti v e t h era p e u tics , c u m b ers o me l og istics s urround i ng t he ir ad mi n i s tr a ti on h a v e si gn ifica n tl y limite d t h eir u se . D es p ite s i gn ifi can t p r ec li n i ca l e v i d e n ce s uppo rti ng t h e u se o f RIT f o r s olid mali gn a nc i es, c li n i ca l r esu lt s ha v e no t d em on strate d c on siste n t a n tit u m o r acti v it y

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

nan nan

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

T rastuzumab

nan nan

T rastuzumab

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

T rastuzumab

nan nan

T r ast u z u m ab ( He r cep ti n ) i s a hu ma n ize d I g G 1 t h at ta r g ets do mai n IV o f t h e HER2 /Er bB2 m e m be r o f th e EGFR/Er b B famil y o f rece p t o r t y r o si ne k i n ases . Gene a m p lifi ca ti on as j udg e d by fl uo resce n ce i n sit u hyb ri d izat ion (FI S H) wit h conco mit an t ove re xp ressi on o f HER 2 p r o tei n meas u re d by imm unoh i s t oche mi s tr y (I HC ) is see n i n a pp r ox imatel y 25 % o f b reast ca n ce r s . H E R2 a m p lifi ca tio n a nd ov ere xp ressi on is no w rec ogn ize d t o als o b e a c riti ca l d ri ve r i n a sub set ( 7 % t o 34 %) o f g astric ca n cers .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

T rastuzumab

nan nan

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

T rastuzumab

nan nan

T r ast u z u m ab i nh i b it s t u m o r c ell g r o wt h by b i nd i ng t o HER 2 a nd b l o c k in g t h e unr e gu l a t ed H E R2 s i gna li ng t h at is ass o ciate d wit h its h i gh le v el ov e r e xp r ess i on. T r ast uzu m ab beca m e t he f i rst FDA-a pp r ov e d m ono cl on al a n ti body f o r t h e t r eatm en t o f so li d t u m o r s b ase d on a series o f st ud ies carrie d ou t i n t he setti ng o f H E R2 - pos iti ve m e t a static b reast ca n ce r . A s ub se qu e n t ph a se III t r ial in ves ti ga ti ng tr as t uzu ma b i n c o m b i n ati on wit h c y t o t ox ic c h em o t he r apy de m ons tr a t ed a n im p r ov e d res pon se rate c o m p are d t o c h em o t he r apy a l one, fr o m 25.0 % t o 57.3 % wit h a ta x a n e re g ime n . T r ast uzu m ab i s a l so app r ov e d f o r u se i n t h e a d j uv a n t setti ng b ase d on an a pprox im a t e l y 50 % r educ ti on i n rec u rre n ce after 1 y ear i n m u lti p le ph as e III t r ials . Myoca r d i a l dys f un cti on, see n wit h a n t h rac y cli n e t h era p y , was ob se rv e d w it h i nc r eased fr equ e n c y i n p atie n ts recei v i ng a n ti body al on e o r w it h doxo r ub i c i n o r ep ir ub i c i n. Rec ogn iti on o f H E R2 as a d ri v er i n a s ub set o f g astric ca n cers le d t o an op e n- la be l , r ando mi zed, phas e III trial ( T o GA) t h at i nv esti g ate d t h e a dd iti on o f tr as t uzu m ab t o s t and ar d o f care c h em o t h era p y a nd s ho we d i n c r ease d m ed i an ove r a ll su r v i v al wit h h i gh er le v els o f HER 2 e xp ressi on. A st udy b y Go m ez - Ma rti n e t a l . i n 99 p atie n ts wit h metastatic g astric ca n c e r b ei ng t r e a t ed w it h fir s t-li ne trast u z u ma b p l u s c h em o t h era py i d e n tifie d a

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

T rastuzumab

nan nan

mea n HER2 / C EP 17 r a ti o o f 4.7 t o b e a n op timal c u t- o ff t o d iscrimi n ate b et w ee n tr as t uzu m ab - sens iti v e a nd refract o r y p atie n ts .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Pertuzumab

nan nan

Pe r t u z u m ab (P e rj e t a ) i s a hum a n ize d I g G 1 MA b t h at b i nd s t o do mai n II o f HE R 2 an d b l ocks li gand - dep e nd e n t d imerizati on o f HER 2 wit h o t h er mem b e rs o f t he E G F R f a mil y Pert u z u ma b, i n c o m b i n ati on wit h t r ast u z u m ab and doce t axe l , i s a pp r ov e d f o r u se as first-li n e t h era py i n HE R 2-pos iti ve m e t as t a ti c b r e ast ca n cer p atie n ts . Use o f t h e c o m b i n ati on is als o a pp r oved f o r t he tr ea tm en t o f HER 2 - po siti v e , l o call y a dv a n ce d, i nf lammat o r y , o r h i gh -ri sk ear l y b reast ca n cer ( >2 cm nod e n e g ati v e o r nod e pos iti ve ) i n t he neoad j uv a n t setti ng. F DA - app r ova l o f pe rt uzu ma b was b ase d on res u lts o f a ph ase III trial ( C LEO P A T RA ) o f 808 pa ti en ts wit h l o call y rec u rre n t , un resecta b le , o r metastati c b r eas t cance r r and omize d t o recei v e trast u z u ma b p l u s do ceta xel w it h or wit hou t t he add iti on of p ert u z u ma b. I n cl u si on o f p ert u z u ma b i n c r ease d t he i ndependen tl y as sesse d PFS by 6.1 m on t h s fr o m 12.4 t o 18.5 (h aza rd r a ti o [ HR ] , 0.62 ( 95 % c on fi d e n ce i n ter v al [CI] , 0.51, 0.75 ) , p < 0.0001], w it h a tr end t owa r d im p r ov e d ov erall s u r v i v a l t h at reac h e d statistic a l s i gn ifi cance ( p = 0.0008 ) after a n a dd iti on al y ear o f f o ll o w- up .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Pertuzumab

nan nan

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Pertuzumab

nan nan

Th e a dd iti on o f pe rt uzu m ab d i d i n crease rates o f g ra d e 3 a dv erse e v e n ts (AE), bu t it d i d no t adve r se l y a f fect car d iac f un cti on. Accelerate d a pp r oval w as gr a n t ed f o r use o f pe rt uzu ma b i n c o m b i n ati on wit h trast u z u ma b a nd do ceta x el f o r t he neoad j uvan t treatme n t o f h i gh -ris k earl y -sta g e b reast ca n ce r . T h i s app r ova l was ba se d on res u lts fr o m a f ou r -arm , op e n -la b el ph ase II s t udy o f 417 pa ti en t s ra ndo mize d t o recei v e trast u z u ma b p l u s do ceta x el , pe rt uzu m ab p l us do ceta x el , p ert u z u ma b p l u s trast u z u ma b, o r the t r i p le c o m b i na ti on. T he tri p l e c o m b i n ati on im p r ov e d t h e p at ho l og ic c o m p let e r esponse ( pCR ) r a t e by 17.8 % ov er t h e trast u z u ma b p l u s do ceta x el a rm ( 39.3 % ve r sus 21.5 %) i n t h e p ert u z u ma b arm . F o ll o w- up st ud ies t o con firm a co rr e l a ti on b etwee n p CR a nd l ong -term cli n ical b e ne f it a r e ongo i ng.

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Cetuximab

nan nan

Cetuximab

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Cetuximab

nan nan

Cet ux i mab (Er b it ux ) t a r ge t s the EGFR . T h is c h imeric I g G 1 b i nd s t o domain III of t h e E G F R, w it h r ough l y a te n f o l d h i gh er a f fi n it y t h a n eit h er EGF o r t r a n s form i ng g r ow t h f ac t o r α (TGF- α ) li g a nd s a nd t h ere by i nh i b its li g a nd -i ndu ce d ac ti va ti on o f t h i s t y rosi n e k i n ase rece p t o r . Cet ux ima b ma y als o fun cti on t o down r egu l a t e E G FR- d e p e nd e n t si gn ali ng by stim u lati ng EG F R i n te rn ali za ti on . Ce t ux im ab is a pp r ov e d f o r t h e treatme n t o f c o l o rectal ca n ce r ( C RC ) and, m o r e r ecen tl y , f o r t h e treatme n t o f s qu am ou s cell ca n c e r of t h e head and neck (S CCH N) . Th e e f fi cacy and sa f e t y o f cet ux ima b a g ai n st CRC was d em on strate d al on e a n d i n co m b i na ti on w it h iri no teca n i n a ph ase II , m u ltice n te r , r a ndo mi zed, and con tr o ll ed trial o f 329 p atie n ts . T h e c o m b i n ati on o f i r i no tec an p l us ce t ux im ab i ncr ease d bo t h t h e ov erall res pon se a nd t h e me d ia n du r a ti on o f r esponse a s c o m p are d t o cet ux ima b al on e . A dd iti on a ll y , p atie n ts wit h iri no t ecan r e fr ac t o r y d isease res pond e d t o treatme n t wit h t he c o m b i na ti on r eg im en. Recen t st ud ies i n p atie n ts wit h c o l o rectal ca n cers h a v e i nd i ca t ed t ha t pa ti en t s wi t h KRAS m u tati on s i n c odon 12 o r 13 s hould no t r ece ive an ti-E G F R t he r ap y An i n t e r na ti ona l , m u lti cen te r , ph ase III trial c o m p ari ng d efi n iti v e r a d i o t h er apy t o r ad i o t he r apy p l u s cet ux ima b i n SCCHN d em on strate d t hat EG FR b l ockade w it h r ad i o t h era py si gn ifica n tl y re du ce d t h e ris k o f l o c or e g i ona l f a il u r e by 32 % and t h e ris k o f d eat h by 26 % . I n a dv a n ce d sta g e non–s m a ll- ce ll l ung can cer (NSCLC) e xp ressi ng EGFR , t h e c o m b i na ti on o f ce t ux im ab and sta nd ar d doub let c h em o t h era py (cis p lati n p l u s v i no r e l b i ne ) was s t ud i ed i n a p r o s p ecti v e ra ndo mize d ph ase III trial .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Cetuximab

nan nan

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Cetuximab

nan nan

Th e a dd iti on o f ce t ux im ab wa s ass o ciate d wit h a sli gh t , bu t statisticall y si gn i f ic an t , bene fit i n ove r a ll su r v i v al ov er c h em o t h era py al on e (me d ia n ov e r all su r v i va l 10.1 ve r sus 1 1.3 m on t h s) . A similar st udy u si ng t h e ca rbop l a ti n p l us pac lit axe l ba c kbon e i n c o m b i n ati on wit h cet ux ima b d i d not meet its prim a r y endpo i n t o f i mp r ov e d PFS , alt hough cet ux ima b -treate d p atie n ts e xh i b it ed h i ghe r ob j e cti v e res pon se rates T h eref o re , t h e b e n ef it

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Cetuximab

nan nan

of a dd i ng ce t ux im ab t o s t and ar d c h em o t h era py f o r p atie n ts wit h a dv a n c ed N SC L C i s unc l ea r .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Panitumumab

nan nan

Pa n it u m u m ab ( V ec ti b i x ) i s a f u ll y hu ma n I g G 2 m ono cl on al a n ti body t hat b i nd s t o E G F R. Simil a r t o ce t ux ima b, p a n it u m u ma b i nh i b its EGFR acti v atio n by b l ock i ng t he b i n di ng o f EGF a nd TGF- α. H o we v e r , it do es so by b i nd i ng t o E G F R w it h a h i gh er a f fi n it y t h a n cet ux ima b ( 5 × 1 0 − 1 1 M v e r s u s 1 × 10 −10 M ) . As p r ev i ou sl y me n ti on e d, t h e I g G 2 class o f a n ti bod i es do es no t i nduce ac ti va ti on o f th e imm un e s y stem cell v ia t h e Fc-rece p t o r mec h a n ism , so pan it u m u m ab ’ s p rimar y acti on a pp ears t o b e i n terfere n c e w it h EGFR– li gand i n t e r ac ti on s . A phase III tri a l o f 463 pa tie n ts wit h metastatic c o l o rectal ca n cer c o m p a red pan it u m u m ab p l us b est s uppo rti v e care (BSC) t o BSC al on e . A p a r tial -response r a t e o f 8 % and a sta b le- d isease rate o f 28 % were re po rt ed for t h e p a n it u m u m ab a rm co m p are d wit h a 10 % sta b le- d isease rate i n t he b est s uppo rti ve ca r e a rm o f t he st ud y . As wit h cet ux ima b, p atie n ts wit h metastati c co l o r ec t a l cance r s who h a v e KRAS m u tati on s i n c odon s 12 o r 13 a r e no t rou ti ne l y o f f e r ed t he ra py wit h p a n it u m u ma b .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Bevacizumab

nan nan

Be v aciz u m ab ( A vas ti n o r r hu MA b VEGF) is a hu ma n ize d m ono cl on al a n ti body t a r ge ti ng V E G F . V E G F is a critical d etermi n a n t o f t u m o r a ng i og e nes i s, a p r ocess t ha t i s a n ecessar y c o m pon e n t o f t u m o r i nv asi on, grow t h, and m e t as t as i s. V E GF e xp ressi on by i nv asi v e t u m o rs h as b ee n s hown t o co rr e l a t e w it h vascul arit y a nd cell u lar p r o liferati on a nd is progno sti c f o r seve r a l hu m an ca n cers I n teresti ng l y , t h e i nh i b iti on o f VEG F si gna li ng v i a bevac i zu ma b treatme n t ma y no rmalize t u m o r v asc u lat u r e, p r o m o ti ng a m o r e e f fecti v e d eli v er y o f c h em o t h era py a g e n t s .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Bevacizumab

nan nan

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Bevacizumab

nan nan

Be v aciz u m ab i s app r oved f o r u se as a first-li n e t h era py f o r metastatic c o l or ectal cance r and N S C L C w h e n g i v e n i n c o m b i n ati on wit h a pp r op ri ate c y t o t ox i c che m o t he r apy r eg ime n s . P h ase III cli n ical trials lea d i ng t o t h e

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Bevacizumab

nan nan

a pprov a l o f bevac i zu m ab f o r t h e treatme n t o f c o l o rectal ca n cer d em on st ra t ed im p r oved r espon se rates fr o m 35 % t o 45 % c o m p are d t o f l uorourac il ( 5 -F U ) –based ch em o t h era py al on e . E nh a n ce d res pon se dur ati on s and im p r oved pa ti e nt s u r v i v al were see n i n p atie n ts treate d wi th c h em o t he r apy p l us bevac i zum a b as c o m p are d t o p atie n ts recei v i ng c h em o t he r apy a l one A su r v i v al b e n efit was als o see n i n t h e setti ng o f N SC L C . A r ando mi zed phase III trial (ECOG 4599 ) o f p aclita x el a nd ca rbop l a ti n w it h o r w it hou t bev aciz u ma b i n p atie n ts wit h a dv a n ce d non s qu am ous N S C L C l ed t o a si gn ifica n t im p r ov eme n t i n me d ia n s u r v i val (12.5 m on t hs ve r sus 10.2 m on t h s; p = 0.0075 ) f o r p atie n ts i n t h e b e v aciz u m ab a rm w it h s i gn ifica n tl y h i gh er res pon se rates . A h i gh er i n ci d e n ce o f b l eed i ng was ass ociate d wit h b e v aciz u ma b ( 4.5 % v ers u s 0.7%). F i ve o f 10 tr ea tm en t-r e late d d eat h s o cc u rre d as a res u lt o f h em op t ys i s, a ll i n t he bevac i zu ma b arm . A phase III tri a l r ando mi z e d 722 p atie n ts wit h metastatic b reast ca n c e r w it h no p ri o r che m o t he r apy f o r a dv a n ce d d isease t o eit h er p aclita x el o r p aclita x el and bevac i zu m ab . PFS was si gn ifica n tl y b etter i n t h e p aclit axel p l u s b e v a c i zu m ab a rm (m ed ia n, 1 1.8 v ers u s 5.9 m on t h s; HR f o r progr ess ion, 0.60 ; p <0.001 ) wit h a n i n crease d res pon se rate ( 36.9 % v ers us 21.2%, p <0.001 ) . Ove r a ll su r v i v al , ho we v e r , was simila r . In c on tr as t , i n a r ando mi z e d ph ase III trial , ca p ecita b i n e/ b e v aciz umab i n c r ease d r esponse r a t es co m p are d wit h ca p ecita b i n e al on e i n 462 a n t hr acy c li ne and t axane p r e treate d metastatic b reast ca n cer p atie n ts bu t did no t meet it s p rim a r y endpo i n t o f im p r ov e d PFS . O v erall s u r v i v al a nd ti me t o d ete r ior a ti on i n qua lit y o f life were c o m p ara b le i n bo t h treatme n t g r oups. Be v a c i zu m ab has no t de m on strate d acti v it y i n t h e a d j uv a n t c o l o recta l a nd br ea s t cance r se tti ngs . T h ere was no im p r ov eme n t i n ov erall s urv i v al be t ween t he t wo g r o u p s a nd t h e rate o f i nv asi v e d isease-free s urv i v al was a l so no t s i gn ifi c a n tl y d i f fere n t b etwee n t h e treatme n t g r oups. Be v a c i zu m ab i s a l so app ro v e d f o r t h e ma n a g eme n t o f rec u rre n t g li ob las to m as based on r esu lt s o f ph ase II st ud ies .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Ado- T rastuzumab Emtansine

nan nan

Ado- T rastuzumab Emtansine

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Ado- T rastuzumab Emtansine

nan nan

Ado- t r ast uzu m ab e mt ans i ne ( T -DM 1, Ka d c y la) is a n ADC c o m po se d o f the a n ti -HER2 MAb tr as t uzu m ab li nk e d t o DM 1, a h i gh l y po te n t d eri v ati v e o f ma y ta n si ne, t h r ough a s t ab l e t h i o et h er li nk e r Based on t wo s i ng l e - agen t ph ase II trials o f T -DM t h at d em on st ra t ed s i ng l e - agen t ac ti v it y i n t h e setti ng o f metastatic b reast ca nce r , t wo se pa r a t e phase III s t ud i es were c ondu cte d. T h e 991 p atie n t EMILIA t r ial d em ons tr a t ed t ha t T - DM1 si gn ifica n tl y p r o l ong s bo t h PFS a nd ov er all s urv i v al as co m pa r ed t o a r eg ime n o f la p ati n i b p l u s ca p ecita b i n e w h e n used i n t h e setti ng o f m e t as t a ti c b reast ca n cer t h at h a d p r og resse d after treatme nt w it h t r a s t uzu m ab p l us a t axane Gra d e 3 a nd w o rse AEs were l o wer i n the T -D M 1 arm ( 200, 40.8 %) as co m p are d t o t h e la p ati n i b p l u s ca p ecita b i n e a r m (278, 57 %) . Resu lt s a r e st ill awaite d fr o m t h e ongo i ng MARIANNE t r ial t h at i s assess i ng fir s t-li ne efficac y a nd safet y o f T -DM 1 al on e a nd T - D M 1 p l us pe rt uzu m ab ve r sus trast u z u ma b p l u s ta x a n e (NCT 0 1 120184 ) .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Denosumab

nan nan

Denosumab

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Denosumab

nan nan

D e no s u m ab ( Xgeva ) i s a f u lly hu ma n I g G 2 RANK li g a nd (RANKL) n e u t r ali z i ng an ti bod y . Denosu ma b is FDA-a pp r ov e d f o r u se i n a du lts a nd s k eletall y m a t u r e ado l escen t s w ho h a v e eit h er s u r g icall y un sal v a g ea b le g ia n t ce l l t u m o r s o f t he bone (GCTB) o r w h ere resecti on is a n tici p ate d t o r es u lt i n seve r e m o r b i d it y . App r ov al was b ase d i n p art on tw o op e n -la b e l, ph ase II tri a l s exa mi n i ng sub c u ta n e ou s a d mi n istrati on o f 120 m g q4 we ek w it h a dd iti ona l l oad i ng doses on d a y s 8 a nd 15 o f t h e first c y cle .

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Denosumab

nan nan

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Denosumab

nan nan

a pprov e d t o i nc r ease bone m as s i n p r o state ca n ce r a nd b reast ca n ce

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Denosumab

nan nan

ANTIBODIES APP R OVED F OR USE IN SOL I D TUMORS

Denosumab

nan nan

p atie n ts at h i gh ri sk f o r bone fract u re du e t o ho rm on e-a b lati on t h era p ies .

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

nan nan

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

Rituximab

nan nan

Rituximab

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

Rituximab

nan nan

Rit ux im ab ( R it uxan ) i s a ch i m eric a n ti-CD 20 m ono cl on al a n ti body t h at w as t h e f i r st MAb t o be app r oved by t h e FDA f o r u se i n hu ma n mali gn a nc y . St ud i es hav e s ho w n t h at m u lti p le do ses ca n b e safel y a d mi n is te r ed, and i n v it r o s t ud ies h a v e d em on strate d m u lti p le mec h a n is ms by wh ic h an ti- CD20 an ti bod i e s ca n lea d t o cell d eat h . E f ficac y o f r it ux ima b m ono t he r apy i s wel l esta b lis h e d . Rit ux im ab has been t es t ed i n c on j un cti on wit h c h em o t h era py b ase d on s uppor ti ve p r ec li n i ca l da t a . T h e c o m b i n ati on o f rit ux ima b wit h c y cl ophospha mi de, doxo r ub ici n, v i n cristi n e , a nd p re dn is o l on e (CHOP) r es u lte d i n a 95 % ove r a ll r espon se rate ( 55 % c o m p lete res pon se , 40 % p a r tial r e sponse ) a m ong 40 p atie n ts wit h l o w- g ra d e o r f o llic u lar B-cell non– Hodgk i n l y m pho m a, w it h m o lec u lar c o m p lete remissi on s ob ser v e d . A l ong- te rm s t udy o f e l de rl y pa tie n ts wit h p re v i ou sl y un treate d d i f f u se la r ge -cell l y m pho m a r ando mi zed t o eit h er CHOP c h em o t h era py p l u s rit ux ima b ( R - C HO P) o r CHO P a l one de m on strate d a si gn ifica n t im p r ov eme n t i n e v e n t -free su r v i va l , PFS , d i se ase-free s u r v i v al , a nd ov erall s u r v i v al f o r t he c o m b i na ti on a rm . No s i gn ifica n t d i f fere n ces i n l ong -term t ox icit y wer e no te d. Low - g r ade B - ce ll l y m phom a p atie n ts po ssessi ng t h e 158 V/V po l y m orph i s m i n F cγR III exp erie n ce s up eri o r res pon se rates a nd ou tc omes wh e n t rea t ed w it h rit ux im ab . T h ese fi nd i ng s si gn if y t h at a n ti body Fc do mai n ::F c r ecep t o r i n t e r ac ti on s und erlie at least s o me o f t h e cli n ical b e n e f it o f rit ux im ab, and i nd icate a po ssi b le r o le f o r ADCC t h at d e p e nds on s u c h i n ter ac ti ons.

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

Rituximab

nan nan

A c o m b i na ti on o f ac ti ve ag e n ts (s u c h as le n ali do mi d e a nd t h ali do mi de ) t h at a r e al so imm une m odu l a t ing ma y b e a dd iti v e wit h rit ux ima b , a nd p e rh a p s s yne r g i ze by i nc r eas i ng ADCC . C y t ok i n es s u c h as i n terle uk i n - 2 (IL-2), I L- 12, o r IL- 15 and m y el o i d g r o wt h fact o rs ma y als o e nh a n ce t h e r a p euti c an ti body ac ti v it y a s s ugg este d by p recli n ical d ata d em on strat ing t h at IL-2 can p r o m o t e NK ce ll p r o liferati on a nd acti v ati on a nd ca n e nh a nce r it ux ima b ac ti v it and c li n i c al e f ficac y M y el o i d g r o wt h fact o rs , i n c o m b i na ti on w it h rit ux im ab, m a y als o acti v ate ADCC . Alter n ati v e a ppro ach es t o i nduce e f f ec t o r cell acti v it y by c o m b i n i ng T o ll-li k e rece p t o r s (TL R ) a gon i s t s, such as CpG oli gonu cle o ti d es , h a v e b ee n i nv esti g ate d .

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

Rituximab

nan nan

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

Rituximab

nan nan

A lte r i ng t he ba l ance o f p r oapop t o tic a nd a n tia pop t o tic si gn als c ou l d g e n e r ate m o r e rit ux im ab -i nduc e d c y t o t ox icit y . BCL- 2 do w n re gu lati on by a n tise n s e o li gonuc l eo ti des wa s f ound t o e nh a n ce rit ux ima b e f ficac y i n pr ecli n i ca l t es ti ng Howe ve r , small m o lec u les t h at b i nd t o t h e BH- 3 do mai n co mm on t o m any m emb ers o f t h e BCL- 2 famil y o f p r o tei n s ma y be b ette r t he r apeu ti c agen t s .

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

Ofatumumab

nan nan

Ofatumumab

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

Ofatumumab

nan nan

Th e a n ti- CD20 o f a t u m u m a is a f u ll y hu ma n a n ti body t h at b i nd s a n e p it op e on CD20 d i s ti nc t fr o m t h at bound by rit ux ima b a nd is e ng i n eere d for b ette r co m p l e m en t ac ti va t ion, alt hough it i ndu ces less ADCC . Of at u m u m ab has r ece i ved r e g u lat o r y a pp r ov al f o r t h e treatme n t o f p atie nts w it h f l uda r ab i ne -r e fr ac t o r y ch r on ic l y m pho c y tic le uk emia (CLL) . I n a r ece n tl y r epo rt ed, p l anned i n terim a n al y sis t h at i n cl ud e d 138 CLL p atie nts w it h t r e a tm en t-r e fr ac t o r y d i sea se o r bu l ky ( >5 cm) l y m ph a d e nop at h y , t r eatme n t w it h o f a t u m u m ab le d t o a n ov erall res pon se rate ( p rimar y e ndpo i n t) o f 47 % i n pa ti en t s wit h bu l ky d isease a nd 5 % i n p atie n ts r e fr act ory t o bo t h a l e mt uzu ma b a nd fl ud ara b i n e . Add iti ona l hu m an i zed an ti-CD 20 a n ti bod ies ( v elt u z u ma b a nd o c r eliz u m ab ) a r e unde r deve l op me n t .

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

Alemtuzumab

nan nan

A lemt uzu m ab ( Ca m pa t h - 1H ) ta r g ets t h e CD 52 g l y c op e p ti d e , w h ic h is h i gh l y e xp r essed on T and B l y m pho c y tes . It h as b ee n teste d as a t h e r a p euti c agen t f o r C LL an d p r o m y el o c y tic le uk emias , as well as o t h er non–Hodgk i n l y m pho m as.

ANTIBODIES US E D IN HE M A T O LO GIC MA L I G NA N CIES

B r entuximab V edotin

nan nan

B r entuximab V edotin