BBiiosiimiillar MMonocllonall AAnttiibboddy: Pharmaceutical and Clinical Considerations Fadi Sami Farhat, MD President of the Lebanese Society of Medical Oncology President of the Cancer Research Group 1188 OOcttobber 22001155, BBeiirutt, LLebbanon WWhhaatt AArree ‘BBiioossiimmiillaarrss’?? ““BBiioossiimmiillaarrss,, ssiimmiillaarr bbiioollooggiiccaall mmeeddiicciinnaall pprroodduuccttss,, ffoollllooww--oonn bbbbiiiioooollllooooggggiiiiccccssss,, ssssiiiimmmmiiiillllaaaarrrr bbbbiiiiooootttthhhheeeerrrraaaappppeeeeuuuuttttiiiicccc pppprrrroooodddduuuuccccttttssss,, ffffoooolllllllloooowwww----oooonnnn pppprrrrooootttteeeeiiiinnnn pprroodduuccttss,, sseeccoonndd--eennttrryy bbiioollooggiiccaallss,, ppoosstt--ppaatteenntt bbiioollooggiicc......”” • Biosimilars are not generics • Biosimilars are products that have been shown to be similar to the reference products in appropriate comparattiive, hheadd-tto-hheadd, qualliitty nonclliiniicall andd clinical studies • TThhey are approvedd on tthhe bbasiis off abbbbreviiattedd nonclinical and clinical development programs ddeeppeennddiinngg oonn ssiimmiillaarriittyy ttoo aa rreeffeerreennccee bbiioollooggiicc product WWhhaatt IIss tthhee DDiiffffeerreennccee BBeettwweeeenn BBiiootteecchh MMeeddiicciinneess aanndd CChheemmiiccaall MMeeddiicciinneess?? • Biotech medicines are made from living cells – Chemical medicines are made from chemical processes • Biotech medicines are complex in structure – Chemical medicines have a simple and well-defined structure • Because of the way they are expressed by living cells, biotech medicines contain a mixture of related molecules and are difficult to characterize – Chemical medicines, on the other hand, are easy to characterize There are more than 150 biotechnology medicines on the market. MMoorree tthhaann 332255 mmiilllliioonn ppaattiieennttss wwoorrllddwwiiddee uussee bbiiootteecchh mmeeddiicciinneess. 50% of medicines in clinical development are biotech medicines. CCCCoooommmmpppplllleeeexxxxiiiittttyyyy ooooffff BBBBiiiioooollllooooggggiiiicccc PPPPrrrroooodddduuuuccccttttssss IInnhheerreenntt ccoommpplleexxiittyy AAddddeedd ccoommpplleexxiittyy • Size • Manufacturing process • Structure • Formulation • Physiochemistry • Handling • Heterogeneity • Route of administration Impossible to make an exact copy SSSSiiiizzzzeeee,, SSSSttttrrrruuuuccccttttuuuurrrreeee aaaannnndddd CCCCoooommmmpppplllleeeexxxxiiiittttyyyy SSmmaallll CChheemmiiccaall Chemical Molecule Large Bilogical Molecule Molecule Human growth IgG Antibody hhoorrmmoonnee ~2255000000 aattoommss (hGH) Aspirin ~3000 atoms E Z 21 atoms II S Car Commercial jet Y Bike T ~ 3000 lb ~ 25000 lb (without oil) XIX ~ 2200 llbb E L P M O CC MMoonnoocclloonnaall AAnnttiibbooddiieess AArree MMoorree CCoommpppplleexx TThhaann ‘‘SSiimmppllee’’ BBiioollooggiiccss Aspirin Insulin Erythropoetin Monoclonal Antibody Small molecule ‘Simple’ biologics ‘Complex’ biologics drug BBBBiiiioooollllooooggggiiiiccccaaaallll PPPPrrrroooodddduuuuccccttttssss:::: SSSSttttrrrruuuuccccttttuuuurrrreeee Asppirin = C H O CChheemmiiccaall pphhaarrmmaacceeuuttiiccaall 99 88 44 – Simple structure of elements Biopharmaceutical – Multiple levels of structural complexity Primary Secondary Tertiary Quaternary Amino acid Alpha, beta Folding Polypeptide sequence sheets arrangement Adapted from: Four levels of protein structure, ref: http://bioinformatics.weizmann.ac.il/ TThhee SSttrruuccttuurree ooff MMoonnoocclloonnaall AAAAnnttttiiiibbbbooddddiiiieess IIIIss HHHHiiiigghhhhllllyy CCCCoommpplllleexx ppyyrroo-EE ppyyrroo-EE OO OO • Pyro-Glu (2) D D D • Deamidation (3 x 2) D O O • Methionine oxidation (2 x 2) G G • Glyycation ((2 x 2)) D D • High mannose, G0, G1, G1, G2 (5) • SSiiallyllattiion ((55)) G G • C-term Lys (2) The large number of sites for modification K K means exponential potential for diversity: 2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600 potential variants of each HALF of the antibody! Kozlowski S, et al.Adv Drug Deliv Rev. 2006;58(5-6):707-722. EEvveenn SSmmaallll GGllyyccoossyyllaattiioonn DDiiffffeerreenncceess MMaayy HHaavvee SSSSiiiiggggnnnniiiiffffiiiiccccaaaannnntttt EEEEffffffffeeeeccccttttssss oooonnnn IIIImmmmmmmmuuuunnnneeee EEEEffffffffeeeeccccttttoooorrrr FFFFuuuunnnnccccttttiiiioooonnnnssss • Both amino acid seqquence and glycosylation pattern of C 2 influence H FcR binding and ADCC activity •• TThhee pprreesseennccee oorr aabbsseennccee ooff oonnee ffuuccoossee residue can affect the biologic activity (killing of target cells via ADCC) • EEven very smallll ddiifffferences iin fucosylation may have significant effects on in vitro ADCC R. Garnick (2008) Biogenerics 2008 Conference BBiioollooggiiccss HHaavvee aa CCoommpplleexx MMMMaaaannnnuuuuffffaaaaccccttttuuuurrrriiiinnnngggg PPPPrrrroooocccceeeessssssss Cloningg into AATTGG ....AATTGG GGeennee SSeeqquueennccee SSTTOOPP... DNA Vector Stop DDNNAA VVeeccttoorr Transfer into Host Cell Expression Screening/Selection Fermentation Downstreaming/ Purification eg, bacterial or mammalian cell