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641

Index

A280, 444 agroinfiltration, 33 Ab affinity, 86, 89 agitation, 412–413, see also bioreactor Ab‐Ag binding properties, 85, 90, 98 process and scale up Ab‐based mechanism of action (MOA), aHUS, see atypical hemolytic uremic 85–88, 91–94, 96–98 syndrome , 81, 91 , 82 Ab , 86, 97 alanine, 444 Ab‐mediated depletion, 85, 90–91, 94, 96 albumin fusions, 568, 573–575 Ab serum half‐life, 86, 90 with FcRn, 573, 578 ACE inhibitor, 75 with immunoglobulin, 574–575 Actemra, 79 , 81, 92, 96, 220–221 Acute lymphoblastic , 79 allergic reactions, 442 Acute myeloid leukemia, 81 , 78 ADA, see antibody, antidrug Alopexx, 286 adalimumab, 80, 82, 86–87, 89, 447, 449 Alpha toxin (S. aureus), 286 ADCC, 86, 90, 94, 96, 457, 458, 460, 462, alternative immune repertoire, 463 21–22 Adcetris, 79 alternative scaffolds, 23–25 ADCP, 85, 90, 94 AMD, see age‐related adotrastuzumab, 79 amid action, 162 ado‐ emtansine, 93, 97, amino acid analysis, 444 218–220 amino acid sequence, 426, 444 aeration, 412–413, see also bioreactor 2‐aminobenzoic acid, 431, 433, 434, see also process and scale up glycan, N‐glycans , 304 amperometric detection, 433 age of antibiotics,COPYRIGHTED 283 analytical MATERIAL similarity, 465 age‐related macular degeneration (AMD), angiotensin II receptor antagonist, 75 293, 300, 301, 304 Animal Efficacy Rule, 117 wet AMD, 293, 300, 301, 304 Anthrax, see infectious diseases, Bacillus dry AMD, 301 anthracis Agilent, 431, see also mass spectrometer, Anthrax infection, 79 QTOF Antiarrhythmics, 75

Biosimilars of Monoclonal Antibodies: A Practical Guide to Manufacturing, Preclinical, and Clinical Development, First Edition. Edited by Cheng Liu and K. John Morrow, Jr. © 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

0002883283.indd 641 11/14/2016 5:29:40 PM 642 Index

antibody drug conjugate (ADC), 97, 98, 590 antibody antibodies bispecific definition, 574 activity, 426, 436, 446 fragments, 568, 570–572, 574, 577 aggregation, 439, 441, 443 history of, 548–549, 566 antidrug, 450 recombinant, 547–548 , 426–428, 431, 433, 438, 439, antibiotics, 442 441, 446–450 antidrug antibodies (ADAs), 8 bispecific, 426 anti‐drug assay (ADA), 458, 465, 469, 470, charge variation, 438, 441 472, 473 chimeric, 450 characterization, 472 deglycosylated, 427, see also interference on PK, 469 glycosylation, deglycosylated , 444–449 denatured, 428 , 448 design, 17–29 Applied Biosystems, 442 display, 12–15 asparagine, 433, 436, 440 effector functions, 431 aspartate, 436, see also proteolytic enzymes, efficacy, 426 Asp‐N Fab, 431, 444, 445 AR‐301, 287 Fc, 426, 428, 431, 444–446, 449 Arsanis, 286 fragments, 17–19 Artemisinin, 75 humanized, 450 arthritis, see autoimmune diseases, libraries, 13 inflammatory arthritis identity, 426 Arzerra, 79 integrity, 426 asparaginaes, 75 mixtures, 29 atenolol, 75 monoclonal, 426, 427, 431, 433, 434, 436, atypical hemolytic uremic syndrome 441, 443, 444 (aHUS), 293, 298, 299, 300 mutations, 428 autoimmune diseases, 120–127 pI, 436, 438, 440 antineutrophil cytoplasmic antibody polarity, 438 (ANCA)‐associated vasculitis, purity, 426, 436, 441 126–127 production, 30–36 cryopyrin‐associated periodic syndromes quantity, 426 (CAPS), 125–126 reference, 431, 449 inflammatory arthritis, 123–124 safety, 426, 442 inflammatory bowel disease (IBD), serum half‐life, 441, 445, 446 120–123 stability, 426, 436, 439, 443 multiple sclerosis (MS), 120 structure, 65 psoriasis, 125 therapeutic, 426, 431, 441, 445, 447, 448 rheumatoid arthritis, 254–255 antibody‐dependent cell‐mediated systemic lupus erythematou (SLE), cytotoxicity (ADCC), 431, 444–446, 124–125 448, 547–549, 582 type 1 diabetes mellitus (DM), 127 activation of, 548–550, see also constant Avastin, 80, 300, see also region (fc) enhancement technology, 547–557, 553, Bacillus anthracis PA, 86, 88 see also mutagenesis; glycol Back mutation, 65 engineering baculovirus expression system, 32

0002883283.indd 642 11/14/2016 5:29:40 PM Index 643

bacteria, gram‐negative, 443 biosimilar pipeline database, 381–384, 385 Balto, 284 bispecific antibodies (BsAb), 19–20 basiliximab, 81, 91, 293, 311−312, 314, 315 , 78, 93, 97 basophils, 72 Blincyto, 79 B‐cell depletion, 449 BLyS, 79, 88 Begelomab, 78 metastases, 293, 304, 305, 307 Behring, Emil von, 284 BPCIA, 504, 507, 508, 510, 512 bevacizumab, 300, 301, 304, 315 breakthrough, 360 belimumab, 79, 88 breast (BC), 133–134, 219–220, benzodiazepines, 75 246–248, 262 Benlysta, 79 brentuximab, 79 beta blockers, 75 , 93, 95, 225–227 bevacizumab, 80, 86, 87, 221–225 brodalumab, 78 Bexxar, 80 Biacore, Inc., 445 C5, 86–87 binding calcein AM, 448 affinity, 444–446, 449 Campath‐1H, 220–222 antigen, 444, 445, 447, 448 Canakinumab, 79, 87 blocking, 445 cancer, 426 competitive, 445 cancer‐testis (CTAs), 135, 138 ligand–receptor, 444, 445 candidate , 385, 492–496 binding capacity capillary electrophoresis, 433, 438, 440 dynamic, 360 captopril, 75 static, 360 Castleman’s disease, 79 biobetters, 379–392, 564, 581–582 carboxyl peptidase B, 438–441 definition of, 381, 563 Casadevall, Arturo, 285 bioconjugation, 593 catabolism, 176 biogenerics, 379–381, 384–385 catalytic antibodies, 28–29 definition of, 379 , 80, 92 biolayer interferometry technology, 444, 445 CD3, 91–93, 97, 307, 309, 312−314 Biologics Price Competition and Innovation CD11α, 80, 92 Act of 2009, 517–529 CD19, 93 application for licensure of a biosimilar, CD20, 90–94, 96 518–519 CD25, 307−311 confidentiality, 523–524 CD30, 93, 95, 97 exclusivity period, 519–522 CD33, 81, 91, 95, 98 pediatric exclusivity, 520 CD52, 81, 92, 96 biosimilars, 565, 576–577, 581–582 CDC, 85, 89–91, 93–94, 96, 457, 458, 460, biosimilarity, 459, 460, 463, 470, 471, 473 462, 463 b4* ion, 436, see also posttranslational CDR, 64, 65 modifications, pyroglutamation CE‐IEF, 436, 440 BioRad, 445 Celecoxib, 75 bioreactor, disposable, 340–341 cell‐based assays, 460, 462, 472 bioreactor process and scale up, 407–413 cell culture processes, 404–416 biosimilar development, 385–386 fed‐batch, 405–406 biosimilar manufacturing, 389–390, perfusion, 405–406 395–417 medium and feeding, 406–407

0002883283.indd 643 11/14/2016 5:29:40 PM 644 Index

cell culture technology transfer, 414–416 classical pathway, 176–177 cell‐free translation, 34–35 clinical development, 490–492 cell line(s) clinical studies, 504, 505, 506, 510 Chinese hamster, 426, 441 clinical trials, 441, 446 Daudi, 447 Clostridium difficile, 287 generation, 335–336 (CC), 134–135, 222–223, mouse fibroblast, 447 229–230, 244 nonhuman, 431 co‐translational modifications (CTM), PER.C6, 426 157–158,181–182 Raji, 447 column Ramos, 447 C18, 428, 434 SP2/0, 426 HILIC, 431–434 specificity, 399 protein A, 434 stability, 403–404 reverse phase HPLC, 433 Wil2‐s, 447 size exclusion, 428, 439, 440 cell line development, 400–404 commercial marketing, 389, see also expression vector construction, 400 Biologics Price Competition and transfection, 400–402, 404 Innovation Act of 2009 cell line engineering, 398–400 comparability assessment, 459, 465, 466, 472 inducible expression systems, 399 comparability protocol (CP), 481 Celltrion, 426 compartmental model, 205–206 certolizumab, 80 complement‐dependent cytotoxicity certolizumab pegol, 87, 89 (CDC), 444–448, 548 CE‐SDS, 438 complement protein C5, 297−300 , 80, 90, 92, 97, 227–230, 448 components cGMP manufacturing, 414–416 animal‐derived, 442 chain shuffling, 65 serum‐derived, 442 charge heterogeneity, see antibody, charge compliment activation, 176–177 variation conjugated antibodies, 20–21 chimerization, 5–6 consistency, lot–to–lot, 428, 431, 433, 441 Chinese hamster ovary cells (CHO), constant region (fc), 548–550, see also Fc 325–344, 396, see also cell line(s), region Chinese hamster contamination, bacterial and fungal cell, 443 Chondrichthyes, 67 continuous downstream processing chromatography carrousel chromatography, 366, 368 anion‐exchange, 433 continuous annular chromatography cation‐exchange, 436, 438, 439, 441 (CAC), 366–368 ion exchange, 438 countercurrent tangential Protein A, 442 chromatography (CCTC), 370–371 size exclusion, 427, 439, 441 multicolumn countercurrent solvent chromium‐51, 448 gradient purification (MCSGP), chromium‐Eu, 448 368–370 circular dichroism spectrum multicolumn periodic countercurrent far‐UV, 431 chromatography (PCC), 361–364 near‐UV, 431 simulated moving bed (SMB) chronic lymphocytic leukemia, 79 chromatography, 364–366 Cimzia, 75, 80 staggered cycling purification, 361

0002883283.indd 644 11/14/2016 5:29:40 PM Index 645

contract research organization, 442, 443 disulfide reduction, 605 Cosentyx IL‐17, 78 DME, see diabetic C1q, 444, 446 DNA, 442 Crohn’s disease (CD), 79, 293, 294, 296, see DNA laddering assay, 448 also autoimmune diseases, DNASEQ, 442 inflammatory bowel disease dose, 442, 449, 450 C‐terminal lysine cleavage, 436, 438–441 dose‐response curve, 466 deamidation, 436, 438, 440, 441 “double selection” technology, 402, see also deglycosylated, 427, 433 cell line development glycosylation, 426–428, 431–433, see also drug, 426, 441–443, 446 glycosylation dry AMD, see subentry of age‐related identification, 428 macular degeneration N‐terminal glutamine, 436, 438, 440 DTT, 428 oxidation, 436, 441 pyroglutamation, 436, 440 Ebola, see infectious diseases, ebola virus C‐terminal residues, 159–160, 163 family CTLA‐4, 79, 93 eculizumab, 80, 87, 233–235, 293, 297−300, Cyramza, 79 314, 315 Cygnus Technologies, 441 Efalizumab, 80, 92 Cynomolgus, 449 EGF, 447 cysteine, 160–161 EGFR, 79, 80, 86, 90, 92, 96–97 Ehrlich, Paul, 284 Dabigatran, 78 ELISA, 441, 444–447, 461 daclizumab, 81, 91, 293, 307−310, , 78 314, 315 EMA, 504, 507, 508, 509 , 78 Empliciti SLAMF7, 78 Darzalex CD38, 78 endotoxins, bacterial, 443, see also deamidation, 162 lipopolysaccharides deimmunization, 8 engagement of cytotoxic T cell, 85, 96 , 79, 88, 90, 230–233, 293, engineered Fc, 96 304−307, 314, 315 enzymes, proteolytic, 427, see also proteases de novo pathway, 552, 553 eosinophils, 448 diabetic macular edema (DME), 293, 300, EPCAM/CD3, 80, 92 303, 304 equilibrium, 445 dimer, 439 Erb2, 447 , 78, 93 Erbitux, 80, 431 diphtheria, 284 Error‐prone PCR, 65 dipolar cycloaddion, 611 EU, 504, 505, 507, 511 disposable bag bioreactors, 360 European Medicines Agency, 444, 448, 450 disruption of ligand‐receptor interaction, , 78 85, 86, 90 Exclusivity Guidance, 521, see also Biologics disulfide bonds Price Competition and Innovation Act cysteine, 428 of 2009 formation, 160–161 extinction coefficient constant, 444 mapping, 434 extrapolation of indication, 505, 506, 510, nonreduced, 434, 436, 438 511 reduced, 427, 428, 434 expression platform, 181–182

0002883283.indd 645 11/14/2016 5:29:40 PM 646 Index

expression vector construction, see cell line , 82 development , 224 extrapolation of indication, 488–490 glycan ex vivo stimulation, 9 analysis, 434 Eylea, 304, see also aflibercept beta 1, 3‐galactose, 450 derivatized, 432 fab arm exchange, 161 dissociation, 433 Fab, F(ab)’2, 71 fucose, 431, 446 FACS, 447 galactose, 431 Fc, 71 mannose, 450 Fc receptor (FcyR), 173–175, 548, 551, N‐glycans, 427, 433 555–557, 565 sialic acids, 440 classes of, 548–549 glycation, 172–179 Fc region, 555–556, 563, 567, 582 glycoengineering, see glycol engineering FcRn, 444, 446, 449, 572, 573, 578–579, 582, glycol engineering, 549, 550–551, 553, 554, 583 582 and IgG stabilization, 567–569 GlycoFi, 554 molecular structure of, 569–570 GlycoMab, 553–554 FcγR, 444, 446, 448 GlymaxX, 552–553 FcyR, see Fc receptor (FcyR) MAGE, 555 FDA, 365, 442, 450, 460, 472, 504, 505, 507, Potelligent, 551–552, 554 508, 509, 510, 511 SEA, 554 fermentation, see process‐related glycoproteins profiles, 168 modifications, fermentation glycosylation, 35–36, 162–172, 179–181, filamentous fungi, 32 457, 458, 549, 575, 577–578, see also first‐order two‐compartment model, 206 half‐life, extension strategies FlowCAM, 443 glycopeptide, 433 fluorescence detection, 432, 433 N‐linked, 427, 433 Food and Drug Administration (FDA), 548, O‐linked, 428 564 pattern, 433, 434 formylglycine, 607 site, 431, 433 ForteBio, 445 golimumab, 79, 82, 87, 89 fucose, 169–171,177 GPIIβ/IIIα, 91 fully human antibodies, 2, 10 granulocytes, 72 functional bioassay, 444, 447 granulomatosis, 255 Fv, 71 Great Race of Mercy, 284 growth factors, 442 galactosylation, 178 guanidine hydrochloride, 428 GAPDH, 448 gastrointestinal , 134–135, 249, 262 half‐life, 563–582, 583 gastrointestinal track, 72 extension strategies, 576–581, 577, see Gazyva, 79 also albumin fusions GD2, 78, 93 future engineering of, 576–581 Gemtuzumab, 81 optimization of, 570–573 , 91 , 227, 228 gene silencing, 337–338, 341–343 heavy chain, 426, 427 genetic transfer, 25–27 hematological malignancies, 129–131

0002883283.indd 646 11/14/2016 5:29:40 PM Index 647

HER2, 79, 90–91, 93, 95–97, 448 IL6R‐α, 92 Herceptin, 448 immune effector functions, 85, 90, 94 Herceptin HER2, 81 immune evasion, 287 high producing cell lines, 335–338 immunoconjugate, 79 high‐throughput, 16–17, 338–340, 399 immunogenicity, 65, 431, 442, 450, 458, 470, HILIC, see column, HILIC 471, 473, 548, 566, 572 HMG‐CoA reductase inhibitor, 75 immunoglobulin Hodgkin’s , 79 IgG, 434, 441, 446 homogeneity, 441 typical, 431 Hospira, 426 immunohistochemical localization, 579 host cells, 333–335, 396–398 immunomodulatory agents, 289 DNA, 442 immunotherapy, 426 protein, 441, 442 IND, 448 HPLC, 431, 444 inflammatory bowel disease, see Crohn’s HPMA, 573, see also half‐life, disease (CD) optimization of Inflectra, see infliximab Human B‐cell hybridoma, 8–9 infectious diseases, 117–119 Human IgG allotype, 65 Bacillus anthracis, 117 Humanization, 6–8, 9–12, 65 Ebola virus family (EBOV), 118–119 Humira, 80, 447, see also adalimumab human immunodeficiency virus Hybridoma, 64 (HIV), 118 hydrophilicity, relative, 432 respiratory syncytial virus (RSV), 117 infliximab, 75, 81, 86–87, 89, 426 Iatrogenic, 287 influenza, 288 ibritumomab, 80 INN, 64, 504, 508, 511 , 92, 94, 235–237 , 442 identity, 2, 4, 6 , 294−296 idiotype, 71 α4 integrin, 92 IgA, 67–70 α4β7 integrin, 93 IgD, 67–70 intellectual property, 3–4, 505, 508–509, 512 IgE, 67–70 interchangeability, 505, 506–507, 511 IgG, 115, 158–169, 173–175, 177, 563–565, internalization and degradation, 85, 97 574, 576, 578, 582, 583 iodoacetamide, 428 history of, 566 , 79, 93, 237–238 stabilization of, 567–569 isotype, 67 subtype, subclass, 73 isoelectric focusing, 436, 440, see also IgM, 67–70 CE‐IEF IgY, 67 isoleucine, 444 IgW, 72 IL‐6, 86, 88 J chain, 68 IL 12/23, 86, 88 IL‐17a, 86, 88 Kadcyla, 79 Ilaris, 79 Kaasen, Gunnar, 284 IL1b, 87 KaloBios, 286 IL‐1β, 79 KB001‐A, 286, 287 IL‐2R, 91, 308, 309 kinetic exclusion assays, 444, 445 IL‐6R, 79 KinExA, 445

0002883283.indd 647 11/14/2016 5:29:40 PM 648 Index

L929, see cell line(s), mouse fibroblast DHB matrix, 433 label‐free, 445 fragmentation pattern, 428, 433, 434 label‐free technologies, 461 MALDI–TOF–MS, 433 BLI, 461 molecular weight determination, 427, 433 flow cytometry, 461 QTOF, 431 Octet, 461 Medarex, 287 SPR, 461 Medi3902, 287 , 78 Medi4893, 286, 287 LDH, 448 MedImmune, 286 leached residual protein A, 442 , 78, 131–133, 238, 246 Lemtrada, 81 Mepolizumab, 78 leucine, 444 Merck, 287 leukemia, 239–240, 241, 253–254 method licensure, 518–519, 531–533 parameter comparison, 467 ligand‐receptor interaction, 85–86, 90 recovery estimation, 467 light chain, 426, 427 response comparison, 467 Limulus amoebocyte lysate (LAL), 443 Miller, Anne Scheaf, 285 Linkers (ADC), 612 MM302, 95, 97 lipocalins, 23 monoclonal antibodies (mAbs), 564, lipopolysaccharides, LC–MS/MS, 427, 428, 566–567 433, 434, 436, 441, 443, see also mass background, 564–565 spectrometer Fc‐optimized, 557 liposomes, 581, see also nanotechnology, for history of, 1–37 drug transport targets, 113–139 with bufalin, 581 XmAb, 555–556 Lucentis, 300, see also monomer, 439 Lucentis VEGF, 80 monomethyl auristatin E, 82 , 223–224, 249–250 mouse , 221, 226, 251–253, 255–256, transgenic, 449 258 xenograft, 449 lyophilization, 443 mouse model, 556, 575–576 Ixekizumab, 78 MS/MS, 434 MRSA, 285 MabCampath, 81 Methicillin‐resistant Staphylococcus MabThera, 75, 81 aureus Penicillium, 285 macrophage, 448 Muckle–Wells syndrome, 79 macular edema following retinal vein multiple myeloma, 78 occlusion (RVO), 293, 300, 303, 304 multiple sclerosis (MS), 81, 293, 294, 308, MALDI‐TOF, 289 310 mammalian cell line development, 396–404 multiproduct manufacturing facilities, MassBio, 287 concerns in, 359 mass measurement murine NS0 myeloma cells, 396–398 intact, 427 muromonab‐CD3, 81, 91, 293, 312−314, reduced, 428 315 mass spectrometer, see also LC–MS/MS mutagenesis, 549, 555–557 b/y ion pairs, 434 MacroGenics, 556–557 deconvoluted, 434 XmAb, 555–556

0002883283.indd 648 11/14/2016 5:29:40 PM Index 649

mutations, amino acid, 428 OPG, see osteoprotegerin Mylotarg, 81 Orthoclone, 81 Orthoclone OKT3, 312, see also naming convention, 505, 507–508, 511 muromonab‐CD3 nanomedicine, 579, see also orthogonal biophysical techniques nanotechnology analytical ultracentrifugation, 440 nanosight, 443 field‐flow fractionation, 440 nanotechnology, 579–581 light scattering, 440 definition of, 579 osteoporosis, 293, 304, 306 for drug transport, 579–581 osteoprotegerin (OPG), 305, 306 nanorods, 580 oxidation of methionine, 161 natalizumab, 80, 92–93, 293, 294−297, 314, ozogamicin, 81 315 natural killer cells, 448 Palivizumab, 81, 87 , 78 Pall Life Sciences, 445 neonatal Fc receptor (FcRN), 115, 175–176, , 80, 90, 92, 97, 242–244 see also FcRn patent dance, 509, 510, 512 neoplastic diseases, 127–135, see also paracellular transport, 205 hematological malignancies, solid parallelism malignancies testing, 467 neovascular age‐related macular acceptance criteria, 468 degeneration, see wet AMD lack of, 468 neuroblastoma, 78 paroxysmal nocturnal hemoglobinuria neutrophils, 448 (PNH), 80, 293, 297, 298, 299 NFAT‐RE, 448 particulate matter, 443 , 78, 90, 93 passive immunization, 27–28, 33 nonclonal expression technologies, patent infringement, 522–527, 529 341–343 patenting a biosimilar, 539–541 noncompartmental model, 205–206 patent litigation, 527–539 noninvasive fluorescence sensor patent protection period, 565 technology, 416, see also cell culture PcrV (P. aeruginosa), 286 technology transfer injectisome, 286 Nonnatural amino acids, 599 PD1, 78, 90, 93–94 nonneovascular age‐related macular peak concentration, 204 degeneration, see dry AMD PEG conjugation, 572, see also half‐life, N‐terminal residues, 159 optimization of Nucala, 78 and nanotechnology, 580 nuclear factor kappa‐B (NF‐κB) ligand pegylation, 572 (RANKL), 304−307 , 90, 93, 244–246 pembrolizumab Keytruda, 79 , 78, 79, 93–94, 96, 238–240 peptide mapping , 79, 93–94, 240–241 characterization by, 441 Okt3, 81 RP‐HPLC, 428 oligomers, 439 tryptic, 428, 433, 436, see also proteases, oligosaccharides, branching of, 432 trypsin omalizumab, 80, 87 perfusion cell culture, 360 Opdivo, 81 peripheral blood mononuclear cell, 448

0002883283.indd 649 11/14/2016 5:29:40 PM 650 Index

, 79, 93, 96, 246–248 primates, nonhuman, 449, 450 Perjeta, 79 process characterization, 413–414 pH, 446, 449 process‐related modifications Phage display, 65 fermentation, 438, 441 phage display technology, 548, 578, see also purification, 436, 438, 441, 442 half‐life, extension strategies process validation, 413–414 pharmacology, 202–204, 483–484 definition of, 414 pharmacodynamics (PD), 208–211, 449, profile, glycosylation, 426, see also 450, 458–462, 504, 506 glycosylation; posttranslational Pharmacoeconomic, 290 modifications pharmacokinetic (PK), 204–208, 446, 450, programmed cell death (PCD), 96 458, 463, 504, 506 progression‐free survival, 549 absorption, 204 prokaryotic system, 30–32 analysis, 486–488 Prolia, 79, 304, see also denosumab clearance, 205 proliferation, 447 distribution, 204–205 Promega, 448 impact of ADA, 469 proteases models, 205–206 Asp‐N, 427 parameters, 206, 208 chymotrypsin, 427, 428, 434 pharmacovigilance, 508 Glu‐C, 427, 428 pH‐dependent recycling, 563, 567 trypsin, 427, 428, 433, 434 phenylalanine, 444 protein phosphopantetheinyl transferase, 608 degradation, 443 photometric test, 443 impurity, 442 PHS Act, 504 residual, 442 physiologically based pharmacokinetic stability, see antibody, stability (PBPK) model, 206 structural moieties of, 431, 443 plantibodies, see transgenic plants Protein A, 287 PNGase, 427 advantages, 354–356 Point‐of‐care diagnostics, 289 disadvantages, 356 polishing steps, 354,356 expense, 356,358 polyethylene glycol (PEG), 572, 580 leeching of, 356 polymorphism, genetic, 547, 557 product aggregation, 357 polysaccharide, 74 yields, 356 polysialylation, 573, see also half‐life, protein A, alternatives to optimization of artificial protein A (ApA), 357 Portrazza, 78 nucleotide binding site (NBS), 357 positive control, 469, 471 processes based on conventional post‐translational modifications (PTM), chromatography, 358 155–183,181–182, 575, 599 protein A mimetic ligand (PAM), 357 potency verification, 465 protein G, 354 PNH, see paroxysmal nocturnal ProteOn, 445 hemoglobinuria Pseudomonas aeruginosa, 286 Praluent, 78 Psl (P. aeruginosa), 286 Praxbind, 78 Psoriasis, 78, 80 preclinical development, 479–488 Purification, see process‐related precision medicine, 284 modifications, purification

0002883283.indd 650 11/14/2016 5:29:40 PM Index 651

purine nucleotide synthesis salvage pathway, 552, 553, 565 salvage, see salvage pathway Sapidyne Instruments, Inc., 445 de novo, see de novo pathway SAR279356, 286 sarilumab, 78 qPCR, 442 Scarff, Matthew, 285 quality control, 428, 433, 439 scFv, 71 Quality by Design (QbD), 479–480, 489, see Schneewind, 287 also biosimilar preclinical development SDS–PAGE quasi‐species concept, 330–333 Coomassie blue stain, 436 quaternary structure, 163–165 gel analysis, 427, 436 silver stain, 438 , 79, 87, 93, 248–250 secondary structure ranibizumab, 80, 87, 293, 300−304, 314, 315 alpha‐helix, 431 RANKL, 79, 86, 88, 90, see also nuclear beta‐sheet, 431 factor kappa‐B (NF‐κB) ligand beta‐turn, 431 Raptiva, 80 Secukinumab, 78, 88 Raxibacumab, 79, 88 sedimentation velocity analysis, 441 receptor downregulation, 85, 96–97 selection systems, 333–335 receptor signaling, 90 SensiQ, 445 recombinant , 442 serum sickness, 288 recombinant glycoproteins, severe eosinophilic asthma, 78 171–172 sialyation, 179 Redotux, 271–272, 276–280 Sierra Biosensor, SPR‐2, 445 reference product (RP), 504 signaling activation, 86, 96 use of, 505–506 signaling blockade, 86, 90 Remicade, 81, 447 , 79, 88 Removab, 80 Simponi, 79 Remsima, see infliximab Simulect IL‐2R, 81 renal cell cancer, 224–225 single‐cell isolation, 16 Reopro GPIIb/IIIa, 81 single use purification equipment, 359, 370 Repatha, 78 site integration technology, 399 repeated dose toxicity, 450 site‐specific bioconjugation, 595 Repligen, 442 solid malignancies, 131–135, reporter assay, 448 231–232 Reptiles, 72 Soliris, 80, 297, see also eculizumab reslizumab, 78 Sortase, 608 resurfacing, 6–7 specificity‐determining residues (SDRs), 6 retention time, 428, 432 spectrotype, 440 rheumatoid arthritis, 79, 449 stable pool technologies, 341–343 RoActemra, 79 Staphylococcus aureus, 285 robustness, 465, 469 Stelara IL‐12/23, 80 , 81, 90–94, 96, 250–256, stepwise approach, 505 269–280, 447–449 surface plasmon resonance, 444–446 RSV, 81, 86–87 Sylvant, 79 RVO, see macular edema following retinal Sym009, 288 vein occlusion Synagis, 81 ruggedness, 465, 469 systemic lupus erythematosus (SLE), 79

0002883283.indd 651 11/14/2016 5:29:40 PM 652 Index

targeted drug delivery, 85, 97–98 ultracentrifugation, analytical, 440 taxol, 448 Unituxin, 78 T‐cell receptor (TCR), 308, 309, 312 USAN, 64 TCR, see T‐cell receptor ustekinumab, 80, 88 teleostei, 67 tertiary structure, 431, 434 vaccination, 26–27 TGE, 341–343 vectibix, 80 Thermo Fisher Q Exactive, 431, 434 vedolizumab, 93 thiazolidine, 604 vedolizumab entyvio, 79 tiuxetan, 80 vedotin, 79 TNFα, 86–87, 90, 447, 449 VEGF, 80, 86–87, 90–91, 93, TNFR, 85–87, 89 300−304 tocilizumab, 79, 92, 94 VEGFR, 86, 90, 93 , 256–258 viral contamination, 442 tositumomab‐I131, 80, 92, 94 virus inactivation, 354 totality of evidence, 505, 506, 511 toxicity, 442, 446, 450 Waters, 431, 434, see also mass transcellular transport, 205 spectrometer, QTOF transglutaminase, 607 Welch, Curtis, 284 transcytosis, 175, 563, 567, 582, 583 wet AMD, see subentry of age‐related transfection, see cell line development macular degeneration transgenic animal cells, 9–12, 34 whole cell assays, 447, 449 transgenic plant cells, 32–34 World Health Organization (WHO), 442, trastuzumab, 81, 90–91, 93, 95, 97, 504, 505, 506, 508 258–262, 447, 448 written description requirement, , 93, 95, 97 540–541 trifunctional antibodies, 76 trimer, 439 Xgeva, 304, see also denosumab two‐compartment model, 206 Xolair, 80 trypsin, see proteases, trypsin TUNNEL assay, 448 Yervoy, 79 Tysabri, 80, 294, see also natalizumab Zenapax, 81, 308, see also daclizumab ulcerative colitis, 79, see also autoimmune Zevalin, 80 diseases, inflammatory bowel disease Zinbryta, 81

0002883283.indd 652 11/14/2016 5:29:40 PM