629

Index a anticancer drug discovery 477, 478 abatacept 171, 172 anti-citrullinated antibodies (aCPAs) Abbreviated New Drug Application (ANDA) 137 294 antidiabetic drug discovery 477 absorption enhancers 343 anti-drug-antibodies (ADAs) 224, 245, 352 absorption, distribution, metabolism, antifungal drug discovery 477 excretion, and toxicity (ADMET) of drugs antigen presenting cells (APCs) 392–394, 130 430 N-acetyl cysteine 611 antigen targeting 437 acid-degradable hydrogel-based particles – humoral immune response 437, 438 (ADHPs) 398, 399 antimicrobial drug resistance 477 actinorhodin 26 antiviral assay (AVA) 228, 329 active pharmaceutical ingredients (APIs) applicability domain 121 224, 225 aqueous two-phase extraction (ATPE) activity-based probe profi ling (ABPP) 473, systems 186 474 Arabidopsis 510, 511 activity-based probes (ABPs) 472 arachidonic acid (ARA) 609, 610 adalimumab 322 aranciamycin adjuvants for recombinant vaccines 441, – biosynthetic gene expression production 442 18 adsorption chromatography 188 – microorganism production 16 affi nity-based probes (AFBPs) 472 – structure 17 affi nity chromatography 188 archaeosomes 402, 403 Agrobacterium tumefaciens 61 L-arginine 611 AIDS vaccine 375–378 arnica Montana 616 alefacept 172 Artemisia annua 511, 512 allele-specifi c inhibition (ASI) 576 artemisinic acid 20, 514 alternative therapies 605, 606 artemisinin 494, 511, 512 Alzheimer’s disease (AD) 488 artifi cial lymph node (ALN) 127, 128 amino acids, essential 610, 611 artifi cial proteins 171, 172 amorpha-4,11-diene 20 assays, in vitro 129, 130 amorphadiene synthase 21 atmospheric pressure chemical ionization amphiphilic block-graft copolymers (APCI) 212 405–407 attenuated bacterial vaccines, recombinant amphotericin 433 – microorganism production 16 aureothin Anthriscus sylvestris 508, 509 – microorganism production 16 antibody dependent cellular cytotoxicity automated rule induction systems (ARIS) (ADCC) 228, 229, 323 121

Pharmaceutical Biotechnology: Drug Discovery and Clinical Applications, Second Edition. Edited by Oliver Kayser, Heribert Warzecha. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA. 630 Index

avilamycin biological therapies 574 – microorganism production 16 – cell therapy 575, 576 – structure 17 – gene therapy 576 – monoclonal antibodies 575 b – recombinant human proteins 575 Bacillus species – RNA interference 576, 577 – B. subtilis 22 Biologics License Application (BLA) 265, – recombinant therapeutic proteins 30, 31 295 bacterial–fungal interactions 19 biomarkers 136–138 basiliximab 321 – personalized medicine 559, 560 batch cell microarrays 469 Biomolecular Interaction Network Database batch chromatography 196, 197 (BIND) 134 bead array technology 234 bioreactors, dynamic 127, 128 Beer–Lambert Law 201 Biosimilar Act 296 beta-amyloid senile plaques (SPs) 488 biosimilars 3, 174–176, 285, 286, 332, 333 bicistronic tetracycline-responsive expression – analysis method development 328–330 cassette (NTA) 81 – defi nition 287–290 binding assays 222–224 – development and requirements 325, bioactivity 326 – antibody dependent cellular cytotoxicity – fi rst wave in EU 305, 306, 313 (ADCC) 228, 229 – – erythropoietin (EPO) 307–310 – antiviral assay (AVA) 228 – – granulocyte-colony stimulating factor – assay qualifi cation and validation 230, (G-CSF) 310–312 231 – – human (hGH) 306, – bead array technology 234 307 – binding assays 222–224 – – interferons and (rejected) 312, – bioassays 219–221 313 – cell-based assays (CBA) 225, 226 – non-clinical and clinical development – complement dependent cytotoxicity (CDC) 330, 331 229 – patents 297–305 – cytotoxicity assay 227, 228 – process development 327, 328 – defi nition 221, 222 – regulation 266, 267, 297 – enzyme linked immuno-spot (ELIPSPOT) – – basic principles 290, 291 assays 230 – – European guidelines 291–294 – Fcγ-receptor binding assays (Fcγ-RA) 222, – – other territories 296, 297 223 – – USA 294–296 – fl ow-cytometric assays (FACS) 230 – second wave in EU – immunogenicity testing 234, 235 – – PEGylated protein drugs 313–316 – ligand binding assay (LBA) 222 – – recombinant antibodies and Fc-fusion – neutralizing assay 227 proteins 316–325 – proliferation assay 226 bird egg-extracted biopharmaceuticals 78 – reporter gene assays 229, 230 black cohosh 616 – surface plasmon resonance spectroscopy blood-extracted biopharmaceuticals 77 (SPR-spectroscopy) 223, 224 bone marrow-derived mesenchymal stem biobetter 64 cells (BM-MSCs) 484 biobricks 9 bromelain 616 biochips for personalized medicine 566, butyrylcholinesterase 75, 76 567 biodegradable nanoparticles c – acid-degradable hydrogel-based particles C-terminal sequencing 217, 218 (ADHPs) 398, 399 8-cadinine hydroxylase 21 – poly(D,L-lactic-co-glycolic acid) (PLGA) and (+)-δ-cadinine synthase 21, 513, 514 polylactic acid (PLA) 396–398 (+)-camphor 21 bioinformatics 140, 141, 560 canakinumab 322 Index 631 cancer vaccines, personalized 577, 578 chaperone systems 27 – see also nanobiotechnological strategies for chemical ionization (CI) 212 cancer vaccines chemical microarrays 467 capillary electrophoresis (CE) – dry chemical microarray 468 – recombinant protein analysis 209, 210 – immobilized technology 467 capillary gel electrophoresis (CGE) 210 – small molecule microarray (AMM) 467, capreomycin 468 – biosynthetic gene expression production – solution phase microarray 468, 469 18 chemical proteomics 471 capture chromatography 189, 190 – applications 475 cardarchaeol 403 – probe structure 471, 472 β-carotene 20 – strategies for drug discovery 473 Carthamus tinctorius 65 – – activity-based probe profi ling 473, 474 (−)-carvone 20 – – fragment-based probe profi ling 474 cation-exchange chromatography (CEX) chemistry, manufacturing, and controls 207, 208 (CMC) 292, 293, 325 cationic liposomes–DNA complexes (CLDC) chikungunya 443 402 Chinese hamster ovary (CHO) cells 43 cell culture systems – high-throughput bioprocess development – cell fractions 122, 123 50, 51 – cell monolayers 123, 124 – process concepts 44–46 – challenge on a chip 129 – production cell lines 46, 47 – co-cultures, organotype cultures, and – rapid generation of high-producing cell reconstituted tissue constructs 124 lines 47, 48 – dynamic bioreactors 127, 128 – stabilty of expression 49, 50 – in vitro assays 129, 130 chlorobiocin – multi-organ systems 128, 129 – biosynthetic gene expression production – soma specifi c in vitro systems 127 18 – stem cells 125–127 chondroitin 615 – suspension cultures 123, 124 chromatography 187 – tissue engineering 125 – adsorption chromatography 188 – Vitrocellomics project 130 – affi nity chromatography 188 cell microarrays 469 – batch chromatography 196, 197 – applications 470 – capture chromatography 189, 190 – formats 470 – column chromatography 187, 188 – types 469 – gas chromatography–mass spectrometry – – batch or non-positional 469 (GC-MS) 534 – – positional 469 – hydrophilic interaction chromatography cell therapy 575, 576 (HILIC) 207 cell-based assays (CBAs) 219–221, 225, 226 – hydrophobic interaction chromatography cell-based proliferation assays (CSF) 329 (HIC) 189, 192, 193 cellomics 132 – hydroxyapatite (HA) chromatography 192 Center for Biologics Evaluation and – immobilized metal ion affi nity Research (CBER) 262–265 chromatography (IMAC) 190 Center for Devices and Radiological Health – ion-exchange chromatography 191, 192, (CDRH) 265 207, 208 Center for Drug Evaluation and Research – liquid chromatography–mass spectrometry (CDER) 262–265 (LC-MS) 534, 535 centrifugation 181, 182 – membrane chromatography 188, 189 cephamycin C – micellar electrokinetic chromatography – biosynthetic gene expression production (MEKC) 210 18 – polishing chromatography 191–193 cetuximab 321 – reversed-phase chromatography (RPC) challenge on a chip 129 193, 206, 207 632 Index

– simulated moving bed chromatography – biosynthetic gene expression production (SMBC) 193, 194 18 – size-exclusion chromatography (SEC) – microorganism production 16 193, 205, 206 data visualization 460 – ultrahigh pressure liquid chromatography– Database of Interacting Proteins (DIP) 134 mass spectrometry (UPLC-MS) 535 databases for systems biology 487 circumsporozoite (CS) 439 daunorubicin cisplatin 463 – microorganism production 16 clarifi cation of liquids – structure 17 – centrifugation 181, 182 dead-end fi ltration 183, 184 – fi ltration 182–185 dehydrophos – increasing effi ciency 185, 186 – biosynthetic gene expression production cleaning and/or steaming in place (CIP/SIP) 18 189 denosumab 322 click chemistry 474 6-deoerythronolide B (6dEB) 19–20 clinical imaging 138–140 descriptor-based QSAR methods 458 co-cultures 124 development of new technologies into Cohn process 186 biomedicines 146 column chromatography 187, 188 – drug discovery and development 113, Committee for Medicinal Products for 114 Human Use (CHMP) 287 – models 114–116 comparative genomic hybridization (CGH) – strategic tool use 141, 142 567 – – patient involvement 144, 145 complement dependent cytotoxicity (CDC) – – strategies 142, 143 229, 323 – – systems biology 143, 144 complementary determining regions (CDR) – – tool variety 142 322 – tools available 116, 117 complex cell systems 485, 486 – – bioinformatics 140, 141 complex chromosomal rearrangements – – biomarkers 136–138 (CCRs) 556 – – clinical imaging 138–140 computational pharmacology 457 – – high-content screening (HCS) 131 computational therapeutics 457 – – high-throughput screening (HTS) 131 conjugate vaccines 429 – – in vitro systems 122–131 conjugated linoleic acid (CLA) 610 – – modeling and simulation 134–138 copy number variation (CNV) 557, 558 – – omics approaches 131–134 cross-fl ow fi ltration 183, 184 – translation as two-way process 145, 146 crystallization 196 dhfr gene 46, 47 cucuminoids 515 diafi ltration 194, 195 α-cyano-4-hydroxy-cinnamic acid (CHCA) dialectic of vaccines 426, 427 213 dietary 612 cycloserine dietary fi bers 606 – biosynthetic gene expression production differential scanning calorimetry (DSC) 18 240 cysteine 611 dihydrofolate reductase (DHFR) 43 cytogenetics and personalized medicine 2,5-dihydroxybenzoic acid (DHB) 213 567, 568 dimethyl dioctadecyl ammonium bromide cytomics 132, 568 (DDAB) 401 cytopathic effect (CPE) 228 diode array detection (DAD) 205, 206 cytotoxic T lymphocytes (CTLs) 392–403 1,2-dioleoyl-3-dimethyl ammonium propane cytotoxicity assay 227, 228 (DODAP) 402 1,2-dioleoyl-3-trimethyl ammonium propane d (DOTAP) 401 daclizumab 321 N,N-dioleyl-N,N-dimethyl ammonium daptomycin chloride (DODAC) 401 Index 633 diphtheria, tetanus, and pertussis (whooping dry chemical microarray 468 cough) vaccine (DTaP) 428 dynamic binding capacity (DBC) 187, 188 dipoyl-7-aminodesacetoxycephalosporanic dynamic bioreactors 127, 128 acid 11 dynamic light scattering (DLS) 241 Discrete Multiple Organ Culture (IdMOC®) dysbiosis 611 system 128 disposable bioreactors 51, 52 e DNA microarrays 463 echinacea 615 – application to drug discovery 465, 466 ecome 132 – – anticancer drugs 466 eculizumab 321, 322 – – bacterial disease diagnosis and therapy eggs see bird eggs 466 eicosapentaenoic acid (EPA) 610 – – drug toxicity prediction 466 electron impact (EI) 212 – fabrication 464, 465 electrospray ionization (ESI) 212 DNA vaccines 429 embryonic germ cells (EGCs) 91, 92 docosahexaenioc acid (DHA) 602 embryonic stem cells 90, 91 docosahexanenoic acid (DHA) 609, 610 emulsions, sub-micron 404, 405 Donnan effect 243, 244 encephalomyocarditis virus (EMCV) 228 dose–concentration–effect relationship 338 Engrailed-2 (EN2) 137 downstream processing (DSP) 179, 180 enucleation 94, 95 – chromatography 187 enzyme linked immuno-spot (ELIPSPOT) – – capture chromatography 189, 190 assays 230 – – column chromatography 187, 188 enzyme-linked immunosorbent assay – – membrane chromatography 188, 189 (ELISA) 219, 222 – – polishing chromatography 191–193 ephedra 615 – clarifi cation 181 epigenomics 132 – – centrifugation 181, 182 epitholone 19, 20 – – fi ltration 182–185 Erwinia uredovora 20 – – increasing effi ciency 185, 186 erythromycin – crystallization 196 – microorganism production 16 – fi ltration, fi ne 194 – – E. coli 19, 20 – – ultrafi ltration/diafi ltration 194, 195 erythropoietin (EPO) 307–310 – – virus fi ltration 195, 196 – products 3 – general principles 180, 181 Escherichia coli – recent developments 196, 197 – host for natural product synthesis 19 downstreaming fi ll and fi nish 242, 243 – – isoprenoids 20, 21 doxorubicin – – polyketides 19, 20 – structure 17 – – recombinant therapeutic proteins drug approval 257 27–30 – EU regulation essential amino acids 610, 611 – – EMA 259, 260 ethical considerations – – framework 257, 258 – patents 274, 281 – – new drug approval routes 260–262 – – access to technology 277–280 – international regulatory harmonization – – benefi t sharing 280, 281 265, 266 – – no patents on nature 275, 276 – regulation of biosimilars 266, 267 – – threats to human dignity 276, 277 – US regulation 262 EU – – approvals procedure 263–265 – biosimilars 313 – – CDER and CBER 263 – – erythropoietin (EPO) 307–310 drug reactions (ADRs) 567 – – granulocyte-colony stimulating factor drug-induced liver injury (DILI) 145, 146, (G-CSF) 310–312 147 – – guidelines 291–294, 305, 306 drug-neutralizing antibodies (NAbs) 224, – – human growth hormone (hGH) 306, 225, 227 307 634 Index

– – interferons and insulin (rejected) 312, food (dietary) supplements 604 313 Food and Drug Administration (FDA) 262 – – PEGylated protein drugs 313–316 foot-and-mouth disease (FMD) 378 – – recombinant antibodies and Fc-fusion formulation strategies 235 proteins 316–325 – recombinant proteins 244, 245 – drug regulation – – analytics 240, 241 – – EMA 259, 260 – – downstreaming fi ll and fi nish 242, 243 – – framework 257, 258 – – dry formulations 238 – – new drug approval routes 260–262 – – highly concentrated protein formulations European Federation of Pharmaceutical 243, 244 Industries and Associations (EFPIA) 115 – – market development 241, 242 European Product Assessment Reports – – new proteins and related formulation (EPAR) 305 aspects 244 existing knowledge 117, 118 – – screening 239, 240 expression quantitative trait loci (eQTL) 147 – – stability of protein solutions 235–237 expression vectors – vaccines 245–247 – recombinant therapeutic proteins 31 – – analytics 247, 248 – – mRNA stability 33 Fourier transform infrared spectroscopy – – promoter choice 32, 33 (FTIR) – – replication rate 31, 32 – recombinant protein analysis 203–205 – – tag fusion 33 Fourier transform ion cyclotron resonance – – translation initiation 33, 34 (FTICR) analyzers 213 fowlpox (FP) virus 432 f fragment-based probe profi ling 474 Familial Cold Auto-infl ammatory Syndrome freeze drying 238 (FCAS) 5 functional foods see nutraceuticals fast atom bombardment (FAB) 212 fusion proteins 5 fatty acids 609, 610 fusogenic liposomes (FLs) 403 Fc-fusion proteins 316–325 Fcγ-receptors g – binding assays (Fcγ-RA) 222, 223 garlic 616 – neonatal Gaucher’s disease 63, 64 – – role in protein disposition 350, 351 gel elecrophoresis federicamycin – recombinant protein analysis 208, 209 – biosynthetic gene expression production gelatin nanoparticles 404 18 gene expression profi le screens (GEPS) fi eld desorption/fi eld ionization (FD/FI) 466 212 gene of interest (GOI) 46, 47, 49 fi ll 242, 243 gene pharming 72 fi ltration 182–185 gene polymorphisms 480, 481 – fi ne 194 gene therapy 576 – – ultrafi ltration/diafi ltration 194, 195 GeneGo 134 – – virus fi ltration 195, 196 GeneQuest 134 fi nish 242, 243 genetic variations in human genome 554, fl avonoids 515, 516, 607, 608 555 fl ow-cytometric assays (FACS) 226, 230 – complex chromosomal rearrangements fl uorescence activated cell sorting (FACS) (CCRs) 556 48 – copy number variation (CNV) 557, 558 fl uorescence in situ hybridization (FISH) – insertions and deletions (INDELs) 556, 567 557 fl uorescence spectroscopy – large-scale variations 557 – recombinant protein analysis 202, 203 – sequencing 565 follow-on biologics (FOBs) 294 – single nucleotide polymorphisms (SNPs) food additives 604 555, 556 Index 635

– structural variations 558, 559 Hofmeister series 186 genetically modifi ed (GM) organisms 603, host cell proteins (HCPs) 180, 327, 329 619, 620 HTS 239, 240 genistein 494, 510, 511 human anti-mouse immunoglobulin genome shuffl ing 24, 25 antibody (HAMA) response 352 genome-wide association studies (GWAS) Human Brain Proteomics Project (HBPP) 146, 147, 565, 566 134 germacrene D-4-ol synthase 21 human decay accelerating factor (hDAF) Giardia lamblia guanine PRT (GPRT) 460 582 Gingko biloba 615 human dignity, threats to 276, 277 ginseng 615 human embryonic stem cells (hESCs) 126 α-glucocerebrosidase 7 human genome project (HGP) 471, 477, β-glucocerebrosidase 7, 8 478 glutamine 611 human glucocerebrosidase glutamine synthetase (gs) gene 47 – plant origin 63, 64 glutathione S-transferase (GST) 33 human growth hormone (hGH) 296, 306, glycine 46 307 glycolysation 7 human insulin goldenseal 615 – prokaryotic cell production 36 golimumab 322 human papilloma virus (HPV) 410, 433 Gossypium hirsutum 513, 514 human somatropin (STH) 34, 35 gossypol 513, 514 hydrodynamic radius 209 granulocyte colony-stimulating factor hydrophilic interaction chromatography (G-CSF) 305, 306, 310–312 (HILIC) granulocyte-macrophage colony stimulating – recombinant protein analysis 207 factor (GM-CSF) 305, 306 hydrophobic interaction chromatography green fl uorescent protein, GFP 229 (HIC) 189, 192, 193 hydroxyapatite (HA) chromatography 192 h 5-exo-hydroxycamphor 21 hairy root cultures 497 hypoxanthine 46 half-maximum effective concentration (EC50) 221 i haplotypes 479 imaging, clinical 138–140 heat shock protein (HSP) 407 imiglucerase 7, 8 hematopoietic stem cells (HSCs) 484 immobilized metal ion affi nity herbal medicinal products (HMPs) 527 chromatography (IMAC) 190 herbal nutraceuticals 604, 605, 613, 614 immune cell binding ligands (ICBL) 430 hierarchical cluster analysis (HCA) 536, immunogenicity 537 – protein pharmacokinetics 352, 353 high fi delity fallacy 116 – testing 234, 235 high throughput formulation screening immunopotentiating reconstituted infl uenza (HTFS) 239–241 virosomes (IRIVs) 410, 411 high-content screening (HCS) 131 in chemico approach 118, 119 high-throughput screening (HTS) 131, 453, in silico pharmacology 456, 457 454, 488, 489 – applications 461 – see also microarray HTS technology; RNA – data visualization 460 interference (RNAi) screening – quantitative structure–activity relationship – quality, quantity and cost-effectiveness (QSAR) 458 454, 455 – – descriptor-based methods 458 – stem cells 483 – – knowledge-based methods 458 – – advantages 484 – – rule-based methods 458 – – applications 484, 485 – virtual affi nity profi ling 459 – – defi nition of stem cells 483, 484 – – ligand-based methods 459, 460 – traditional versus novel targets 455, 456 – – target-based methods 460 636 Index

– virtual ligand screening 457, 459 integrative virtual screening 461 – – ligand-based methods 459 – applications 463 – – target-based methods 459 – – cisplatin tumor therapy 463 in silico techniques – ligand-based methods 462 – drug discovery 120, 121 – target-based methods 462 – methods 119, 120 intellectual property (IP) protection 297, – modeling and simulation 485 298 – toxicology 121, 122 interactomics 132 in silico toxicology 121, 122 interferon in vitro assays 129, 130 – rejected biosimilar 312, 313 in vitro systems 122 interferon-stimulated response elements – assays 129, 130 (ISRE) 229, 230 – cell fractions 122, 123 International Conference on Harmonization – cell monolayer or suspension cultures of Technical Requirements for 123, 124 Registration of Pharmaceuticals for – challenge on a chip 129 Human Use (ICH) 265, 266 – co-cultures, organotype cultures, and international non-proprietary name (INN) reconstituted tissue constructs 124 290, 309 – dynamic bioreactors 127, 128 intranasal administration of proteins 342 – multi-organ systems 128, 129 inverted terminal repeats (ITRs) 89 – soma specifi c systems 127 ion cyclotron resonance (ICR) analyzers – stem cells 125–127 213 – tissue engineering 125 ion trap (IT) analyzers – Vitrocellomics project 130 ion-exchange chromatography 191, 192 independent component analysis (ICA) – recombinant protein analysis 207, 208 536, 537 iontophoresis 342 induced pluripotent stem cells (iPSCs) 92, iron oxide nanoparticles 407, 408 93, 126, 127, 484 isofl avon syntase (IFS) 510, 511 infectomics 477 isoleucine 611 infl iximab 321 iso-migrastatin infl uenza virus (H1N1) 65 – biosynthetic gene expression production informatics 140 18 informed consent 382 isoprenoids Ingenuity Pathway Analysis (IPA) 134 – E. coli production 20, 21 inhalation administration of proteins 341, 342 k Innovative Medicines Initiative (IMI) 115 kaempferol 10 in-process controls (IPC) 328 kava 616 insertions and deletions (INDELs) 556, 557 knowledge-based QSAR methods 458 insulin 3 knowledge-based systems (KBS) 121 – prokaryotic cell production 36 – rejected biosimilar 312, 313 l – saffl ower production 64, 65 lab-on-a-chip (LOC) 129 6 α-lactalbumin 73 integration defi cient lentiviral vectors (IDLV) β-lactoglobulin (BLG) 73, 74 432, 433 landomycin A integrative genomics 476 – biosynthetic gene expression production – applications 476, 477 18 – – anticancer drug discovery 477, 478 – microorganism production 16 – – antidiabetic drug discovery 477 Lavandula laftifolia 511 – – antifungal drug discovery 477 lentiviruses 87, 88 – – infectomics and antimicrobial drug 611 resistance 477 leuprorelin 340 – – toxicogenomics for hepatotoxicity 478 ligand binding assay (LBA) 222 Index 637 ligand epitope antigen presentation system – – ionizer types and sources 212, 213 (LEAPS) 430 – – mass analyzers 213–215 (−)-limonene 20 – – N- and C-terminal sequencing by limonene synthase 21 MALDI-ISD 217, 218 α-linolenic acid (ALA) 610 – – operating principle 211 lipids 609, 610 – – peptide mass fi ngerprinting (PMF) lipomic profi ling 475, 476 215–217 – applications 476 – – sample introduction modes 211, 212 – – rosiglitazone in diabetes mellitus mass-to-charge ratio (m/z) 211 treatment 476 master cell bank (MCB) 327, 380 liposomal nanovectors 399, 400 matairesinol 607 – archaeosomes 402, 403 matrix assisted laser desorption ionization – fusogenic liposomes (FLs) 403 (MALDI) 212, 213, 214 – long-circulating liposomes 400, 401 – MALDI In-Source Decay (MALDI-ISD) – positively charged liposomes 401, 402 – – N- and C-terminal sequencing 217, liraglutid 7 218 log reduction values (LRVs) 180, 195 medical foods 603, 619, 620 long terminal repeats (LTRs) 86 medicinal plants 527, 528, 546, 547 long-circulating liposomes (LCLs) 401 – bioanalytical tools 528–530 loss of heterozygosity (LOH) 576, 577 – – data processing 535–537 luteinizing hormone releasing hormone – – mass spectrometry (MS) 532, 533 (LHRH) 340 – – mass spectrometry (MS), direct injection lycopene 20, 23 533 lysine 611 – – mass spectrometry (MS), GC-MS 534 – – mass spectrometry (MS), LC-MS 534, m 535 major histocompatibility complex (MHC) – – nuclear magnetic resonance (NMR) 392 531, 532 maltose-binding protein (MBP) 33 – – sample preparation 530, 531 mammalian cell production 43, 53, 54 – metabolic engineering – CHO-derived production cell lines 46, 47 – – artemisinin 511, 512 – disposable bioreactors 51, 52 – – genistein 510, 511 – high-throughput bioprocess development – – gossypol 513, 514 50, 51 – – morphine 512, 513 – process concepts 44–46 – – 508, 509 – rapid generation of high-producing cell – – scopolamine 509, 510 lines 47, 48 – – spearmint limone synthase 511 – stability of expression 49, 50 – metabolomics applications 538 – transient gene expression (TGE) 52, 53 – – discrimination for classifi cation Market Authorization Application (MAA) 538–540 291 – – identifi cation of bioactivity 543, 544 Marketing Authorization Applications – – metabolite characterization 540, 541 (MAAs) 260, 261 – – plant toxicity 545, 546 mass spectrometry (MS) – – quality control 541–543 – medicinal plants 532, 533 – – study effi cacy 544, 545 – – data processing 535, 537 medium-chain fatty acids (MCFAs) 610 – – direct injection 533 medium-chain triglycerides (MCTs) 610 – – gas chromatography–mass spectrometry membrane chromatography 188, 189 (GC-MS) 534 mesenchymal stem cells (MSCs) 484, 576 – – liquid chromatography–mass metabolic engineering 491–495 spectrometry (LC-MS) 534, 535 – challenges – recombinant protein analysis 211 – – cell comparmentalization and tissue – – detectors 215 differentiation 507, 508 – – disulfi de linkage analysis 218, 219 – – species specifi c pathways 507 638 Index

– – unexplored regulation of secondary microarray HTS technology metabolism 506, 507 – see also high-throughput screening (HTS) – – unpredicted or unexpected outcome – cell microarray 469 508 – – applications 470 – future prospects 516, 517 – – formats 470 – medicinal plant biotechnology – – types 469, 470 – – artemisinin 511, 512 – chemical microarray 467 – – genistein 510, 511 – – dry chemical microarray 468 – – gossypol 513, 514 – – immobilized technology 467 – – morphine 512, 513 – – small molecule microarray (AMM) 467, – – podophyllotoxin 508, 509 468 – – scopolamine 509, 510 – – solution phase microarray 468, 469 – – spearmint limone synthase 511 – DNA microarray 463 – microorganism production of heterologous – – application to drug discovery 465, 466 plant compounds – – fabrication 464, 465 – – artemisinic acid 514 microarrays – – cucuminoids 515 – personalized medicine 566, 567 – – fl avonoids 515, 516 micro-electromechanical-systems (MEMS) – – stilbenes 514, 515 129 – – vanillin 516 microfi ltration 183 – optimizing biochemical pathways microinjection 83–85 – – metabolic pathways of interest 499–501 microorganisms, natural products from – – strategies and goals 498, 499 15 – – synthetic biology 501, 502 – cloning and biosynthetic gene expression – plants as sources of natural products 18, 19 – – cell cultures 495, 496 – E. coli as host 19–21 – – transgenic plants 496–498 – heterologous plant compound production – strategies and techniques in medical plant – – artemisinic acid 514 biotechnology 502, 503 – – cucuminoids 515 – – downregulating of pathways 506 – – fl avonoids 515, 516 – – redirecting common precursors 505 – – stilbenes 514, 515 – – storage of overproduced metabolites – – vanillin 516 506 – production libraries 16 – – targeting metabolites 505 – silent gene cluster wake up, culture – – upregulating of pathways 504 manipulation 19 metabolomics 132, 546, 547 – silent gene cluster wake up, genomic – applications 538 approaches 19 – – discrimination for classifi cation micro-organoids 129 538–540 micro-total analysis systems (μ-TAS) 129 – – identifi cation of bioactivity 543, 544 milk thistle 615 – – metabolite characterization 540, 541 milk-extracted biopharmaceuticals 73–76 – – plant toxicity 545, 546 minigenes 79 – – quality control 541–543 mithramycin – – study effi cacy 544, 545 – microorganism production 16 Methanosarcina barkeri 22 – structure 17 methicillin-resistant Staphylococcus aureus modeling and simulation (MRSA) 561 – nature of and need for 114–116 methicillin-sensitive S. aureus (MSSA) 561 – pharmacokinetics 134, 135 611 – virtual patient populations 136 methionine sulfoximine (MSX) 47 – virtual tissue modeling 135, 136 methotrexate (MTX) 47 modifi ed vaccinia Ankara virus (MVA) 409, 6-methyl-salicyclic acid (6-MSA) 19, 20 431 micellar electrokinetic chromatography molecular biology 3–5 (MEKC) 210 – future prospects 11, 12 Index 639

– production hosts and upstream/ – – long-circulating liposomes 400, 401 downstream processing 10, 11 – – positively charged liposomes 401, 402 – research developments – nanocarrier cancer vaccines (NCVs) – – muteins 6, 7 391–395 – – post-translational engineering 7, 9 – personalized vaccines 577, 578 – – protein engineering 5 – sub-micron emulsions 404, 405 – – synthetic biology 9, 10 nanofi ltration 183 molecular diagnosis for personalized napyradiomycin medicine 560, 561 – biosynthetic gene expression production – point-of-care diagnostics 564 18 – real-time PCR 561–563 natural products from microorganisms 15 – single biomolecule analysis 563, 564 – cloning and biosynthetic gene expression Molecular INTeraction database (MINT) 18, 19 134 – E. coli as host 19–21 monoclonal antibodies 575 – production libraries 16 – products 3 – silent gene cluster wake up, culture monophosphoryl lipid A (MPL) 441, 442 manipulation 19 monoterpenes 608, 609 – silent gene cluster wake up, genomic morphine 494, 512, 513 approaches 19 mouse embryonic stem cell (mESC) 126 nefazodone 122 mRNA stability 33 neurofi brillary tangles (NFTs) 488 Muckle–Wells Syndrome (MWS) 5 neutralizing assay 227 Multi Compartmental Bioreactor (MCB) new biological entities (NBEs) 5 129 New Drug Application (NDA) 295 multi-organ systems 128, 129 new drug entities (NDEs) 3 multiparametric metabolic responses 132 Nicotiana tabacum 509, 510 multivalent antigen presentation 439, 440 nikkomycin – self-adjuvanting agents 441 – biosynthetic gene expression production – self-assembling peptide nanoparticles 18 440 nominal molecular weight cut-off (NMWCO) muteins 6, 7 194, 195 non-positional cell microarrays 469 n non-small cell lung cancer (NSCLC) 400 N-terminal sequencing 217, 218 novel foods 603 nanobiotechnological personalized medicine novobiocin 572, 573 – biosynthetic gene expression production – cancer vaccines 577, 578 18 nanobiotechnological strategies for cancer – microorganism production 16 vaccines 391–395, 412 – structure 17 – amphiphilic block-graft copolymers nuclear magnetic resonance (NMR) 405–407 – medicinal plants 531, 532 – biodegradable nanoparticles nutraceuticals 599–600 – – acid-degradable hydrogel-based particles – absorption, metabolism and interaction (ADHPs) 398, 399 with drugs 616–618 – – poly(D,L-lactic-co-glycolic acid) (PLGA) – concepts 601, 602 and polylactic acid (PLA) 396–398 – – alternative therapies 605, 606 – gelatin nanoparticles 404 – – food (dietary) supplements 604 – iron oxide nanoparticles 407, 408 – – food additives 604 – – virosomes 410–412 – – functional foods 602 – – viruses 408–410 – – herbal nutraceuticals 604, 605 – – virus-like particles (VLPs) 410 – – medical foods 603 – liposomal nanovectors 399, 400 – – novel foods 603 – – archaeosomes 402, 403 – – phytonutrients 604 – – fusogenic liposomes (FLs) 403 – defi nition 602 640 Index

– epidemiological study and clinical trials parenteral administration of proteins 340, 618, 619 341 – future prospects 621, 622 partial least squares discriminant analysis – health issues 614–616 (PLSDA) 537 – herbal nutraceuticals 604, 605, 613, 614 partial least squares (PLS) regression 537 – human health 600, 601 Patent and Trademark Offi ce (PTO) 271, – medical foods 619, 620 272 – potential health benefi ts 606 patents in pharmaceutical biotechnology – – amino acids, essential 610, 611 industry 269, 281 – – dietary fi bers 606 – biosimilars 297–305 – – fatty acids and lipids 609, 610 – ethical and policy issues 274 – – phenolic products 607, 608 – – access to technology 277–280 – – phytoestrogen 612, 613 – – benefi t sharing 280, 281 – – 609 – – no patents on nature 275, 276 – – prebiotics and probiotics 611, 612 – – threats to human dignity 276, 277 – – terpenoids 608, 609 – patent law nystatin – – defi nition of patent 269–271 – microorganism production 16 – – infringement of patent 273, 274 – – international law 274 o – – obtaining a patent 271, 272 ofatumumab 322 – – subject matter 272, 273 omics approaches 131, 485 – – types of patent 273 – application 132, 133 pathogen-associated molecular patterns – information handling 133, 134 (PAMPs) 441 – personalized medicine 568 patients – – pharmacogenetics 568, 569 – involvement 144, 145 – – pharmacogenomics 569, 570 – modeling virtual populations 136 – – pharmacometabolomics 570–572 PCT, real-time 561–563 – – pharmacoproteomics 570 pegvisomant 9 – strain improvement 22 PEGylated protein drugs 8, 9, 313–316 – variety 132 peptibody 5 one strain many compunds (OSMAC) theory 19 – mass fi ngerprinting (PMF) 215–217 optical coherence topography (OCT) 139 – pharmacokinetics 339 Optimata Virtual Patients (OVPs) 136 peripheral blood mononuclear cells (PBMC) oral administration 229 – proteins 343 personalized medicine 553 oral polio vaccine (OPV) 423 – biological therapies 574 orbitrap analyzers 213 – – cell therapy 575, 576 organotype cultures 124 – – gene therapy 576 orthogonal partial least squares discriminant – – monoclonal antibodies 575 analysis (OPLSDA) 537 – – recombinant human proteins 575 Oryza sativa 62 – – RNA interference 576, 577 out of specifi cation (OAS) 155 – biomarkers 559, 560 over the counter (OTC) drugs 527 – development technologies 560 oxytetracycline – future prospects 578, 579 – biosynthetic gene expression production – genetic variations in human genome 18 554, 555 – – complex chromosomal rearrangements p (CCRs) 556 paclitaxel 494 – – copy number variation (CNV) 557, 558 Paired-End Mapping 559 – – insertions and deletions (INDELs) 556, panitumumab 322 557 Papaver somniferum 512–514 – – large-scale variations 557 Index 641

– – single nucleotide polymorphisms (SNPs) – – hepatic metabolism 349 555, 556 – – proteolysis 346, 347 – – structural variations 558, 559 – – receptor-mediated metabolism 349, 350 – molecular diagnosis 560, 561 – – renal metabolism 347–349 – – point-of-care diagnostics 564 pharmacometabolomics 560 – – real-time PCR 561, 563 – personalized medicine 570–572 – – single biomolecule analysis 563, 564 pharmacoproteomics 560 – personalized vaccines 577 – personalized medicine 570 – – cancer vaccines 577 Phaseolus vulgaris 62 – – viral diseases 577 phenalinolactones – role of biochips/microarrays 566, 567 – biosynthetic gene expression production – role of cytogenetics 567, 568 18 – role of nanobiotechnology 572, 573 – microorganism production 16 – role of omics 568 phenolic products 607, 608 – – pharmacogenetics 568, 569 phenomics 132 – – pharmacogenomics 569, 570 phenylalanine 611 – – pharmacometabolomics 570–572 phosphoribosyltransferases (PRTs) 460 – – pharmacoproteomics 570 physiologically based pharmacodynamic – sequencing 564, 565 (PBPD) modelling 135 – – human genome variation 565 phytoestrogen 612, 613 – – rare variants and disease-causing genes phytonutrients 604 565, 566 phytosterol 609 – systems biology 573, 574 PiggyBac transposon 50, 89 pharmacogenetics 131, 560 pigs as sources of transplantable tissues and – personalized medicine 568, 569 organs 582, 583 – test 561 (+)-α-pinene 21 pharmacogenomics 131, 132, 560 plant biopharmaceuticals 59, 60, 67, 68 – personalized medicine 569, 570 – see also medicinal plants pharmacogenomic test 561 – basic considerations 60–62 pharmacokinetics 327–329, 361 – cell cultures 495, 496 – exposure-related correlations for protein – challenges in plant metabolic engineering therapeutics 353, 354 – – cell compartmentalization and tissue – – cell life span models 356–360 differentiation 507, 508 – – direct link PK/PD models 354, 355 – – species specifi c pathways 507 – – indirect link PK/PD models 355 – – unexplored regulation of secondary – – indirect response PK/PD models 355, metabolism 506, 507 356 – – unpredicted or unexpected outcome – immunogenicity and proteins 352, 353 508 – modeling and simulation 134, 135 – future prospects 516, 517 – peptides and proteins 339 – human glucocerebrosidase 63, 64 – physiologically based pharmacokinetics – insulin from saffl ower 64, 65 (PBPK) 134, 135 – microorganism production of heterologous – protein absorption 339, 340 plant compounds – – inhalation administration 341, 342 – – artemisinic acid 514 – – intranasal administration 342 – – cucuminoids 515 – – oral administration 343 – – fl avonoids 515, 516 – – parenteral administration 340, 341 – – stilbenes 514, 515 – – transdermal administration 342 – – vanillin 516 – protein binding 345, 346 – strategies and techniques in medical plant – protein disposition, role of neonatal biotechnology 502, 503 Fc-receptor 350, 351 – – downregulating of pathways 506 – protein distribution 343, 345 – – redirecting common precursors 505 – protein elimination 346 – – storage of overproduced metabolites – – gastrointestinal metabolism 347 506 642 Index

– – targeting metabolites 505 – – tobacco-based expression systems – – upregulating of pathways 504 65–67 – tobacco-based expression systems 65–67 – prokaryotic cells 15 – transgenic plants 496–498 – – natural products from microorganisms pluripotent cells 15–26 – embryonic germ cells 91, 92 – – recombinant therapeutic proteins – embryonic stem cells 90, 91 26–36 – induced pluripotent stem cells (iPSCs) – transgenic animal biopharmaceuticals 92, 93, 126, 127, 484 71–73, 104, 105 podophyllotoxin 494, 508, 509, 607 – – analysis of transgenic animals 99–102 point-of-care diagnostics for personalized – – constructs 78–82 medicine 564 – – production of transgenic animals polishing chromatography 191–193 82–99 poly(D,L-lactic-co-glycolic acid) (PLGA) – – quality and safety of products 396–398 102–104 polyethylene glycol (PEG) 8, 9 – – recombinant protein sources 73–78 polyketides prokaryotic cell production 15 – E. coli production 19, 20 – natural products from microorganisms polylactic acid (PLA) 398 15 polyunsaturated fatty acids (PUFAs) 600, – – cloning and biosynthetic gene expression 609, 610 18, 19 Pompe’s disease 75 – – E. coli as host 19–21 porcine endogenous retrovirus (PERV) – – production libraries 16 591 – – silent gene cluster wake up, culture positional cell microarrays 469 manipulation 19 positron emission tomography (PET) 139, – – silent gene cluster wake up, genomic 563 approaches 19 post-translational engineering 7, 9 – – strain improvement strategies 21–26 prebiotics and probiotics 611, 612 – recombinant therapeutic proteins 26, prediction model (PM) 130 27 prime–boost staging 438 – – expression vectors 31–34 – case study 438, 439 – – host strains 27–31 – targeting conserved/invariant region 439 – – production steps 34 primordial germ cells (PGCs) 91 – – products 34–36 principal component analysis (PCA) 536, – – prokaryotic expression systems 27–34 540 proliferation assay 226 process analytical technology (PAT) 197 pronuclear DNA microinjection 83 production hosts 10, 11 N-propionyl cysteaminylphenol 407 production methods prostate specifi c antigen (PSA) 137 – mammalian cells 43, 53, 54 Protein A chromatography 190 – – CHO-derived production cell lines 46, Protein Structural Interactome Map 47 (PSIMAP) 134 – – disposable bioreactors 51, 52 proteins – – high-throughput bioprocess development – see also recombinant proteins 50, 51 – administration – – process concepts 44–46 – – inhalation administration 341, 342 – – rapid generation of high-producing cell – – intranasal administration 342 lines 47, 48 – – oral administration 343 – – stability of expression 49, 50 – – parenteral administration 340, 341 – – transient gene expression (TGE) 52, 53 – – transdermal administration 342 – plant biopharmaceuticals 59, 60, 67, 68 – artifi cial 171, 172 – – basic considerations 60–62 – binding 345, 346 – – human glucocerebrosidase 63, 64 – disposition – – insulin from saffl ower 64, 65 – – role of neonatal Fc-receptor 350, 351 Index 643

– distribution 343–345 – proteins derived from recombinant genes – elimination 346 170, 171 – – gastrointestinal metabolism 347 – – post-expression modifi cation 173 – – hepatic metabolism 349 recombinant human erythropoietin (rhEPO) – – proteolysis 346, 347 359, 360 – – receptor-mediated metabolism 349, recombinant human proteins 575 350 recombinant proteins 26, 27, 170, 171, 201, – – renal metabolism 347–349 286, 287 – engineering 5 – biological characterization in vitro – exposure-related correlations for protein – – antibody dependent cellular cytotoxicity therapeutics 353, 354 (ADCC) 228, 229 – – cell life span models 356–360 – – antiviral assay (AVA) 228 – – direct link PK/PD models 354, 355 – – assay qualifi cation and validation 230, – – indirect link PK/PD models 355 231 – – indirect response PK/PD models 355, – – bead array technology 234 356 – – binding assays 222–224 – immunogenicity 352, 353 – – bioactivity, defi ning 221, 222 – pharmacokinetics 339 – – bioassays 219–221 proteomics 132 – – cell-based assays (CBA) 225, 226 proton magnetic resonance spectroscopic – – complement dependent cytotoxicity imaging (PMRSI) 139 (CDC) 229 protoplast fusion 24, 25 – – cytotoxicity assay 227, 228 Pure Red Cell Aplasia (PRCA) syndrome – – enzyme linked immuno-spot 309, 310, 328 (ELIPSPOT) assays 230 – – Fcγ-receptor binding assays (Fcγ-RA) – biosynthetic gene expression production 222, 223 18 – – fl ow-cytometric assays (FACS) 230 – – immunogenicity testing 234, 235 q – – ligand binding assay (LBA) 222 quadrupole analyzers 213 – – neutralizing assay 227 quality by design (QbD) 197 – – outlook 231 quantitative structure–activity relationship – – proliferation assay 226 (QSAR) 458 – – reporter gene assays 229, 230 – descriptor-based methods 458 – – surface plasmon resonance spectroscopy – knowledge-based methods 458 (SPR-spectroscopy) 223, 224 – rule-based methods 458 – classifi cation 4 10 – expression vectors 31 – – mRNA stability 33 r – – promoter choice 32, 33 rapamycin – – replication rate 31, 32 – microorganism production 16 – – tag fusion 33 ravidomycin – – translation intiation 33, 34 – biosynthetic gene expression production – formulation strategies 244, 245 18 – – analytics 240, 241 REACH (Registration, Evaluation, – – downstreaming fi ll and fi nish 242, Authorization, and Restriction of Chemical 243 Substances) system 141 – – dry formulations 238 real-time PCR 561, 563 – – formulation and stability of solutions recombinant antibodies 316–325 235–237 recombinant drugs 155–166 – – formulation development for market – artifi cial proteins 171–172 241, 242 – biosimilars 174–176 – – highly concentrated formulations 243, – classifi cation 166 244 – expression systems 167–170 – – screening strategies 239, 240 644 Index

– host strains – – T-cell receptor peptide and T-cell epitope – – Bacillus species 30, 31 conjugate vaccines 430 – – E. coli 27–30 – – viral vectors 431, 433 – – other species 31 – – virus-like particles (VLPs) 430, 431 – physical chemical characterization – vanguard technologies 436 – – capillary electrophoresis (CE) 209, 210 – – adjuvants 441, 442 – – fl uorescence spectroscopy 202, 203 – – antigen targeting 437, 438 – – Fourier transform infrared spectroscopy – – multivalent antigen presentation (FTIR) 203–205 439–441 – – gel elecrophoresis 208, 209 – – prime–boost staging 438, 439 – – hydrophilic interaction chromatography reconstituted tissue constructs 124 (HILIC) 207 red cell aplasia (RCA) 225 – – ion-exchange chromatography 207, 208 regulator of complement activation (RCA) – – mass spectrometry (MS) 211–219 81 – – other methods 210 reporter gene assays 229, 230 – – reversed-phase chromatography (RPC) respiratory syncytial virus (RSV) vaccine 206, 207 378 – – size-exclusion chromatography (SEC) response units (RU) 223 205, 206 reteplase 6 – – ultraviolet absorption spectroscopy 201, retrovirus vectors, recombinant 432, 433 202 retroviruses 88 – post-expression modifi cation 173 reverse osmosis 183 – production steps 34 reversed-phase chromatography (RPC) 193 – products 34 – recombinant protein analysis 206, 207 – – human insulin 36 reversely transfected cell microarrays – – somatropin 34, 35 (RTCMs) 470 – prokaryotic expression systems 27–34 ribosome binding site (RBS) 33, 34 – top selling 4 rilonacept 5, 172 – transgenic animal sources rituximab 3, 321 – – bird eggs 78 RNA interference (RNAi) screening 482, – – blood 77 576, 577 – – milk 73–76 – see also high-throughput screening (HTS) – – seminal fl uid 77 – applications for HTS 483 – – urine 76, 77 – libraries for HTS 482, 483 recombinant vaccines 423, 443, 444 romiplostim 5 – see also vaccines rosiglitazone 476 – clinical trials 443 rule-based QSAR methods 458 – comparing effi ciency 427 Rules Governing Medicinal Products in the – current market range 424–426 European Union 258 – delivery systems 435, 436 – development 433 s – – deliverability and accessibility 434, 435 Saccarpolyspora erythrea 22 – – manufacturability 433, 434 Saccharomyces cerevisiae 22 – – scalability 434 Saccharomyces coelicolor 22 – dialectic 426, 427 Saccharopolyspora erythrea 25 – identifying attenuated vaccine strains saffl ower – – biological–molecular combination 442, – insulin production 64, 65 443 salinomycin 26 – overview 428 saquayamycin – – attenuated bacterial vaccines, – microorganism production 16 recombinant 433 saw palmetto 616 – – conjugate vaccines 429 scaffold/matrix attachment regions (S/ – – DNA vaccines 429 MARs) 49 – – subunit vaccines 428, 429 scopolamine 494, 509, 510 Index 645 screening strategies 239, 240 – microorganism production 16 607 – structure 17 self-adjuvanting agents 441 stealth liposomes 401 self-assembled monolayer (SAM) 468 stem cells 125–127 self-assembling peptide nanoparticles for – defi nition 483, 484 multivalent antigen presentation 440 – high-throughput screening (HTS) 483 seminal fl uid-extracted biopharmaceuticals – – advantages 484 77 – – applications 484, 485 sequencing for personalized medicine 564, stilbenes 514, 515 565 Stoke’s radius 194 – human genome variation 565 strain improvement strategies 21 – rare variants and disease-causing genes – synthetic biology tools 22, 23 565, 566 – – promoter library 23 Shine–Dalgarno (SD) sequence 33, 34 – – tunable intergenic regions library 23, short tandem repeats (STRs) 464 24 silencing 49, 50 – system biology, system biotechnology and silent gene cluster wake up omic approaches 21, 22 – culture manipulation 19 – translation and transcription engineering – genomic approaches 19 25, 26 simulated moving bed chromatography – whole genome engineering 24 (SMBC) 193, 194 – – protoplast fusion and genome shuffl ing simulation see modeling and simulation 24, 25 sinapinic acid (SA) 213 streptomycin single biomolecule analysis for personalized – biosynthetic gene expression production medicine 563, 564 18 single nucleotide polymorphisms (SNPs) structure–activity relationship (SAR) 458 464, 479, 480, 481, 555, 556 sub-micron emulsions 404, 405 sitagliptin 11 subunit vaccines 428, 429 size-exclusion chromatography (SEC) 193 supplementary protection certifi cates (SPC) – recombinant protein analysis 205, 206 298 small molecule microarray (AMM) 467, surface plasmon resonance spectroscopy 468 (SPR-spectroscopy) 223, 224, 468 sodium dodecyl sulfate–polyacrylamide gel suspension cultures 123, 124 electrophoresis (SDS-PAGE) 209 synthetic biology 9, 10, 22, 23 solution phase microarray 468, 469 – promoter library 23 soma specifi c in vitro systems 127 – tunable intergenic regions library 23, 24 somatic cell nuclear transfer (SCNT) 94–98 system biotechnology 22 somatropin systems biology 21, 22, 143, 144 – prokaryotic cell production 34, 35 – drug discovery 485 sonoporation 342, 436 – – applications 486–488 spacers 472 – – industry approaches 485, 486 spearmint limone synthase 511 – – simulation models 486 specifi c pathogen-free (SPF) 434 – personalized medicine 573, 574 sperm mediated gene transfer 88, 89 spermatogonial stem cells 93, 94 t spinosyn T-cell epitope conjugate vaccines 430 – microorganism production 16 T-cell receptor peptide vaccines 430 St. John’s wort 542, 616 tag fusion 33 Standardized Operating Procedure (SOP) tags 471, 472 231 Tamm Horsfall protein 76 Staphylococcus aureus 20 taxadiene synthase 21 staurosporin terpenoids 608, 609 – biosynthetic gene expression production thermospray ionization (TSP) 212 18 thiazolylpeptide GE2270 26 646 Index

thiocoraline – – transfer and gestation 84, 85 – biosynthetic gene expression production – – transposon mediated gene transfer 89 18 – – viral mediated gene transfer 86–88 thioredoxin (Trx) 33 – constructs 78–80 thunder god vine 616 – – irreducible expression 81 thymidine 46 – – non-integrating vectors 81, 82 time-of-fl ight (TOF) analyzers 213 – – organ specifi c expression vectors 80 time-resolved fl uorescence resonance energy – quality and safety of products 102–104 transfer (TR-FRET) 455 – recombinant protein sources 73 tissue engineering 125 – – bird eggs 78 tissue plasminogen activators (tPAs) 6 – – blood 77 tissues – – milk 73–76 – virtual modeling 135, 136 – – seminal fl uid 77 tobacco mosaic virus (TMV) 62 – – urine 76, 77 tobacco-based expression systems 65–67 transgenic plants 496–498 Toll-like receptors (TLR) 437, 441 transient gene expression (TGE) systems – ligands 394 46, 52, 53 N-tosyl-L-phenylalanine chloromethyl ketone transposon mediated gene transfer 89 (TPCK) 216 tryptophan 203, 611 toxicogenomics 132, 478, 479 TubeSpins 50, 51 – animal models 480 tumor-associated antigens (TAAs) 392–394 – applications 481 tunable intergenic regions (TIGRs) 24 – drug discovery 479, 480 tylosin – gene polymorphisms 480, 481 – microorganism production 16 – hepatotoxicity 478 tyrosine 611 – in vitro models 480 toxoid vaccines 428 u Trade Related Aspects of Intellectual ubiquitous chromatin opening elements Property agreement (TRIPS) 274 (UCOEs) 49 trans fats 610 ultrafi ltration 183, 194, 195 transcription activator-like effector (TALE) ultrahigh pressure liquid chromatography– nucleases 99 mass spectrometry (UPLC-MS) 535 transcriptomics 132 ultrasound and microbubble targeted transdermal administration delivery (UMTD) 436 – proteins 342 ultraviolet absorption spectroscopy transgenic animal biopharmaceuticals – recombinant protein analysis 201, 202 71–73, 104, 105 upstream/downstream processing 10, 11 – analysis of transgenic animals 99 urine-extracted biopharmaceuticals 76, 77 – – collection, processing, and protein uromodulin 76 purifi cation 101, 102 uroplakins 76 – – integrated transgenes 100, 101 USA – – transgene expression profi le 101 – drug regulation 262 – animal production methods 82 – – approvals procedure 263–265 – – DNA injection 83, 84 – – biosimilars 294–296 – – DNA preparation 83 – – CDER and CBER 263 – – fertilised egg collection 83 ustekinumab 322 – – founders identifi cation and breeding 85, 86 v – – highly specifi c DNA endonucleases 99 vaccina virus, recombinant 431, 432 – – pluripotent stem cells 90–93 vaccine associated paralytic poliomyelitis – – pronuclear DNA microinjection 83 (VAPP) 423 – – somatic cell nuclear transfer 94–98 vaccines 371, 387, 388, 391–395 – – sperm mediated gene transfer 88, 89 – see also recombinant vaccines – – spermatogonial stem cells 93, 94 – conventional Index 647

– – toxoid 428 – target-based methods 460 – – whole organism 428 virtual ligand screening 457, 459 – economic aspects of development 384 – ligand-based methods 459 – – costs of development 384–386 – target-based methods 459 – – risks and opportunities 386, 387 virtual patient populations 136 – formulation strategies 245–247 virtual tissue modeling 135, 136 – – analytics 247, 248 Virtual ToxLab 122 – from research concept to development virus fi ltration 195, 196 candidate 372, 373 virus-like particles (VLPs) 66, 410, 430, – overview 428 431 – personalized 577 viruses 408–410 – – cancer vaccines 577, 578 visualization of data 460 – – viral diseases 577 Vitrocellomics project 130 – recombinant DNA approach to identifying attenuated vaccine strains w – – biological–molecular combination 442, West Nile virus (WNV) 437, 444 443 whey acidic protein (WAP) 73, 80 – research projects 373–375 whole organism vaccines 428 – scientifi c challenges of R&D 375–378 working cell bank (WCB) 327, 380 – technical aspects of development 379, 380 x – – clinical development 382, 383 xenotransplantation 581 – – licensing and registration 383, 384 – alternative sources of transplantable – – manufacturing facilities 381, 382 tissues 581, 582 – – preclinical development 380, 381 – – pigs 582, 585 valerian 616 – biological barriers valine 611 – – accommodation 588 vancomycin – – acute vascular rejection 586–588 – microorganism production 16 – – cellular mediated immune response – structure 17 588, 589 vanillin 494, 516 – – complement activation 585, 586 (+)-cis-verbenol 21 – – graft vascularization 583, 584 vesicular stomatitis virus (VSV) 228 – – hyperacute rejection 584, 585 vincristine 494 – clinical applications 592, 593 viral mediated gene transfer 86–88 – physiological and infectious barriers viral vectors 431 – – interspecies challenges 590, 591 – fowlpox (FP) virus 432 – – zoonosis 591 – retrovirus vectors, recombinant 432, 433 – vaccina virus, recombinant 431, 432 z virosomes 410–412 zeaxanthin 20 virtual affi nity profi ling 459 zinc-fi nger nucleases (ZFNs) 99 – ligand-based methods 459, 460 zoonosis 591