2143

Index

a ado-trastuzumab emtansine (T-DM1) abatacept 936, 943, 949, 1087, 2027 – HER2-positive metastatic breast cancer abciximab 120 – ALX-0081 624 – MTD 2059 – CAPTURE study 2089 – and pertuzumab 1879 – data supporting marketing approval 2088 – role 2060, 2061 – EPILOG 2088–2089 – structure 2060 – GPIIb/IIIa receptor 2087 adoptive cellular immunotherapy 538–540 – percutaneous coronary intervention (PCI) adult non-renal transplantation 2087 – heart 1386–1387 – placebo 2088 – liver 1383–1385 – treatment 2089 – lung 1385–1386 AbGn-168 (Abgenomics) 1137 – pancreas 1387–1388 ABT-122 (Abbvie) 991–992 adult T-cell leukemia (ATL) ABT-308 (RCP4046; Receptos and Abbvie) – and CTCL 2115 1005 – murine model 1356–1357 ABT-981 (Abbvie) 982 – NHL 2115 abYsis 208, 215 – tumor progression 2116 ACCEPT (NCT00454584) 2073 adverse effects, omalizumab AD. See atopic dermatitis (AD) Ⓡ – anaphylaxis treatment 1803 adalimumab (Humira ) – approved indications 1312–1313 – immune complex diseases 1804 – BD 1313–1314 – local reactions 1803 – HS 1316–1318 – long-term treatment 1804 – principles, clinical use 1310 – malignant neoplasms 1803–1804 – safety 1310–1312 – systemic side effects 1803 – sarcoidosis 1318 AEX. See anion-exchange (AEX) – uveitis 1314–1316 chromatography ADCC. See antibody-dependent cellular affinity chromatography cytotoxicity (ADCC) – boronate 688 ADCs. See antibody–drug conjugates (ADCs) – description 622 ADEPT. See antibody-directed enzyme – exemplified binding sequences, ligands prodrug therapy (ADEPT) 622 adipsin 1169–1170 – immobilized mannan-binding protein 31 adjuvants 22, 1299, 1876–1877, 2042–2043, – and ion-exchange chromatography 1910 2049–2050, 2053 – mAb purification 643 Administration of Radioactive Substances – mouse monoclonal IgG antibodies 31 Advisory Committee (ARSAC) 1584 – protein A/G 1301

Handbook of Therapeutic Antibodies, Second Edition. Edited by Stefan Dubel¨ and Janice M. Reichert. c 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA. 2144 Index

affinity maturation – Campath-1G 1324 – enzyme activation-induced cytidine – CD52 antigen 1325–1326 deaminase (AID) 20 – CD52-subclones 1327 – and humanization 4 – cell lysis. See cell lysis – in vitro, 93, 107, 117–119, 313, 321, 908 – chemotherapeutic agents 1339 – in vivo, 115–117, 119, 317, 495 – CLL 1326–1327 afiibercept 836, 1177–1178, 1893–1894 – consolidation therapy 1341–1342 afutuzumab 754–755 – CR 1340–1341 age-related macular degeneration (AMD) –CTCLs.See cutaneous T-cell lymphomas 944–945, 1394 (CTCLs) – aflibercept 1898–1894 – fludarabine and alemtuzumab 1339–1340 – ANCHOR and MARINA 1888, 1889 – grade 1/2 toxicities 1340 – bevacizumab 1892–1893 – hematologic toxicities 1344–1346 – clinical trials 1889 – hepatomegaly/splenomegaly 1338 – CNV development 1884 – IgM antibody 1324 – occult and classic neovascularization – immunogenicity and antiglobulin response 1884, 1885 1328 – pathogenic mechanisms 1884, 1885–1886 – immunosuppression and infectious events – wet form 1884 1346–1347 aggressive B-cell lymphoma, rituximab – immunotherapy combination 1342–1343 – BL/BLL 1958 – infusion-related adverse events 1343–1344 – Cunningham study 1955 – lymphocyte cell surface 1326 – GELA LNH98-5 trial 1950, 1951 –MRD.See minimal residual disease (MRD) – gemcitabine-based regimens 1955 –MS.See Multiple sclerosis (MS) – HDT 1945 – ORR 1341 – HOVON-46 study 1954 – serum concentrations 1329–1330 – intergroup E4494 trial 1950, 1951–1952 alirocumab – MabThera International Trial (MInT) – LDL-C level reduction 858 1952–1953 – phase III trials 859, 860–864 – monotherapy 1956–1957 – treatment 858–859 –PMBCL.See primary mediastinal B-cell allergic diseases lymphoma (PMBCL) – anti-immunoglobulin E treatment. See – previously untreated 1945–1947, 1950 omalizumab – relapsed/refractory 1945, 1948–1949 – asthma 945–947 – retrospective population analyses, DLBCL – atopic dermatitis 948–949 1953 – rhinitis. See allergic rhinitis (AR) – RICOVER-60 trial 1954 allergic rhinitis (AR) AGS-009 (Argos Therapeutics) 997, 998 – anti-TSLP-R mAb 1009 albumin binding – clinical efficacy 1812, 1813 – anti-RANKL (ALX-0141) 331 – potential indications and contraindications – description 330 1805, 1806 – fusion with serum albumin 441 – randomized and double-blind clinical trials – human PK data 332 1812, – pharmacokinetics, AlbudAbsT 330, 331 altered complement activation 157–158 – protein component, human serum 330 altered immunity 934 – sdAbs 311 ALX-0061 (Ablynx, Abbvie) 314, 506, 986 ALCL. See anaplastic large cell lymphoma Alzheimer’s disease (AD) (ALCL) – active immunotherapy, Aβ 1218 alemtuzumab – disease and target 1217–1218 – antibody features and production – IL-4 and IL-5 role 948 1324–1325 – and mini mental state examination (MMSE) – B-CLL 1323–1324 906 – blood lymphocyte 1338–1339 – murine and human models 1011 – BMT 1329 – mutation 908 Index 2145

– passive immunotherapy, Aβ 1218–1220 – hypoxic and acidic tumor milieu 825 – pathology, APP transgenic mice 906 – integrins 837–838 – pyroglutamate-3 Aβ 1220 – macrophages 825, 944 – serum IgE 948 – MET tyrosine kinase 838–839 – treatment 906 – molecular regulators 825–830 AMD. See age-related macular degeneration – natural stimulators 827 (AMD) – organogenesis and wound healing 1177 AMG 139 (MEDI-2070; Amgen/Medimmune) – p53 mutations 828 993 – pleiotropin 828 AMG 157 (MEDI9929; – PLGF 827 Amgen/AZ-Medimmune) 1010 – TAMs 828 AMG-317 (Amgen) 1002 –TGF-β receptors 827 AMG 557 (Amgen/AZ-Medimmune) 1089 – tumor cell accumulation 824 AMG 729 (XmAb5871; Amgen from Xencor) – tumor-induced blood vessels 830 1117 – wound-healing processes 827 AMG 811 (Amgen) 1000 anifrolumab 998 amyloid β protein anion-exchange (AEX) chromatography – bapineuzumab 906–907 624, 625 – cerebral plaques 906 ankylosing spondylitis (AS) 1605–1606 – gantenerumab 908–909 anrukinzumab 1001, 1004 – immunoconjugate approach 906 anthrax bacillus 1200–1201 – proteins and polypeptides 905 anthrax toxin receptors (ATRs) 1899–1900 – solanezumab 907–908 anthrax toxins amyotrophic lateral sclerosis (ALS) – B. anthracis, 1900 – active immunotherapy 1224 – LF and EF 1900–1901 – disease and target 1223–1224 – raxibacumab. See raxibacumab – and HD 1216 anti-α4β7/MAdCAM-1 – passive immunotherapy 1224 – AMG 181 1129–1130 anaplastic large cell lymphoma (ALCL) – etrolizumab 1130 – and ALK 1432 – PF-00547659 (Pfizer) 1130–1131 – brentuximab vedotin 1432–1433 – vedolizumab 1129 – CD30-positive hematologic malignancies anti-C5/C5a/C5aR 1166–1169 1435 anti-CD22 (epratuzumab) 755–756 – chemotherapy 1436 anti-CD20 × anti-CD3 lymphomun – chromosome translocation 1432 – adverse events 1486 – and Hodgkin lymphoma 344 – allogeneic SCT 1484 – primary cutaneous CD30-positive – diffuse large B cell lymphoma (DLBCL) lymphoproliferative disorders 1485 1433–1435 –graftvs. leukemia (GvL) effect 1484 – and TNF 759 – HAMA response 1487 anastrozole plus trastuzumab 2047 – hematological remission 1487 ANCA-associated vasculitis 1983–1984 – mantle cell lymphoma (MCL) 1485 angiogenesis – NHL 1484 – angiopoietin type 2 836 – in pediatric patients 1485, 1486, 1488 – angiotensin-2 receptor 837 – tumor progression 1485 – anti-angiogenic antibodies 840, 841 anti-EpCAM × anti-CD3 catumaxomab – anti-S1P inhibitors 1178–1181 – abdominal EpCAM-positive cancer diseases – anti-VEGF inhibitors 1177–1178 1474 – bevacizumab 795 – cancer stem cells (CSCs) 1477–1478 – cadherins 838 – CASIMAS trial 1476 – cancer development 764, 823–824 – completed clinical trials 1475 – ECM 839, 841 – gastric cancer treatment 1480–1481 – endothelial and mural cells 824 – locoregional administration 1478–1479 –HIF1-α 824 – median antibody concentrations 1477 2146 Index

anti-EpCAM × anti-CD3 catumaxomab (contd.) –serogroupBNeisseria meningitidis capsular – in ovarian cancer patients 1481 polysaccharide 418 – peritoneal carcinomatosis 1479–1480 – syngeneic and xenogeneic models 414 – QoL Questionnaire-Core 30 items – vaccines, Ab2βs 414 1475–1476 anti-immunoglobulin E treatment, allergic – SECIMAS study 1476 diseases. See omalizumab – T cells adhesion 1477 anti-infectious monoclonal antibodies – vascular endothelial growth factor (VEGF) – anthrax bacillus 1200–1201 levels 1477 – botulinum neurotoxins 1201 anti-EpCAM antibodies – Clostridium diffcile, 1197–1198 – adecatumumab 761 – eculizumab 1200 – description 760 – HUS 1200 – edrecolomab, murine IgG2a antibody 760 – InhibitexⓇ 1198–1199 – European phase II trials, catumaxomab – KaloBiosⓇ 1199–1200 761 – pagimaximab BSYX-A110 1198 anti-GD2 × anti-CD3 ektomab 1488–1490 – Pseudomonas aeruginosa, 1199 anti-HER2/neu × anti-CD3 ertumaxomab – PVL 1199 1482–1484 – SAR279356 1198 anti-idiotypic antibody (Ab2) – staphylococcal enterotoxins 1199 – Ab1/antigen-derived peptide and Ab1/Ab2 – Staphylococcus aureus, 1198 complexes 410 anti-inflammatory effects, omalizumab – amino acid identity 408 – B cells 1801 – antibody-antigen interaction 408 – cytokines 1799 – antigen-mimicking synthetic peptides 408, – dendritic cell APCs 1800 410 – eosinophils 1800–1801 – B cell malignancies 415 –FcεRI cell expression 1799 – in cancer. See cancer, Ab2 – humoral and cellular parameters 1797, – description 409 1798 – Fab mimicking 417 – serum free IgE levels 1797, 1798 – function and specificity 407 anti-T-cell costimulators – functional mimicry 410, 411 – anti-CD26 (DPPIV) 1095–1097 – Guillain–Barre´ syndrome 417 – anti-CD28 1087–1088 – homobodies 408 – anti-HVEM/LIGHT 1093–1095 – human hepatitis B surface antigen (HBsAg) – anti-ICOSL (B7RP-1) 1088–1091 410 – anti-NKG2A 1097–1098 – human immunodeficiency type 1 virus – anti-OX40/OX40L 1091–1093 (HIV-1) 418 anti-TNF mAbs 1670 – hydrogen bonds and solvent interactions antibody affinity 410 – affinity maturation. See affinity maturation – immunotherapeutic strategies 417 – antibody concentration 133 – IVIg, autoimmune diseases 413 – antigen binding and potency 120–121 – molecular mimicry, infectious agents and – biolayer interferometry (BLI) 129–132 controversial theory 414 – cell-based titration experiment 133 – mouse Ab1 formulations, rodents – vs. cell surface antigens 127–128 immunization 414 – description 115 – mouse dams 417 – determination 128 – Neu5Gc-gangliosides 412 – ELISA 132–133 –normalγ-globulins 407 – hybridoma cell lines 126 – physiological significance and therapeutic – in vitro binding and potency. See in vitro potentials 407 binding and potency – racotumomab 774 – in vivo binding and potency. See in vivo – recombinant fragments 414 binding and potency – with self-binding activity 408 – KinExA instruments 132 – self/non-self discrimination 412–413 – vs. soluble antigens. See soluble antigens Index 2147

–SPR.See surface plasmon resonance (SPR) – basic principle 476 antibody-dependent cell-mediated cytotoxicity – carcinoembryonic antigen (CEA) 475 (ADCC) – catalytic antibodies. See catalytic antibodies – ART621 506 – CPG2 and benzoic mustard prodrugs – CD20 receptor 789 477–478 – and complement-dependent cytotoxicity – cytotoxic agents and toxins 475 (CDC) 17 – drug molecules 476 – D270A mutant 157 – Enterobacter cloacae beta-lactamase 327 – elotuzumab 757 – F(ab) 2 fragments conjugated to CPG2 479 –FcγRIIIA 1117 – immunogenicity. See immunogenicity – glycoforms 181 – indirect drug targeting 363 – glypican-3 790 – mammalian and non-mammalian origin – in human lymphocytes 1324 478 – K326W-E333S mutants 158 – murine monoclonals 476 – leukemic cells 186 – normal tissue toxicity 475 – SD1-Fc fusion protein 504 – radiolabeled intact IgG 476 – T-cell depletion capacity 1091 antibody-dependent cellular cytotoxicity – recombinant scFv-CPG2 fusion protein (ADCC) 479–480 – aglycosylated/deglycosylated IgG molecules – tumor antigens 475 609 antibody engineering – and phagocytosis 278 – fluid-phase pinocytosis 158 – approved mAbs with 670 – human IgG2 binding 159 – chimeric antibodies 148 – M428L-N434S Fc variant 159–160 – ensituximab (NPC-1C) 790 – novel Fc variants 159 – epratuzumab 756, 757–758 – receptor (FcRn) 158 – Fc receptors (FcRs) 1911, 1912 – serum half-life 159 –FcγRIIIa-F/F158 donor cells 153 antibody isotype – GC-33 (RO5137382, RG7686) 790 – classical complement pathway 146 – GlymaxX technology 611 – Fc region binding 146 – GM-CSF 1931 –FcαRI-transgenic mice 150 – homodimers 1470 – Gm allotype system 146 – human immunological effector functions – granulocyte colony-stimulating factor 17 (G-CSF) 149 – human tumor xenografts in vivo, 290 – human Fcγ receptors 146, 147 – humoral immune response 461 – human IgG2 148 – immune effector cells 789 – human myeloid cells activation 149 – K326W and K326W-E333S mutants 158 – in human serum 172 – lenalidomide 1932 – IgE molecule, allergic diseases 1778 – mAb-opsonized cells 1748 – immunoreceptor tyrosine-based inhibitory – natural killer cells (NK cells) and motif (ITIM) 146 macrophages 789 – isoforms, schematic representations 149 – NK cell-mediated activity 156 – obinutuzumab 1702 – isotypes 149 – ocrelizumab 903–904 – mAbs, PK profiles 1253 – rituximab 789, 789–790 – neutrophil-expressed FcγRIIIb 148 – trastuzumab and pertuzumab 1874 – polymeric immunoglobulin receptor (pIgR) – tumor cell-bound antibodies 35 149 – ublituximab (TGTX-1101, LFB-R603) – production 1297 789–790 – ratio of activation to inhibition (A/I ratio) – veltuzumab 1121 145 antibody-directed enzyme prodrug therapy – subclasses 145, 146, 148 (ADEPT) – therapeutic applications 150 – advantages 482 – in tumor rejection 149 2148 Index

antibody preparations – cytotoxic compounds. See cytotoxic – animal, choice of 1299 compounds, ADCs – blood samples collection 1300 – description 341–344 – oligoclonal. See oligoclonal antibodies – first-generation 366 – polyclonal antibodies. See polyclonal – gemtuzumab ozogamicin 1236 antibodies – HER2 inhibition 804 antibody purification 1300–1301 – linkers. See linkers, ADCs antibody selection – lorvotuzumab mertansine (IMGN-901, – in vitro, 118 N901-DM1, BB-10901) 805 – libraries 395–396 – mesothelin 804–805 – and maturation in vitro. See In vitro – milatuzumab 805 maturation and antibody selection – vorsetuzumab mafodotin (SGN-75) 804 – microarrays 393 antigen binding and potency 120–121 – phage, cell-surface and ribosome display antigen-presenting cells (APCs) 393–395 – allergen presentation 1786 – proteomic studies 393 – anti-CD4 1083 – recombinant systems 44 – B cell and Th0 cells 1777 – ribosome and mRNA display 398–399 – caveolin-1 1095 – ribosome display. See ribosome display – CD28 1087 antibody sequences – CD40 1089–1090 – abYsis 215 –CD4+ Th2 cells 1786 – antibody sequence databanks 210 – DCs 1786, 1800 – databanks 210 –FcεR expression 1809 – germline components identification 214 – T-cell activation 792 – germline sequence databases 211 APCs. See antigen-presenting cells (APCs) – ‘‘humanness’’ 214 apoptosis – subgroups assignment, tools 213 – B cells 1162, – unusual features identification 214 – benralizumab 1006 – web resources. See web resources – CEA-positive cells 809 antibody structure prediction – CTLs 279 – automated modeling tools 217–218 – CXCL10 1019 – CDRs 216 – description 1175 – data 213 – eosinophil 1801, – light and heavy chains 216 – gene insertions 531 antibody-targeted drugs – HuM291 153 – antibody-directed enzyme prodrug therapy – IL-18 983 (ADEPT) 363 – infliximab 1600 – chemical immunoconjugates. See chemical – mAbs 1175–1177 immunoconjugates – related genes 575 – cytotoxic payloads 363 – requiem 579 – recombinant cytotoxic fusion proteins. See applied genomics and cell line engineering recombinant cytotoxic fusion proteins – apoptosis 576–577 antibody V domain humanization – CHO cell lines 573–574 – amino acid interactions, FR-IMGT and – CHO-K1 genome 576 CDR-IMGT 247 – chromosome mapping 574 – CDR-IMGT grafting 246, 247 – description 576 antibody–drug conjugates (ADCs) – Fadd, Faim, Alg-2 and Requiem 575 – ADC glembatumumab (CDX-011) – FUT8 and guanosine diphosphate 805–806 (GDP)-mannose 4,6-dehydratase 579 – ado-trastuzumab emtansine 1236 – gene expression profile 575 – bioanalysis 677 – gene knockout 577 – brentuximab vedotin 1236 – gene silencing 576 – for cancer treatment 344–346 – LDH-C 574–575 – chemically linked 369, 371, 374 – miRNAs 575 Index 2149

– non CHO-derived DNA microarrays 574 – RA 1980–1982 – rAAV-based genome engineering 578 – SLE 1982 – RNAi-mediated knockdown/mRNA automated modeling tools overexpression 578 – MODELLER 217 – shRNAs 578 – Molecular Operating Environment (MOE) – siRNA knockdowns 579 218 – TALENs 577–578 – Prediction of ImmunoGlobulin Structure – transcriptomics, proteomics and (PIGS) 217, 218 metabolomics 574 – ‘‘RosettaAntibody3’’ 217 – ZFNs 577 – SwissModel 217 approved indications – WAM Web site 217 – abciximab 2088–2089 – adalimumab 1312–1313 b – eculizumab 2102–2103 B-cell-activating factor (BAFF). See – natalizumab 2105–2107 B-lymphocyte stimulator (BLyS) AR. See allergic rhinitis (AR) B-cell chronic lymphocytic leukemia (B-CLL) arcitumomab (CEA-Scan™) 2124–2126 91, 754, 1088, 1323, 1703 ARG098 1176–1177 B-cell inhibitors arresten 829 – anti-BAFF 1117–1119 asialoglycoprotein receptor (ASGPR) 184 – anti-CD19 1115–1117 ASKP-40 1090–1091 – anti-CD20 1119–1121 asthma B-cell lymphoma – anti-IgE mAb omalizumab 947 – anti-CD20 antibody treatment 540 – anti-TNFs 947 – anti-CD20 monoclonal antibody rituximab – atopic 945 343 – CNTO-3157 1149 – bispecific antibodies 288 – description 945 – BO20999 phase 1 1715 – TH17 and TH1 cells 946 – BO21003 phase I 1715–1717 – therapies 946–947 – BO20999 randomized phase II – TLR3 1148 1717–1718, 1719–1720 – TLR9 agonists 1149 – BO21000 randomized phase II 1720, 1721 –TNFα blockers 947 – BO21003 randomized phase II 1718–1719 asymmetric heterodimerization domains. – DLBCL 367, 1435 See also recombinant bispecific antibody – FBTA05 283 molecules – JO21900 1717 – CrossMab format 277 – obinutuzumab 1716, 1721–1722 – dock-and-lock (DNL) method 278 – ofatumumab 754 – electrostatic steering effects 276–277 – phase III studies 1721–1722 – feasibility 278 – redirected T cells 540 – jun-fos leucine zippers 278 – veltuzumab 1121 – knobs-into-holes approach 276 B-cell lymphoma, rituximab – SEEDbodies 277 – classification 1915 – toxins 278 – immune modulators 1931–1933 atacicept 941, 1119 – induction therapy 1917–1921 atopic dermatitis (AD) 876, 948–949, 1160 – maintenance therapy 1937–1944 ATTRACT trial 1601, 1604, 1610 – meta-analysis 1930–1931 autoimmune disorders – mortality rates 1914–1915 – ANCA-associated vasculitis 1983–1984 – phase II studies, chemotherapy – autoimmune cytopenias and hemophilia 1922–1924 1982–1983 – phase III studies, chemotherapy – CD22 antibodies 1555 1924–1927 – chronic GVHD 1983 – relapsed/refractory indolent – MG 1984–1985 1927–1930 – OMS 1984 – rituximab monotherapy 1933–1935 2150 Index

B-cell lymphoma, rituximab (contd.) – immunosuppression adverse events 1410 – rituximab SC 1985–1994 – lupus patients 1409 B-cellular non-Hodgkin’s lymphoma – malignancy adverse events 1410 – anti-CD20 antibody rituximab 758 – mortality adverse events 1411 – description 753 – phase I clinical trial 1407 – elotuzumab (anti-CS1) 757–758 – placebo-controlled trial 1408 – epratuzumab (anti-CD22) 755–756 – psychiatric adverse events 1411 – galiximab (anti-CD80) 757 – RA 937, 1115 – inotuzumab ozogamicin (anti-CD22) – RCT 1407 756–757 – reproduction adverse events 1411 – obinutuzumab 754–755 – scFv 1406 – ofatumumab 753–754 – side effects 1409 B-CLL. See B-cell chronic lymphocytic – SLE 899, 942, 1115, 1405 leukemia (B-CLL) – standard-of-care (SOC) therapies 1118 B-lymphocyte stimulator (BLyS) 898–899, – steroid dosage reduction 1409 1117–1119, 1405 – TNF homolog 1405–1406 Bacillus species 562 benralizumab 955, 1006–1007 – B. megaterium, 565 benzoic mustard prodrugs. See –B.subtilis and B. brevis, 564 carboxypeptidase G2 (CPG2) – intracellular and extra cytoplasmic bertilimumab 1017 molecular chaperones 564 besilesomab (ScintimunⓇ) 2131–2132, 2136 – polypeptide chains 565 best supportive care (BSC) 1861 – signal peptides/secretion domains 564 bevacizumab bapineuzumab 906–907, 1218 – in breast cancer 2091–2092 basic fibroblast growth factor (bFGF) – cervical cancer 2095 – angiogenesis stimulants 826 – clinical trials 1893 – heparin 827 – EU-and US-approved indications 2090 – normal fibroblasts 827 – Fc receptors 1892 – tumor cells 824 – in glioblastoma 2094–2095 basiliximab and daclizumab – marketing approval 2090 – action mechanisms 1376 – molecular weight 1892 – human organ transplantation. See human – in ovarian cancer 2092–2093 organ transplantation – PRN protocol 1893 – IL-2R antibodies. See IL-2R antibodies – safety 2090–2091 – lymphocytes 1375 – second-line CRC treatment 1508 – renal transplantation 1377 – solid tumors 2089–2090 – solid organ transplantation and IL-2R-based – VEGF-A 2089 therapy 1377–1378 bFGF. See basic fibroblast growth factor – TAC 1376–1377 (bFGF) BAX-69 (Baxter Healthcare Corp) 1018 bi-specific T-cell engagers (BiTEs) BD. See Behc¸et disease (BD) – blinatumomab (MT-103, MEDI-538) 808 bDMARDs. See biological disease-modifying – carcinoembryonic antigen (CEA) 808–809 antirheumatic drugs (bDMARDs) – defined 808 BEGEDINAⓇ 1096–1097 – description 1466–1467 Behc¸et disease (BD) – solitomab, EpCAMs 808 – anti-TNF therapies 1313 – tandem scFv molecules 281 – phase 3 study 1314 – and trifunctional antibodies 804 belimumab Biacore system 130, 654 – BLISS-52 and BLISS-76 1405 BIIB023 (Biogen-IDEC) 979 – BLISS-52 RCT outcome 1408 BIIB033 (Biogen-IDEC) 1183 – BLISS-76 RCT outcome 1409 bioinformatics tools, antibodies analysis – BLISS-SC study 1411–1413 – antibody sequence data. See antibody – BLyS and autoimmunity 1406 structure prediction – hypersensitivity adverse events 1410 – antibody structure 201–202 Index 2151

– CDRs and related regions 208–209 – ‘‘totality-of-the-evidence for biosimilar and – Chothia numbering scheme 204–205 innovator development’’ 693, – enhanced Chothia (Martin) numbering – US 684 scheme 206, 207 bispecific antibodies – Honegger and Plückthun (Aho) numbering – applications 268 scheme 206 – B-cell lymphoma 288 – IMGT numbering scheme 206 – catumaxomab (Removab) 1464–1465 – Kabat numbering scheme 203 – chemical conjugation 269–271 – numbering schemes 202–208 – CTLs, clinical trials 282 biolayer interferometry (BLI) 129–132, 131 – dual targeting strategies 289–291 biological disease-modifying antirheumatic – effector cells retargeting. See effector cells drugs (bDMARDs) 2027–2028 retargeting and bispecific antibodies Biologics Price Competition and Innovation – effector molecules retargeting 285–289 Act (BPCI Act) 684, 1238 – Fc receptor, recombinant 285 biopsy-proven acute rejection (BPAR) 1378 – generation 268 biosimilar monoclonal antibody – hapten-binding 289 – asparagine residues 691 – recombinant. See recombinant bispecific – biologics complexity and manufacturing antibody molecules process 687, 690 – somatic gene therapy 291–293 – biosimilar candidate and RMP 687, 688 – somatic hybridization 268–269 – chemistry, manufacturing and controls BL/BLL. See Burkitt’s and Burkitt-like lymphoma (BL/BLL) (CMC) standards 685 BLI. See biolayer interferometry (BLI) – chimeric/humanized recombinant mAbs blisibimod 942, 1119 681 BMS-981164 1011 – clinical development. See clinical bone marrow transplant (BMT) 1329 development, biosimilar monoclonal bone metabolism. See sclerostin antibodies botulinum neurotoxins 1201 – cysteine oxidation 691 BPCI act. See Biologics Price Competition and – disulfide bonds 687 Innovation Act (BPCI Act) – drug development 685–686 branch retinal vein occlusion (BRVO) 1886, – in emerging markets 684–685 1888, 1890–1891 – EU approach. See European Union (EU) breast cancer approach, biosimilars – anastrozole plus trastuzumab 2047 – glycation 688 – eLEcTRA trial 2048 – glycosylation 688 – gemcitabine 2046 – healthcare systems 681–682 – monoclonal antibodies 2048 – immunoglobulin G (IgG) Fc fusion proteins – TAnDEM trial outcome 2047 694 – taxanes, trastuzumab in combination – in living organisms 682 2044–2046 – lysine-clipping results 688 – TKI 2048 – manufacturing process development – trastuzumab monotherapy. See trastuzumab 691–692 monotherapy – physical stress 691 – triple combinations, trastuzumab 2047 – physicochemical and biological properties brentuximab vedotin 685 – ALCL. See anaplastic large cell lymphoma – preclinical development. See preclinical (ALCL) development – antibody-drug 1417–1418 – pyroglutamate formation 688 – CD30 1417–1418 – QTPP 686–687 – description 1417 – regulatory authorities 682 – DLBCLs 1435 – ‘‘stand-alone’’ CMC part and comparability – Hodgkin’s lymphoma 759–760 exercise 693 – MMAE 1417 – state-of-the-art methods 687, 689–690 – preclinical activity 1419 2152 Index

brentuximab vedotin (contd.) – CeaVac and TriAb 416 – primary cutaneous CD30-positive – Ep-CAM 416 lymphoproliferative disorders – phase II clinical trials 417 1433–1435 – protein and non-protein tumor-associated briobacept 1119 antigens 415 BRVO. See branch retinal vein occlusion – racotumomab and TriGem vaccines (BRVO) 415–416 BSC. See best supportive care (BSC) – sialic acid-containing glycosphingolipids BT-063 (Biotest AG) 1008 415 BTT-1023 (Biotie) 1135 – tumor-associated antigens 416 Burkitt’s and Burkitt-like lymphoma (BL/BLL) cancer therapy 1958 – hybridomas 787 – immunoconjugates. See immunoconjugates c – innate immunity. See innate immunity C-chemokine receptor 4 (CCR4) 947, – intracellular signaling. See intracellular 1018–1019, 2115, 2116 signaling C-chemokine receptor 5 (CCR5) 1203 – rituximab, anti-CD20 antibody 787 C5 glycoprotein 1166–1168 – unclear/unknown mechanisms 809–811 CA IX. See carbonic anhydrase IX (CA IX) – unique mechanisms 811–812 calicheamicin conjugates canonical residues – action mechanisms 1552 – CDR-grafting 93 – antibody-lysine site modification 357 – light-and heavy-chain variable regions 102 – cellular uptake and intracellular processing canstatin 829 1551 capromab (ProstaScint™) 2126–2129 – conjugate design/preclinical activity carbonate linkers 356 1549–1550 carbonic anhydrase IX (CA IX) 543, 767–768 – DNA binding 1550 carboxypeptidase G2 (CPG2) –GO.See gemtuzumab ozogamicin (GO) – CC3 xenograft model 477 – immunoconjugates 1555 – dimethyl sulfoxide (DMSO) 477 –IO.See inotuzumab ozogamicin (IO) – drug-resistant ovarian xenograft model 478 – linker choice 1550–1551 – Pseudomonas species 477 – resistance mechanisms 1552–1553 – radioimmunoassay 477 – stable hydrazone linkage 356 – xenograft-bearing mice, CEA 477 canakinumab cardiac adverse events –CAPS.See cryopyrin-associated periodic – cardiotoxicity 2055 syndrome (CAPS) – clinical trial data 2054 – cardiovascular risk. See cardiovascular risk – HERCULES multicenter phase II trial – gouty arthritis 1450–1452 2057 – interleukin-1 (IL-1) 1445 – left ventricular ejection fraction (LVEF) – marketed drug product 1446, 1447 2055 – production, pharmacology and – symptomatic cardiac events 2056–2057 pharmacokinetics 1446 cardiovascular risk –RA.See rheumatoid arthritis (RA) – atherosclerosis 1457 – sJIA 1452–1454 – CRP 1457 – type II diabetes 1456–1457 – phase III outcome 1457 cancer CARs. See chimeric antigen receptors (CARs) – drug targeting 503–504 Castleman’s disease 2032 – eAds blocking, cell signaling 503 catalytic antibodies – imaging 502–503 – bispecific anti-tumor/abzyme molecules – soluble ligands, irreversible removal 479 504–505 – description 478 cancer, Ab2 – synthetic antibody libraries 478–479 – B cell malignancies 415 catalytic protease. See pro-protein convertase – carcinoembryonic antigen (CEA) 416 subtilisin kexin (PCSK)-9 Index 2153 cation-exchange (CEX) chromatography 624 – ocrelizumab 903–904 catumaxomab (Removab). See also TriomabⓇ – ofatumumab 753–754, 791, 903 trAb family – rituximab and ofatumumab 143 –anti-EpCAM× anti-CD3. See anti-EpCAM × – rituximab mechanisms 1912 anti-CD3 catumaxomab – tetramers 1696 – bispecific antibodies 1464–1465 – therapeutic target 1910–1911 – CTLs 283 – type I and II 1695–1697, 1696 – gastric cancer treatment 1480–1481 –with90Y-ibritumomab tiuxetan 1583 – ovarian cancer patients 1481 CD22 – peritoneal carcinomatosis 1479–1480 – ADCs with uncleavable linkers 371 – systemic treatment outcome 1478–1479 – B-cell lineage restricted transmembrane – trAb. See trifunctional antibodies (trAb) glycoprotein 371 – tumor treatment 1469, 1471 – epratuzumab 904–905 C5b-9 MAC 1166 – expression, B-cell neoplasias 1547–1548 CD6 – SIGLECs 904 – 105–130-kDa surface glycoprotein 901 – targeting inotuzumab ozogamicin 353 – CD6-positive T cells 902 CD30 – itolizumab 902 – HDACs 1419 – ligands 901 – mutations 1419 – mature thymocytes 2113 – preclinical activity 1419 – positive effects, alloHSCT without GvHD – TRAF 1418–1419 1096 CDC. See complement-dependent cytotoxicity – T cell activation 2114 (CDC) CD20 CDP7657 (UCB and Biogen-IDEC) 1091 – 33–37-kDa non-glycosylated CDR-grafting phosphoprotein 902 – anti-Tac antibody 92 – ADCC and ADCP activity 1697 – B-cell chronic lymphocytic leukemia (B-CLL) – ADCC potency 1706 91 – B-cell expression 1115–1116, 1702 – 3D computer modeling, antibody structure – on B cells 1749–1752 95–97 – B-cellular non-Hodgkin’s lymphoma 753 – design cycle 92 – in bloodstream 1748 – donor anti-hapten antibody B1–8, murine – CDC and ADCC 903 90 – characteristics 1696, 1698–1699, – human framework sequences. See human 1748–1752 framework sequences, CDR-grafting – chimeric murine/human mAb 1342 – identification, putative backmutations. See – complement exhaustion, killing impact putative backmutations 1750 – P67.6 antibody 1550 – cynomolgus monkeys 376 – source (donor) sequence analysis 92–95 – cytotoxicity mediated, type I mAbs 1735 – stability 104 – exhaustion, two-step in vitro model 1751 – VL and VH, rat antibody Campath-1R 91 – expressing Z138 tumor cells 1702–1703 CDR-IMGT grafting 246, 247 – FDA, cancer treatment 1733 CDRs. See complementarity determining – humoral immunity 902 regions (CDRs) – hypothetical model 1698 cell culture – in vitro action mechanism 1695–1697 – ‘‘continuous’’ processes 615, 616 – in vitro trogocytosis 1751 – culture medium and aeration 615 – interactions 1735–1736 – disadvantages 615 – internalisation 1707, 1752 – feeder 30 – intravenous infusion 1749 – feeding strategies 617 – MS4a family, integral membrane proteins – fully disposable manufacturing, drug 1737–1738 substance 615, 616 – next-generation 1735–1736 – growth characteristics 615, 616 – obinutuzumab 754–755, 1698–1699 – in vitro cultivation systems 614–615 2154 Index

cell culture (contd.) – monoclonal antibody 225 1503 – inoculum phase 615 – NSCLC, clinical results. See non-small-cell – mammalian 571 lung cancer (NSCLC) – media 614 – preclinical results 1506 – media and tailor-made process design 604 – production 1511 – nonoptimal agitation/aeration 641 – SCCHN, clinical results. See squamous cell – perfusion 616–617 carcinoma of head and neck (SCCHN) – recombinant Sp2/0 murine myeloma cell CEX. See cation-exchange (CEX) line 2069 chromatography cell distribution, IgE chaperonin 10 1150 – APCs 1786 CHD. See congenital heart disease (CHD) – physiologic and pathophysiologic chemical immunoconjugates significance 1786–1787 – ADCs first-generation, within phase I/II – surface of effector 1785–1786 clinical trials 364, 366 cell fusion – clinical efficacy 364 – bacterial and viral infections, rodents 24 – cross-linkage heterogeneity. See – hybridoma production 18 cross-linkage heterogeneity – immunized mice 23 – cytotoxic drugs 363–364 – monoclonal antibodies generation 23, 24 – effector moities. See effector moities – nonproducing variants 23 – GPNMB glembatumumab vedotin 364 – poly ethylene glycol (PEG) 23 – hybridoma technology 364 – time course, hybridoma development – infusional and hypersensitivity reactions 24–25 364 cell lysis – ITCs first-generation, within phase I/II – ADCC 1328 clinical trials 364, 365 – alemtuzumab 1327–1328 – linker stability 364, 367–368 – apoptosis 1328 – target antigens, characteristics 370–371 cell surface antigens 127–128, 341, 791 chemokine inhibitors cell-surface receptors – anti-CCR4 1018–1019 – CD6 901–902 – anti-CXCL10 1019–1021 – CD20 902–904 – anti-CXCR5 1017–1018 – CD22 904–905 – anti-eotaxin-1 1015–1017 central retinal vein occlusion (CRVO) 1886, 1890 – anti-MIF 1022–1023 certolizumab pegol – anti-RANTES 1021–1022 – CD 2096, 2097 – bertilimumab 1017 – description 2095 chimeric antigen receptors (CARs) – investigational indications 2100–2101 – adoptive cellular immunotherapy 520, – marketing applications 2096 538–540 – methotrexate (MTX) 2096 – antibodies and T cell receptors 521–522 – and RA 2098–2100 – autologous tumor-specific T cells 519 – safety 2096 – capping, shedding/endocytosis 519 cetuximab (Erbitux) – CAR-modified T lymphocytes 540–545 – advanced pancreatic cancer 1511 – double chain CARs 523–524 – in cancer 1502 – extracellular spacer domains 528–529 – carboplatin and 1511 – first signal 525–526 – chimerization 1503 – immunoglobulin T cell receptors 522–523 – in clinics 1511–1512 – immunological effector lymphocytes 519 – colon cancer, clinical results. See colon – monoclonal antibodies 519 cancer – neovascularization, solid tumors 546 – epidermal growth factor receptor (EGFR) – preclinical studies. See preclinical studies, 1501–1502 CARs – KRAS and 1505 – receptor gene-modified effector lymphocytes – mechanism of action 1503–1505 546 Index 2155

– redirected T cells/alternatively T-bodies clinical development, biosimilar monoclonal 520–521 antibodies – second and third signals 529–530 – efficacy and safety 699–700 – signal domains, downstream signal – pharmacokinetics and pharmacodynamics molecules 526–528 697, 698–699 – single-chain CARs 524–525 – pharmacovigilance and risk management – TAA 520 701 – transmembrane domain 528 CLL. See chronic lymphocytic leukemia (CLL) – tumor taxis and CAR+ effector cells CMV. See Cytomegalovirus (CMV) 545–546 CNOP. See cyclophosphamide, mitoxantrone, CHOP. See cyclophosphamide, doxorubicin, vincristine and prednisone (CNOP) vincristine, prednisone (CHOP) CNTO-3157 1149 choroidal neovascularization (CNV) CNV. See choroidal neovascularization (CNV) – choroidal vessels 1887 colon cancer – development 1884 – bevacizumab 1508 – macrophages 944 – COIN and NORDIC-VII trails 1508 – PDT treatment 1891 – combination therapy 1507–1509 – prevalence 1886 – CRYSTAL phase III trial 1508 – pro-angiogenic cytokines 1885 – EGFR on tumor tissue 1506 – REPAIR clinical trial 1891 – grade 3/4 adverse events 1507 – right eye 1888 – II/III clinical trials 1507–1508 – KRAS mutation status 1508 – S1P levels 1179 – NORDIC-VII study 1508 Chothia numbering scheme 204–205, 207 – toxicity 1507 chronic lymphocytic leukemia (CLL) commercial manufacturing processes – alemtuzumab 86, 1330–1331 – biosimilar mAb 682 – FC chemotherapy 1971 – description 639–640 – FCR therapy 1968 – downstream manufacturing 643–645 – fludarabine 1333, 1334–1336 – economy of scale 645–646 – FR-based regimens 1970–1971 – harvest 642–643 – grade 3/4 hematologic toxicities – large-scale unit operations and systems 1335–1336 639 – hematologic toxicities 1334 – process characterization and validation – infections 1334 646–647 – infusion-related and hematological toxicity – upstream manufacturing 640–642 rates 1964, 1968 comparability and risk assessment 653–652 – malignant cells 87, 1331, 1334–1335 complement-dependent cytotoxicity (CDC) – monotherapy 1753 – antibodies, indirect effects 143 – non-CHEMO agents 1971–1973 – CD20-positive lymphoma cells elimination – ORR 1335 144 – p53 abnormalities 1336 – C1q binding capacity 146 – R-chlorambucil vs. chlorambucil alone – description 791 1970 – Fc-mediated Mo 145 –R-FCvs. FC 1968–1969 –Fcγ receptor polymorphisms 145 – rituximab monotherapy 1964, 1965–1967 – ofatumumab, human mAb 791 – rituximab retreatment 1973–1974 – rebmab 100 (hu3S1932) 791–792 – rituximab SC 1985–1994 – rituximab 1911–1912 – salvage therapy 1331 – veltuzumab (IMMU-106) 791 – and SLL 1936 complement inhibitors – symptoms 1917 – anti-C5/C5a/C5aR 1166–1169 – thrombocytopenia 1331 – anti-factor D 1169–1170 – treatment 1333–1334 – CD55 1913 cixutumumab (IMC-A12) 766–767, 799 complement system clazakizumab 869, 987–988 – activation 157–158 2156 Index

complement system (contd.) costimulatory molecules 1086, 1087, 1090, –CDC.See complement-dependent 1093 cytotoxicity (CDC) CPG2. See carboxypeptidase G2 (CPG2) – as confounding factor 1745–1746 CQA. See critical quality attribute (CQA) – IgG antibodies, classical complement CRAds. See conditionally replicative pathway 146 adenoviruses (CRAds) – monoclonal antibodies, MoA 143 critical quality attribute (CQA) – ofatumumab 1735, 1750 – non-human glycan patterns 692 complementarity determining regions (CDRs) – physicochemical and biological properties – ‘‘abbreviated CDRs’’ 105 685 – antibody engineering, chimeric and CRO. See Contract Research Organisation CDR-grafted mAbs 91 (CRO) – antibody structure prediction 216, 217 Crohn’s disease (CD) – antigen binding and specificity 668 – CERTIFI (NCT00771667) 2077 – bioinformatics tools, antibodies analysis – infliximab 1602–1603, cross-linkage heterogeneity 208–209 – drug antibody ratio (DAR) 369 – chimeric/humanized antibodies 36 – EU and Kabat numbering 369 – Chothia definitions 92–93 – maleimide-linked payloads 370 – description 92 – ‘‘naked’’ IgG contaminations 369 – error-prone PCRs 118 – SMCC and SMPT 369 – murine 107 CRS. See cytokine release syndrome (CRS) – murine complementary regions 665 CRVO. See central retinal vein occlusion – obinutuzumab (GA101, GAZYVA) 1697 (CRVO) – structure, antibody 26–2F FAB 93 cryopyrin-associated periodic syndrome conditionally replicative adenoviruses (CRAds) (CAPS) 293 – canakinumab 1448, 1449 congenital heart disease (CHD) – and FCAS 1448 – children, RSV hospitalization 1838–1839 – inflammatory markers 1448 – mechanical ventilation 1837 – NLRP3 gene 1448 – motavizumab 1845 – treatment 1450 – prevalence 1841 cryptic and conformational epitopes congestive heart failure – amyloid fibrils 323 – adalimumab 1311 – chemokine receptor (CXCR4) 323 – cardiac adverse events 2055 – enzyme active sites and viral clefts 323 – safety 1613 – inhibition, fibril formation 323 – trastuzumab trials 2056 CSF2 (GM-CSF) 1025–1026 contiguous hypervariable loop region Cunningham study 1955 – adnectins 451 Ⓡ cutaneous T-cell lymphomas (CTCLs) – Anticalins 452 – CD52 expression 1353 – CTLA-4 450 – CMV reactivation 1355 – fynomers 451 – mycosis fungoides/Sezary´ syndrome 1353 – human fibronectin type III (FN3) 450–451 – PTCL 1355 – lipocalins 451–452 – response rates, alemtuzumab 1353–1355 – natural immune system 450 CVP. See cyclophosphamide, vincristine, – neutrophil gelatinase-associated lipocalin prednisone (CVP) (NGAL) 453 CXCL10 990, 1019–1020, 1021, 1148 – phagemid display library 451 CXCR5 1017–1018 – 174-residue bilin-binding protein (BBP), cyclophosphamide-based regimens 1922 Pieris brassicae, 452 cyclophosphamide, doxorubicin, vincristine, – tendamistat, soluble 74 amino acid inhibitor prednisone (CHOP) 450 – DLBCL 1955 Contract Research Organisation (CRO) – failure-free survival (FFS) rate 1951–1952 729–730 – HIV-associated lymphomas 1977 Index 2157

–MCL.See mantle cell lymphoma (MCL) – bispecific antibodies, clinical trials 282 – median PFS 1942 – catumaxomab 283 – MInT 1952–1953 – CD28 binding to monoclonal antibodies – ORR and CR rates 1930, 1950 281–282 –PMBCL.See primary mediastinal B-cell – ertumaxomab 283 lymphoma (PMBCL) – major histocompatibility complexes (MHCs) – sequential rituximab 1923 279 – VNCOP-B 1945 – monoclonal antibodies, chemical cyclophosphamide, mitoxantrone, vincristine heteroconjugation 283 and prednisone (CNOP) 1922, 1930 – TriomAbs 283 cyclophosphamide, vincristine, prednisone – tumor cells 280 (CVP) 3D computer modeling, antibody structure – CLL. See chronic lymphocytic leukemia – ab initio methods 96–97 (CLL) – cocaine-binding antibody 97 – CT 1941–1942 – humanized antibody 95–96 – R-CVP 1924–1925 – putative backmutations 96 – SABRINA 1992 – QUANTA and CHARMm 96 cytokine inhibitors – SCRs 96 –anti-αVβ6 integrin 1013–1014 – stereochemical verification model 97 –TGFβ inhibitors 1011–1013 – Swiss PDB Viewer and academic servers – TH1 cytokines 970–1000 97 – TH2 cytokines 1000–1011 – V and C domains 97 cytokine release syndrome (CRS) – anti-TNF mAbs 1670 d – in vitro cytolytic assays 1662 dacarbazine (DTIC) – indomethacin 1669 – adverse events 1640 – M-CD3 and 1665–1666 – melanoma patients 1622 – management 1666 – patients without brain metastasis – methylprednisolone 1666–1668 1628–1629 – pathophysiology 1662–1663 – phase II open-label trial (MDX010-08) – pentoxifylline 1668–1669 1625 – recombinant human soluble tumor necrosis dalotuzumab (MK-0646) 766, 800 factor receptor 1669–1670 Data Bank of Japan (DDBJ) 233 – symptoms 1663–1664 Db. See diabodies (Db) – T cell function 1662 DC-SIGN. See dendritic cell-specific cytomegalovirus (CMV) intercellular adhesion molecule 3-grabbing – antigenemia 1343 nonintegrin (DC-SIGN) – IgG 1203 dekavil 1185 – infection 1342 dendritic cell APCs 1800 – MSL-109 resistance 1203 dendritic cell-specific intercellular adhesion – pneumonitis and oral candidosis 1338 molecule 3-grabbing nonintegrin – reactivation 1343 (DC-SIGN) 184 cytotoxic compounds, ADCs denosumab (ProliaⓇ) – DNA-/DNA-topoisomerase-targeted – diseases and targets 775–776 cytotoxic agents 352–353 – FDA guidelines 1526–1527 – microtubule-targeted cytotoxic agents – FREEDOM (phase 3 study) 1524–1525 346–352 – HALT (phase 3 study) 1526 cytotoxic T-lymphocyte antigen 4 (CTLA-4) – osteoporosis 1521 – B7 ligands binding 1620 – osteoprotegerin-immunoglobulin Fc –CD4+ 1620 segment complex (OPG-Fc) 1521 – immunomodulatory cytokines 1620 – phase 1 study 1522–1523 – MYPPPY sequence 1620 – phase 2 study 1523–1524 cytotoxic T lymphocytes (CTLs) – RANK/RANKL signaling pathway 1522 – anti-CD3 antibody TR66 281 – RANKL 1521 2158 Index

denosumab (ProliaⓇ) (contd.) double chain CARs – STAND (phase 3 study) 1525–1526 – antibody V regions 524 – urinary NTX/creatinine 1523 – chimeric TCR variants 523 dermatology life quality index (DLQI) 1317, – Fab fragments 524 1539, 2072, 2074 – functional antigen-binding Fv/Fab fragment diabetes 524 – type I 152, 413, 876, 949–950, 1080, 1886 downstream processing. See also commercial – type II 853, 873, 875, 950–951, 1095, manufacturing processes 1456–1457 – AEX 624 diabetic macular edema (DME) – affinity chromatography 622–623 – blood-retinal barrier 1886 – antibody’s purity and monomer content – definition 1886 623 – FDA approval 1889 – automation/miniaturization 627, – macular laser procedures 1890 – binding proteins 440 – retinal hemorrhages, intraretinal cysts and – biotherapeutic molecules 619, microanevirsms 1887 – CEX 624 diabodies (Db) 272, 273–274 – description 618 diffuse large B-cell lymphoma (DLBCL) – development concepts 628 – CD30-positive 1435 – disposable and single-use concepts 627, – CR rates of R-ICE 1955 628 – DA-EPOCH 1950 – drug substance manufacturing 625 – GELA LNH98-5 trial 1950, 1951 – efficacious and safe therapeutic antibodies – intergroup E4494 trial 1950, 1951–1952 620 – MInT 1952–1953 – HIC 623 – and relapsed MCL 1973–1974 – IEC 623–624 – retrospective population analyses 1953 – microfiltration 1833 dipeptidyl peptidase IV (DPPIV) 1095–1096 – monoclonal antibodies 620–622 direct cell death induction, obinutuzumab – process-related impurities 619–620 – ability 1702 – product-related impurities 620 – B-cell malignancies 1703 – and production, antibody 1833–1835 – CD20, B-cell cycle progression 1702 – resins and ligands 626 – CD40-induced resistance mechanisms – separation technologies 626–627 1703 – small-scale and large-scale processes 643 – fluorescence-activated cell sorting (FACS) – stress conditions 620 analysis 1703 – ultra/diafiltration (UF/DF) 622 – HLA-DR 1702 – validation, DNA removal 624–625 – host immune response 1704 – virus clearance 625, – murine type II CD20 antibody B1 1702 – virus filters 644 – primary B-cell chronic lymphocytic dromedary IgG2 and IgG3 247–248 leukemia (B-CLL) cells 1703 DTIC. See dacarbazine (DTIC) – ROS in human B-lymphoma cell lines dual targeting strategies, bispecific antibodies 1703 289–291 – in Z138 MCL cells 1702 dupilumab 948, 1002–1003 disease-modifying antirheumatic drugs (DMARDs) 505, 936–937, 986, 1120, e 1567, 1571, 1980, 2027, 2029, 2030, 2096 E. coli S30 399–400 disk stack centrifugation system 642–643 eAds. See engineered antibody domains (eAds) disulfide linkers 355–356 early breast cancer (EBC) DLBCL. See diffuse large B-cell lymphoma – adjuvant trastuzumab 2049–2050 (DLBCL) – adjuvant treatment 2053 DLQI. See dermatology life quality index – disease-free survival, EBC trials 2052 (DLQI) – docetaxel 2054 DLX105 ESBA-105 974 – FinHer trial 2052 DME. See Diabetic macular edema (DME) – HERA trial 2050, 2051 Index 2159

– infusion-related reactions 2054 elotuzumab (anti-CS1) 757–758 – MBC 2049 endostatin – and PST 2048 – anticancer spectrum 829 – response rate 2049 – Down syndrome 828 – trastuzumab monotherapy/combination – functions 828 therapy 2053–2054 – integrin deficiency 828 – trastuzumab treatment, tumor types 2053 – NSCLC 829 eculizumab 1167 – proteolytic cleavage 828 – adverse reactions 2101 – wnt-signaling pathway 828 – approved indications 2102–2103 engineered antibody domains (eAds) – C5 2101 – cancer, targeting. See cancer – IgG2 sequences 2101 – clinical/preclinical development 489, – investigation use 2103–2104 490–491 efalizumab (Raptiva) – HCAbs 489 – absorption 1537 – hematological disorders. See hematological – action mechanism 1535 disorders, eAds – administration, psoriatic plaques 1536 – vs. HIV-1. See human immunodeficiency – anti-mouse CD11a antibodies 1535–1536 virus type 1 (HIV-1) – antibody, development and characterization – human IgG CH2 495 1531–1532 –inflammation.See inflammation, eAds – biotransformation 1537 – libraries. See libraries – chimpanzees, immunization 1536 – VH and VL 494 – dose-dependent nonlinear pharmacokinetics –V H 492, 493 1537 H – VNAR 492, 493 – elimination 1537 – X-ray and NMR structures 489 – health-related quality of life (HRQoL) 1539 enhanced Chothia (Martin) numbering – in vitro studies 1535 scheme 206, 207 – long-term efficacy 1538–1539 envelope (env) proteins 1183–1184 – psoriasis treatment. See psoriasis enzyme-linked immunosorbent assay (ELISA) – randomized controlled clinical trials (RCTs) – ADA measurement against antibodies 672 1540–1541 – HCPs 648 – randomized, placebo-controlled, – heavy-and light-chain subclasses, hybridoma double-blind studies 1538 – safety and tolerability 1539–1540 antibodies 27 – single-dose intravenous study 1536 – hybridoma supernatants 27 – subcutaneous effects 1537 – microtiter plates and binders 126 effector cells retargeting and bispecific – polyclonal phage preparations 46 antibodies – RSV replication 1832 – CTLs 279, 279–283 – solid phase 27, 28 – Fc receptor 283–285 – SPR, BLI and KinExA 132 – phagocytosis 278 eotaxin-1 1015–1017 effector moities epidermal growth factor receptor (EGFR) – calicheamicins and microtubule inhibitors – acne-like skin rash 761 372 – drug hypersensitivity reactions 762 – cytostatic drugs 372 – necitumumab 762 – diphtheria toxin (DT) 372 – nimotuzumab 762–763 – onconase (ONC) 373–374 – ramucirumab (VEGF-R) 764 – pancreatic RNase A family 373 – signaling proteins, K-RAS/N-RAS 761 – proapoptotic proteins 374 – squamous cell carcinoma 761–762 – Pseudomonas exotoxin (PE) 372 – trastuzumab emtansine (Her2/Neu) – ribosome-inactivating proteins (RIPs) 373 763–764 EGFR. See epidermal growth factor receptor – tumor cell proliferation and (EGFR) neoangiogenesis 761 eldelumab 1020–1021 – zalutumumab 762 2160 Index

epithelial cell adhesion molecule (EpCAM). evolocumab (AMG 145) See anti-EpCAM antibodies – GAUSS trial 853 epitope recognition – human monoclonal immunoglobulin G2 – avidity and bivalent binding 1699 (IgG2) antibody 853 – binding properties and 1699 – phase III trials with 854–857 – ofatumumab 1737–1739 – RUTHERFORD trial 853 – rituximab and 2H7 binding 1701 expression systems – Scatchard analysis 1699 – ADCC and CDC 609 – type II and crystal structure 1700 – ammonia 607 epratuzumab 904–905 – antibody-derived formats and scaffold error-prone PCRs proteins 605–606 – amino acid exchange 118 – biopharmaceuticals 612 – and mutated sequences 153 – cell engineering strategies 609 – PCR-based mutagenesis and DNA shuffling – cell variance, host cell lines 610 118 – cis-active elements 608 ERVWE1 env (syncytin-1) 1184 – clone-screening platforms 610–611 ESBA1008 1178 – co-transfection 608 ESBA-105 Novartis 973–974 – endogenous DHFR/GS activity 607 Escherichia coli – Escherichia coli, 613 – aglycosylated IgG antibodies 562 – Fc-linked N-glycans 609 – BAC purification 79, 80 – fundamental problems 613 – Campylobacter jejuni, 563 – gene expression 606 – conventional expression systems 440 – glycostructures 609 – cyclodextrin glycosyl transferase 564 – GlymaxX technology 610, 611 – genetic modifications 563 – high-mannose-type O-glycosylation 612 – prokaryotic cell expression 374 – internal ribosomal entry site (IRES) 608 – protease-deficient strains 563 – mammalian-cell-based systems 606 – proteins purification 563 – metabolic selectable marker genes 607 – random mutagenesis 563 – mRNAs 606 – recombinant protein expression 562 – nonviral DNA delivery methods 607 –redoxmutant(trxB gor) strains 563 – post-translational modifications, protein – S30 cell-free lysate 399 609 – Sec-secretion pathway 563 – recombinant biopharmaceuticals 605 esophageal and gastric cancer 1684–1685 – recombinant proteins 605 etrolizumab 1130 – redominant mammalian host cell line 606 eukaryotic expression systems – targeted integration systems 608–609 – filamentous fungi 569–570 – transient 607 – hosts 565 extracellular spacer domains, CARs 528–529 – insect cells 570–571 – mammalian cells. See mammalian cells f – plants 579–580 fanolesomab (LeuTechⓇ, NeutroSpecⓇ) – protein secretion 565 2132–2134 – transgenic animals 580–581 farletuzumab (MORAb-003) 769 – yeast 565–569 Fc engineering European Organization for Research and – ADCC 156 Treatment of Cancer (EORTC) 1475, 1930, – bacterial-based screening system 157 1942 – 113F variant 156 European Union (EU) approach, biosimilars – Fc-attached carbohydrate structures 156 – CHMP 684 – Fc variants harboring amino acid exchanges – Epoetin alfa 683 156 – European Medicines Agency (EMA) –FcγRIIIa binding affinity 156 guidelines 682 – lacking Fc glycosylation 156 – marketing approvals 683 Fc-fusion – regulated markets 684 – anti-EGFR sdAb 329 Index 2161

– anti-TNF Fc-fusion molecule ART621 330 – inotuzumab ozogamicin 367–368 – and approved mAbs 1234–1235, 1237 – monotherapy 1753–1756 – description 329 – ocrelizumab 903 – neo-epitopes 677 – ofatumumab 380 – proteins 1234–1235, 1237, 1238 – rituximab, phase I/II study 903 Fc receptor. See also protein-engineered – 90Y-ibritumomab tiuxetan 1585 antibodies follow-on monoclonal antibody 684–685 – CD16 284 foralumab 1083 – granulocyte colony-stimulating factor Fracture Reduction Evaluation of Denosumab (G-CSF) 284 in Osteoporosis Every 6 Months – NK cellmediated cytotoxicity 284 (FREEDOM) – recombinant bispecific antibodies 285 – denosumab efficacy 1524–1525 – toxicity 284 – hypocalcemia 1525 FcεRI (high-affinity IgE receptor) – nonvertebral fractures 1525 – cell activation 1782–1783 free serum IgE concentration, rhuMAb-E25 – expression, basophils and mast cells 1783, 1790, 1791 1784 freedom to operate analysis – IgE binding 1781–1782 – CDR sequences 714 – mast cells, basophils and DCs 1781, – divisional applications 714 FcεRII (low-affinity IgE receptor) – Europe and United States 713 – activation 1784 – ‘‘infringement’’ 711, 712–713 – CD23 functions 1784–1785 – licensing negotiations 711 – IgE binding 1784 – parameters 713 – transmembrane polypeptides 1783, 1784 – specialist skills 713 FFP-102 1091 – therapeutic antibodies 711 figitumumab (CP-751,871) 767 freeze-dried protein formulations 638 filamentous fungi fresolimumab 794–795, 1013 – antibody fragments 569 fucose and bisecting N-acetylglucosamine – Aspergillus species 570 – anti-epidermal growth factor receptor – description 569 (EGFR) 181 – fungal high-mannose glycans 570 – complement-dependent cytotoxicity (CDC) – IgG antibodies, fungal expression 570 182 – KexB cleavage site 569 – ‘‘knockout’’ CHO cell line 181 – recombinant heterologous products 569 – neutrophil-mediated ADCC 181 – T. reesei cellobiohydrolase I (CBHI) 569 – Potelligent technology 181 first-in-man (FIM) safety fusion peptide 1827 – clinical trial authorization 1277–1278 fusion protein. See recombinant scFv-CPG2 – comparability investigations 1275–1276 fusion protein – modes of action 1273 – post-marketing activities 1279–1280 g – pre-authorization interactions gag-encoded protein 1183 1276–1277 galactosylation – risk management plan 1278–1279 – DC-SIGN 184 – Tegenero case 1272–1273 – dendritic cells 183 first signal, CARs – glycoforms 182 – effector mechanisms, CAR+ cytotoxic – hydrogen/deuterium exchange 183 lymphocytes 525 – mannan binding lectin (MBL) 183 – signaltransduction, T cells 526, 527 – recombinant IgG antibody therapeutics – TCR complex and FcεRIγ chain 526 183 FL. See follicular lymphoma (FL) – rheumatoid arthritis (RA) 182 fludarabine 1333, 1334–1331 – tumor necrosis factor receptor 183 follicular lymphoma (FL) galiximab 757, 1087–1088 – CD80 expression 757 ganitumab (AMG 479), 765–766 – DLBCL 1485 gantenerumab 908–909, 1219–1220 2162 Index

GELA LNH98–5 trial 1950, 1951 – CHO cells 189 gemcitabine – direct simulation Monte Carlo (DSMC) – and bleomycin 1437 188 – and carboplatin 2092 – fucose and bisecting N-acetylglucosamine – and nimotuzumab 1685 180–182 – and placebo group 1685–1686 – galactosylation, IgG-Fc activities. See – regimens 1955 galactosylation – and rituximab 1979 – IgG-Fc glycans, chemo-enzymatic synthesis gemtuzumab ozogamicin (GO) 185 – allogeneic stem cell transplantation 1555 – IgG-Fc oligosaccharide moiety 176–177 – CD33-positive leukemic cells 1553 – IgG-Fc protein/oligosaccharide interactions – CMA-676 1553 177–179 – composition 1548 – IgG-Fc, quaternary structure 174–175 – conjugate design/preclinical activity 1548 – IgG glycoforms, in cellular FγRs recognition – dose and schedule 1554–1555 180 – French ALFA trial 1555 – IgG molecule 172–173 – IgG4 moiety 1549 – N-linked glycosylation 187 – Italian GIMEMA assessed 1554 – polyclonal human IgG-Fab, analysis 187 – myeloid cells 1553 – protective mechanisms activation 180 – relapsed AML patient 1554 – recombinant antibodies 188 – single-agent phase II evaluations – sialylation, IgG-Fc oligosaccharides 1553–1554 184–185 – target antigen selection, ADC therapy. See – VH deglycosylated molecule 189 target antigen selection, ADC therapy – X-ray crystallographic studies 188 – veno-occlusive disease/sinusoidal GM-CSF. See granulocyte-macrophage obstruction syndrome (VOD/SOS) 1554 cerebrospinal fluid (GM-CSF) GenBank/European Nucleotide Archive GMALL regimen. See German Multicenter (ENA)/DNA 233 acute lymphoblastic leukemia (GMALL) German Multicenter acute lymphoblastic regimen leukemia (GMALL) regimen 1958 GnbAC1 (GeNeuro Innovation SAS) 1184 germline components identification 214 GO. See gemtuzumab ozogamicin (GO) germline sequence databases 211 golimumab gevokizumab 875–876, 877 – adverse events (AEs) 1569 girentuximab (CA IX) 767–768 – arthritis 1567 glioma – binding affinity 1568 – high-grade 836, 2094 – cynomolgus macaques 1568, – malignant 377, 1683 – DMARDs 1567 – pediatric 1684 – full-length human IgG1 antibody 1568 – recursive partition analysis (RPA) 1683 – market competitors 1575 – types 1682–1683 – pharmacokinetic (PK) properties 1568 glycoengineering, obinutuzumab – phase 3 studies 1566 – antibody glycoengineering 1704 – recommended SIMPONI dose regimen – carbohydrate and Fc region 1705 1565 – in Chinese hamster ovary (CHO) cells – rheumatoid arthritis. See rheumatoid 1706 arthritis – Fc receptors 1704 – TNF levels reduction 1567 – ‘‘GlycoMab technology’’ 1704 gouty arthritis – human glycosylphosphatidylinosotol (GPI) – canakinumab 1451 anchored FcγRIIIb 1706 – colchicine vs. canakinumab groups 1451 – mogamulizumab 1705 – joint inflammation 1450 – posttranslational modifications 1704 – NSAIDs 1452 glycosylation – treatment 1452, 1453 – aglycosylated IgG-Fc 186–187 graft-versus-host disease (GVHD) – cetuximab (Erbitux) 188 – chronic 1983 Index 2163

– donor T cells 1360 hepatomegaly/splenomegaly 1338 – and graft rejection 1361 HESs. See hypereosinophilic syndromes – immunosuppression 1096 (HESs) – and nephrotoxic serum models 979 heterobifunctional cross-linkers 270 – pathogenic role 1096 HIC. See hydrophobic interaction – prophylaxis 1361 chromatography (HIC) granulocyte-macrophage cerebrospinal fluid hidradenitis suppurativa (HS) 1316–1318 (GM-CSF) 1931, 1971 HIF1-α. See hypoxia-inducible factor 1 alpha growth factor inhibitors (HIF1-α) – anti-CSF1 (M-CSF) 1023–1025 high-dose therapy (HDT) – anti-CSF2 (GM-CSF) 1025–1028 – ASCT and allogeneic SCT 1959 GS-5745 (Gilead Sciences Inc.) 1182 – beneficial effect 1976 GSK-1070806 (GSK) 984 – in vivo purging process 1974 GSK-1995057 (GSK) 975–976 – immunochemotherapy 1975–1976 GSK-2434735 1003 – PFS and OS rates 1975 guselkumab 993 – posttransplant maintenance 1975 GVHD. See graft-versus-host disease (GVHD) HIV-1. See human immunodeficiency virus type 1 (HIV-1) h HIV-associated lymphomas 1977 HACA. See human antichimeric antibodies Hodgkin’s disease (HD) 1979 (HACA) Hodgkin’s lymphoma hairy cell leukemia (HCL) 1978–1979 – ABVD 1429 HALT. See hormone ablation therapy (HALT) – allogeneic transplant 1427 hapten-binding bispecific antibodies 289 – anaplastic large cell lymphoma 1420 HBsAg. See human hepatitis B surface antigen – before/after auto-SCT 49. 1427 (HBsAg) – brentuximab vedotin 759–760, 1429 HCL. See hairy cell leukemia (HCL) – CD30-positive hematologic malignancies HD. See Hodgkin’s disease (HD) 1429, 1432 HDT. See high-dose therapy (HDT) – combined modality therapy 1421 head and neck, nimotuzumab – SCT 1421, – advanced carcinomas 1680 – treatment 1421 – CRT treatment 1682 Honegger and Plückthun (Aho) numbering – inclusion criteria 1680 scheme 206 – ionizing radiation 1680 hormone ablation therapy (HALT) 1526 – irradiation, CR 1681 HOVON-46 study 1954 – nasopharyngeal tumor 1681 HRQoL. See health-related quality of life – pharmacodynamic effect 1680 (HRQoL) – radical surgery 1681–1682 HS. See hidradenitis suppurativa (HS) health-related quality of life (HRQoL) human and chimeric IgH loci 1539 – anti-human κ anti-human λ L-chain affinity heart transplantation matrix 84 – basiliximab 1386–1387 – B-cell numbers 83 – daclizumab 1387 – description 83 hematological disorders, eAds – IgM and IgG titers 83 – ALX-0081, bivalent humanized VHH – immunization, antigens 85 507–508 – in OmniRat 84 – von Willebrand disease type 2B (VWD2B) human anti-human antibody (HAHA) 507 responses 2078 – von Willebrand factor (VWF) 507 human antichimeric antibodies (HACA) hemolytic uremic syndrome (HUS) 1909, 1910, 1973, 1984 – drug designations 2103 human epidermal growth factor receptor 2 – eculizumab 1200 (Her2) – pathophysiology 1200 – adjuvant treatment 2042–2043 – treatment 1200 – age considerations 2058 2164 Index

human epidermal growth factor receptor 2 – defined 89 (Her2) (contd.) – engineered mAb 89 – breast cancer. See breast cancer – history 89–90 – cardiac adverse events. See cardiac adverse – phage libraries. See phage libraries events – removal, T-and B-cell epitopes 106 – dosing/scheduling 2059 – resurfacing/veneering 104–105 – FDA approval 2062 – SDR-transfer. See specificity-determining – infusion-related reactions 2057–2058 residue (SDR)-transfer – intracellular signaling 2042 Huntington’s disease (HD) – natural killer (NK) cells 2042 – active immunotherapy, DNA vaccines – patients considerations 2058 1223 – safety and side effects 2061–2062 – disease and target 1222 – trastuzumab 2041–2042 – passive immunotherapy, intrabodies human family chronology 1222–1223 – heavy chain variable genes (VH) 219 HUS. See hemolytic uremic syndrome (HUS) – light chain variable genes (Vλ and Vκ) 219, hydrazone linkage 356 220 hydrophobic interaction chromatography human framework sequences, CDR-grafting (HIC) 623 – affinity, specificity and activity 97 hyper-CVAD 1958, 1959, 1962 – biopharmaceuticals, FDA 97, 98–99 hypereosinophilic syndromes (HESs) 876, – database search 101–102 877 – donor sequence (homology) matching 100 hypoxia-inducible factor 1 alpha (HIF1-α) – donor VH and human frameworks 100 824 – germline 101 – subgroup consensus/expressed 101 i – VL/VH 100–101 IBD. See inflammatory bowel disease (IBD) 10th Human Genome Mapping Workshop ibrutinib 1972–1973 (HGM10) 233 IEC. See ion-exchange chromatography (IEC) human heavy-chain diseases (HCD) 248 IgA antibodies, antibody isotype. See antibody human hepatitis B surface antigen (HBsAg) isotype 410 IgE. See immunoglobulin E (IgE) human Ig transloci construction IGF-1R. See insulin-like growth factor type I – BAC and YAC libraries 78 receptor (IGF-1R) – IgH 78–80 IgG antibodies, antibody isotype. See antibody –Igκ 80 isotype –Igλ 80–81 IgG-Fc oligosaccharide moiety – in transgenic animals 78 – galactose residues 176 human IgG CH2 495 – glycoforms 176, 177 human immunodeficiency virus type 1 – heterogeneity 176 (HIV-1) – plasma cell clone 177 – CD4bs, HIV-1 gp120 500 – polyclonal IgG 176 – CoRbs, HIV-1 gp120 499–500 – soluble and cell-surface-expressed receptor – coreceptors 501 176 – implications 501 IgG-Fc protein/oligosaccharide interactions – MPER, HIV-1 gp41 500–501 – glycosidases and glycosyl transferases 178 – MPER of gp41 499 – inter-heavy chain disulfide bridge 179 – vital immune cells 498 – PNGase F enzyme 178 human organ transplantation – sugar residues, interactions 178 – adult non-renal transplantation. See adult – X-ray crystallographic analysis 177, 179 non-renal transplantation IGHG CH amino acid positions – BPAR 1378 – IGHG1 alleles and G1m allotypes 251, –renal.See renal transplantation 252, 253, 257 humanization – interface ball-and-socket-like joints 251, – CDR-grafting. See CDR-grafting 253 Index 2165

– knobs-into-holes methodology 249, 251, – killer cells 279 253 – network theory 412 – N-linked glycosylation site 249, 250 immune thrombocytopenia purpura (ITP) Igκ, human Ig transloci construction 80 1350 Igλ, human Ig transloci construction immunization, monoclonal antibody – description 80 – adjuvants 22 – endogenous 81 – antibody response outcome 21 –YAC,17Vλ and all J-Cλs 80–81 – factors 21 IgM. See immunoglobulin M (IgM) – in vitro, 22 IL-2R antibodies – KLH/BSA 22 – ADM 1394 immunoconjugates –ATL.See adult T-cell leukemia (ATL) –ADCs.See antibody–drug conjugates – GVHD 1394–1395 (ADCs) –MS.See multiple sclerosis (MS) – bispecific antibodies 807–808 – TSP/HAM 1393 – bispecific mAbs 803–804 – uveitis 1393–1394 –BiTEs.See bi-specific T-cell engagers (BiTEs) IMGT Collier de Perles – brentuximab 803–794 – C domain 241 – mAbs/mAb fragments 802–803 – graphical 2D representation 237 –RAIT.See radioimmunoconjugates (RAIT) – V domain 239, 241 – SWOG S0106 803 IMGT-ONTOLOGY concepts immunogen – genes and alleles 233–236 – animals 1299 – Homo sapiens IG chain labels 235 – carrier proteins, preparation 1298–1299 – IMGT Collier de Perles 237–241 – definition 1298 – IMGT unique numbering concept – immunogenicity 1298 236–237 – properties and preparations 1298 – immunogenetics and immunoinformatics immunogenicity 231 – of Abs 668, 669 – labels 233 – ADAs bioanalytical assessment vs. – standardized keywords 232–233 therapeutic antibodies 671–673 IMGT unique numbering concept – ADCC and/or CDC function 669, 670 – CDR-IMGT length 237 – advantages 482 – IG and TR gene allelic polymorphisms 237 – AEC 482 – IG and TR V-DOMAIN 236 – antibody-based drugs 667, 675, 676 – MH superfamily (MhSF) 237 – approved mAbs, USA and Europe 665, 667 – structural level 237 – B-cell modification approach 480 imicromab (MyoScint™) 2129–2130 – bispecific antibodies 677 immune-complex-mediated arthritis (ICA) – chimeric ADCs 677 model 1150 – clinical 1256–1257 immune library generation 317 – clinical consequences, Abs 671 immune modulators, B-cell lymphoma –FcγRs 669 – GM-CSF 1931 – Food and Drug Administration (FDA) 677 – IFN-α-2α 1931–1932 – fragments 675 – lenalidomide 1932 – glycoengineering 671 – ORR and CR rates 1932–1933 – hexa-histidine tag (His-tag) to C-terminus immune system 480 – adjuvants 22 – and immune system 667–668 – antibody molecules 18 – insufficient tumor penetration 677 – CD100 1085–1086 – mAbs development 668, 669 – CDC 791–792 – murine, chimeric and humanized mAbs1 – disorders 1639 668 – immunocompetent cells 934 – murine monoclonal antibody, bacterial – and immunogenicity 667–668 enzyme 480 – inflammatory diseases 934–935 – nonclinical 1255–1256 2166 Index

immunogenicity (contd.) –AD.See Alzheimer’s disease (AD) – nonimmunogenic enzymatic activities 481 – advantages and challenges 1215–1216 – prediction tools 673–674 –ALS.See amyotrophic lateral sclerosis (ALS) – recombinant-DNA technology 665 – antibody-based therapies 1216 – risk assessment, antibodies 670 –HD.See Huntington’s disease (HD) – T-cell epitope modification strategy – PD. See Parkinson’s disease (PD) 480–481 – transmissible spongiform encephalopathies. – T-cell proliferation assays and in silico See transmissible spongiform analysis 481 encephalopathies – of therapeutic antibodies 674–675 in vitro affinity maturation – tools 482 – anti-2-phenyloxazol-5-one (phOx) antibody immunoglobulin E (IgE) Fv fragment 118 – allergen-binding site 1778–1779 – biotinylated and non-biotinylated antigen – allergic and nonallergic conditions 1778 119 – anti-IgE inhibitors 1161–1162 – CDRs 119 –anti-IgEM1′ inhibitors 1162 – error-prone (PCRs) 118 – cell distribution 1785–1786 – panning 117 – distribution and blood concentration 1779 – physical/chemical parameters 118 – distribution of FcεR 1780 – site-directed mutagenesis 118 – early and late-phase allergic reactions in vitro binding and potency 1776–1777 – cell-based bioassays 121 –FcεRI (high-affinity IgE receptor) – monoclonal antibodies target, cytokines 1781–1783 122 –FcεRII (low-affinity IgE receptor, CD23) – simulated effect, antibody–antigen mixture 1783–1785 123 – physiologic and pathophysiologic in vitro maturation and antibody selection significance 1786–1787 – de novo design 397 – serum concentration, asthma and rhinitis – DNA mutagenesis and display technologies 1775–1776 397 – synthesis and regulation 1779–1780 – guided selection 397 immunoglobulin heavy (IgH) – off-rate selection 397 – BACs with human VH,D,JH segments and – post-selection populations 398 rat C-region locus 79, in vivo affinity maturation – cis-acting control sequences 79 – antibody diversity and germinal center 116 – cYAC/BAC vector 79, 80 – ‘‘germlinized’’/‘‘superhumanized’’ antibody – description 78–79 117 – XenoMouse animals 79 – hypermutation and clonal deletion 116 immunoglobulin M (IgM) 1197 – naive cells 115 immunoglobulin T cell receptors – single B-cell clones 116 – CARs 522–523 – somatic hypermutation 117 – extracellular spacer domains 523 – VDJ rearrangements 115 immunological responses in vivo binding and potency – antitumor immune 770 – affinities 123 – checkpoint blockade/vaccination 770 – tumor penetration 124 – eradication, equilibrium and escape 770 – unbound concentrations 124, 125 – ipilimumab (anti-CTLA4) 771–772 individual extended loops – nivolumab (anti-PD1) 772 – bacterial TEM-1 β-lactamases 456–457 – PD-1 and CTLA-4 ligands 770 – charybdotoxin 456 – tumor regression 770 – cystine-knot motifs 455 immunoreceptor tyrosine-based activation – human plasma kallikrein (pKAL) 454 motif (ITAM)-containing the FcRγ-chain – knottins 455–456 143 – Kunitz-type scaffold, DX-890 454–455 immunotherapeutics, neurological disorders – protease inhibitors 454 – active vs. passive 1216–1217 – thioredoxin (TrxA) 455 Index 2167 indomethacin 1669 – neurological disorders/demyelinating inducible T cell costimulator (ICOS) disease 1612 1088–1089 – pediatric Crohn’s disease 1603 infectiology, mAbs – pediatric ulcerative colitis 1609 – anti-infectious mAbs. See anti-infectious – pharmacokinetics 1600–1601 monoclonal antibodies – preclinical characterization 1600 – antimycotic 1207 – psoriasis 1607–1608 – antitoxinic activity 1196–1197 – psoriatic arthritis (PsA) 1606–1607 – and clinical trials 1196 – RA 1603–1605 – IgM 1197 – serious infections 1609–1610 – infectious diseases 1195 – ulcerative colitis 1608–1609 – viral diseases and anti-infectious mAbs infringement 711, 712–713 1201–1207 infusion reactions/delayed hypersensitivity infectious disease reactions 1611–1612 – cancer 1295 injection-site reactions (ISRs) 1338 – virology 1295 innate immunity – XOMA3AB antitoxin 1295 – ADCC. See antibody-dependent cellular inflammation, eAds cytotoxicity (ADCC) – IBD 507 – BMS-936559 (MDX-1105) 794 – RA 505–506 –CDC.See complement-dependent inflammatory bowel disease (IBD) cytotoxicity (CDC) – conventional methods 788 – acute flares 938 – effector cells, targeting 789 – eAds 507 – ipilimumab 792–793 – mAbs 939 – MPDL3280A, PD-L1 targeting compound – mild 938–939 794 – natalizumab 939 – nivolumab 793–794 – systemic immunosuppressive drugs 939 – pidilizumab (CT-011, hBAT-1) 793 inflammatory diseases – programmed death 1 (PD-1) receptor 793 – allergic diseases 945–949 – rituximab, anti-CD20 antibody 789 – arthropathies 953 – transforming growth factor-beta (TGFβ) – diabetes 949–951 794 – IBD 938–939 – tremelimumab 793 – MS 939–941 inotuzumab ozogamicin (IO) – ocular diseases 943–945 – B-cellular non-hodgkin’s lymphoma – organ transplantation–graft rejection 756–757 951–953 – calicheamicin conjugates. See calicheamicin – psoriasis and psoriatic arthritis 937–938 conjugates – RA 936–937 – CD22 antibodies 1555 – SLE 941–943 – conjugate design/preclinical activity 1549 infliximab – DLBCL 367 – ankylosing spondylitis (AS) 1605–1606 – IgG4 moiety 1549 – antibody characteristics 1599 – relapsed/refractory follicular lymphoma (FL) – antibody formation against 1611 367 – autoantibody formation 1612 – rituximab and 1556 – CD 1602–1603 – side effects 1555 – congestive heart failure 1613 insect cells – hepatic events and pregnancy outcome – disadvantages 570 1613 – N-glycosylation patterns 571 – hepatotoxicity 1639 – recombinant antibody expression 570 – infusion reactions/delayed hypersensitivity – research and development 570 reactions 1611–1612 – secretory proteins 570–571 – malignancies/lymphoma 1612–1613 insulin-like growth factor type I receptor – marketing 1618 (IGF-1R) 2168 Index

insulin-like growth factor type I receptor – inflammatory diseases 985 (IGF-1R) (contd.) – liver function abnormalities 2034–2035 – cixutumumab (IMC-A12) 766–767 – malignancies 2033 – dalotuzumab (MK-0646) 766 – monoclonal antibodies 2024–2025 – description 765 – sarilumab 869–870, 871–872 – figitumumab (CP-751, 871) 767 – sirukumab 870, 873, 874 – functional hybrid receptors 765 – tocilizumab 869 – ganitumab (AMG, 479) 765–766 interleukin 10 (IL-10) 1007–1008 – tumorigenesis 765 interleukin-13 (IL-13) α1β1 integrin (VLA-1 (Cd49a)) – cytokine and receptor-directed inhibitory – binding, monomeric collagens 1131 antibodies 883 – collagen recognition 1131 – lebrikizumab 884–885 – dysregulation 1132 – in lungs, adult mice 883 – macrophages 1132 – monocytes and macrophages 883 – SAN-300 1132–1133 – Th2 T helper cells 883 – T cells 1132 interleukin-18 (IL-18) 982–984 α2β1 integrin (VLA-2) interleukin-20 (IL-20) 993, 994 – binding to collagen 1133 interleukin-21 (IL-21) 994–995 – and ECM ligands interaction 1133 interleukin-23 (IL-23) 992–993 – expression 1133 – BLys 898–899 – vatelizumab 1134 – cytokine family 897 α4β7integrin – IL-23p19 mRNA expression 897 – immunosurveillance 899–900 – Merck–Schering-Plough 897–898 – MAdCAM-1 expression 1128 – tabalumab 899 – memory T lymphocytes 900 interleukin-31 (IL-31) 1010–1011 – natalizumab, humanized IgG4 antibody interleukin-17A (IL-17A) 2104 – anti-IL-17 mAb 990 – tissuetropic migration 900 – brodalumab 892, 895–896 – vedolizumab 900–901 – description 989 integrin-mediated TGF-β1 activation 1014 – expression and dysregulation 990 interface packing residues – granulopoiesis and neutrophil mobilization – 1B4 humanization 94 885 – residues at VL/VH interface 93, 94 – heterodimer 989 intergroup E4494 trial 1950, 1951–1952 – ixekizumab 891–892, 893–894 interleukin-5 (IL-5) – principal activities 989 – anti-IL-5 mAbs 1006 – proinflammatory effects 989 – bone marrow CD34+ progenitor cells 877 – secukinumab 885–891 – eosinophil trafficking 1005 – T helper cells 885 – eosinophils 876, 1005, 1006 interleukin-1β (IL-1β) – HESs 876, 877 – gevokizumab 875–876, 877 – IL-5 KO mice 1006 – interleukin-1 receptor type I (IL-1RI) 875 – IL-5R expression 1005 – over-expression of 873 – mepolizumab 877–881 – Th17 cells 873, 875 – reslizumab 879–881, 882–883 The international ImMunoGeneTics interleukin 6 (IL-6) information systemⓇ (IMGTⓇ) – biological activities and signaling – antibody engineering 231 2023–2024 – antibody humanization 231 – cis-and trans-signaling 869 – database 206, 230 – description 866, 984, 985 – IMGT/Collier-de-Perles tool 241 – functions 866, 869 – IMGT data 212 – hyperlipidemia 2035 – IMGT/DomainGapAlign 244–245 – IL-6 KO mice 985 – IMGT/2Dstructure-DB 244 – immunogenic potential 2036 – IMGT/3Dstructure-DB 241, 243 – infections 2033–2034 – IMGT/HighV-QUEST 246 Index 2169

– IMGT/mAb-DB 231, 232 – ‘‘total tumor burden’’ 1634 – IMGT numbering scheme 206 – toxicity profile 771 – IMGT-ONTOLOGY. See – transfectoma and hybridoma-derived 1622 IMGT-ONTOLOGY concepts – tumor flare reaction 1636 – IMGT/V-QUEST 245, 246 – WHO criteria 1634–1636 – immunoinformatics 229, 230 itolizumab (AlzumabⓇ) – web resources. See web resources – CD6 2114 – WHO-International Nonproprietary Names – description 902 (INN) program 230 – humanization 2113 International Nonproprietary Name (INN) – plaque psoriasis 2114 Working Group Meeting 1283 – RA 2115 intracellular signaling – bevacizumab 795–796 k – cetuximab 795 Kabat data 203, 210, 211–212 – description 795 Kabat numbering scheme 203 – ligand-dependent cell receptor inhibition KB003 1028 798–800 keyhole limpet hemocyanin (KLH) 126 – ligand inhibition 796–797 – and signal propagation 796 l – signal transduction, ligand-independent lampalizumab 1170 alteration 800–802 LBL. See lymphoblastic lymphoma (LBL) –TGFβ 795 lebrikizumab 884–885, 1001 intravenous immunoglobulins (IVIg) 413 lenalidomide IO. See inotuzumab ozogamicin (IO) – combined chemotherapy 1758–1759 ion-exchange chromatography (IEC) – lymphomun applications 1486 623–624 – and rituximab 1933, 1964, 1971 ipilimumab – second treatment cycle 1486 – action mechanism 1621–1622 – tumor volume reduction 757–758 – adverse events 1636–1641 – in untreated FL 1937 – anti-CTLA-4 antibody doses 1624–1625 leucine-rich repeat and Ig domain containing – biomarkers 1630–1631 Neurite outgrowth inhibitor (NOGO) – BRAF mutation status 1630 receptor interacting protein-1 (LINGO-1) – chemotherapy-naive patients 1625 1182–1183 – in combination with chemotherapy 772 leukocyte adhesion and migration inhibitors – cytotoxic T-lymphocyte antigen 4 (CTLA-4) –anti-α1β1 integrin (VLA-1) 1131–1133 1620 –anti-α2β1 integrin (VLA-2) 1133–1134 – grade III/IV autoimmunity 1624 –anti-α4β7/MAdCAM-1 1128–1131 – immune-related adverse events (irAE) – anti-CD162 1136–1137 1636–1641 – anti-VAP-1 1134–1135 – immune-related response criteria (irRC) LFG316A (Novartis, Morphosys) 1168 1634–1636 libraries – initial phase II trials 1623–1625 –CDRH3 59 – lactate dehydrogenase (LDH) 1630–1631 – description 495 – long responders 1629–1630 – ‘‘designer’’ properties 59 – lung cancer 1633–1634 –withgraftedin vivo formed CDRs 497–498 – maximum tolerated dose (MTD) 1622 – HCAbs 495–496 – melanoma 771–772, 1622 – human ‘‘single-pot’’/universal phage display – nonimmunogenic treatment 1625 libraries 59, 60–64 – NSCLC 772 – immune libraries 57 – pharmacokinetics 1622 – lambda subfamilies Vλ4-Vλ10 58 – phase II studies 1625–1628 – naive 57–58 – phase III trial 1628–1629 – semi-synthetic and synthetic 58, – plasma peak concentration 1622 496–497 – prostate cancer 772, 1631–1633 – VH and VL genes 58–59 2170 Index

library generation – genomics and cell line engineering – immune 317 573–579 –na¨ıve 317 – human IgG 573 – synthetic 317–318 – IRES 573 ligand-dependent cell receptor inhibition – transfection, HEK293 cell lines 573 – cixutumumab 799 mammalian expression technology. See – colony stimulating factor 1 (CSF-1) 798 applied genomics and cell line engineering – dalotuzumab 799–800 mantle cell lymphoma (MCL) – insulin-like growth factor receptors (IGFRs) – description 1916 799 – immune modulators 1963–1964 – ‘‘target-able’’ mutations 798 – relapsed 1963 – VEGF pathway 798–799 – rituximab monotherapy 1963 LIGHT 1093–1095 – untreated, rituximab plus chemotherapy linkers, ADCs 1959–1963 – carbonate 356 manufacturing process development – description 353–354 – Chinese hamster ovary (CHO) cells – disulfide 355–356 603–604 – hydrazone linkage 356 – commercial. See commercial manufacturing – noncleavable thioether 354–355 processes – peptide 356 – comparability and risk assessment – site of 357–358 653–652 liquid protein formulations 635–638 – description 603 liver – downstream processing. See downstream – elimination of IgG 1790, 1791 processing – function abnormalities 2034–2035 – drug product development 631–634 liver transplantation – formulation designing 628–629 – basiliximab 1383 – freeze-dried protein formulations, excipients – daclizumab 1384–1385 638 lung transplantation – LCLF to HCLF 638–639 – basiliximab 1385–1386 – liquid formulation and freeze-dried – daclizumab 1386 formulations 629–630 LY2382770 (Eli Lilly) 1013 – liquid protein formulations, excipients lymphoblastic lymphoma (LBL) 1958 635–638 lymphomun. See anti-CD20 × anti-CD3 – monoclonal antibodies (mAbs) 603 lymphomun – novel IgG-derived molecule formats 604 lymphotoxin-alpha (LTα) 976–977, 1662 – protein characterization. See protein characterization m – quality control testing 651, 652–653 M-CD3. See muromonab cluster of – quality parameters 604 differentiation 3 (M-CD3) – rapid formulation 635 mAb-resistant mutants (MARMs) 1829 – resulting drug substance 604 mAbs. See monoclonal antibodies (mAbs) – stability testing 651, 653 MabThera International Trial (MInT) – upstream processing. See upstream 1952–1953 processing macrophage migration inhibitory factor (MIF) marginal zone lymphomas (MZLs) 1022–1023 – chlorambucil arm 1935 mammalian cells – description 1935 – acceptor cell lines 572 – retrospective analysis, SMZL 1935–1936 – advantages 571 MARMs. See mAb-resistant mutants – batch/fed-batch bioreactor processes 573 (MARMs) – CpG islands, promoter regions 572 mast cell activation syndrome (MCAS) 1814 – Cre (cyclization recombination) 572 matrix metalloproteinases (MMPs) 824, 826, – designer substrates 572 828, 1181–1182 – folding and secretion machinery 571 matuzumab 832 Index 2171 mavrilimumab 1026–1027 MODELLER 217 maximum tolerated dose (MTD) MOE. See Molecular Operating Environment – BR96-doxorubicin 353 (MOE) – brentuximab vedotin 1426 mogamulizumab (Poteligeo) – lenalidomide 1964 – allergic rhinitis 2115–2116 – and low immunogenic responses 377 – asthma 1019, 2115–2116 MCAS. See mast cell activation syndrome – ATL and CTCL 2115 (MCAS) – CCR4 expression 2115 MCL. See mantle cell lymphoma (MCL) – clinical trials 1019 mean fluorescence intensity (MFI) values – defucosylated Fc 1019 1474 – description 2115 mechanisms of action (MoA), mAbs – relapsed/refractory ATL 2116 – complement system 143 – side effects 2116 – concentrations, direct growth inhibition Molecular Operating Environment (MOE) 144 218 – epidermal growth factor receptor (EGFR) molecule generation and in vitro pharmacology 141 – mechanism of action, raxibacumab 1901 – Fc-mediated effector functions 143 – raxibacumab generation 1901 –FcγRIIa-H131 144 monoclonal anti-IgE molecule –FcγRIIIa-V158 alloform 144 – formation and tissue distribution, – IgG, structure and function 142 rhuMAb-E25 1788, 1790–1791 – in vitro assays 142 – humanization 1788, 1789 – ‘‘immune checkpoints’’ 141 – IgE-Fcε3 1788 – immunogenicity 141 – interactions with IgE 1792 – lymphoma patients, rituximab therapy 144 – rhuMAb-E25, molecular model 1788, 1789 – ‘‘naked’’ antibodies 141 monoclonal antibodies (mAbs) – polymorphonuclear (PMN) cells 143 – ADC/radionucleotides 751 – radioimmunoconjugates generation 141 – agencies, clinical review 1266–1267 – rituximab therapy, FcγRIIa and FcγRIIIa – anti-EpCAM antibodies. See anti-EpCAM allotypes 144 antibodies – tumor-directed immune responses 144 – anti-neoplastic therapy 751 – tumor necrosis factor (TNF) 141 – antigen–antibody binding 26 – VEGF 141 – antigenic determinants 21 MEDI551 (Medimmune) 1117 MEDI4212 (Medimmune) 1162 – approval timelines 1267–1268 MEDI5117 (Medimmune) 988 – B-cellular non-Hodgkin’s lymphoma. See MEDI7814 (AZ-Medimmune) 1168 B-cellular non-Hodgkin’s lymphoma MEDI8968 981–982 – B lymphocyte 18 mepolizumab – blockage, immunological responses. See – GlaxoSmithKline (GSK) 877, 878 immunological responses – in vitro and in vivo, 877 – cell fusion 23–25 – phase III trials 878, 879–881 – chimeric (mouse/human) rituximab Merck–Schering-Plough antibody 17 – mAb development 897 – clinical development 1264–1265 – phase II clinical trial 897–898 – clinical developments 752 metastatic colorectal cancer (mCRC). See –cloning 30 panitumumab, mCRC – cytotoxicity assays 29 minimal residual disease (MRD) – denosumab 775–776 – blood and bone marrow 1336–1337 – description 737, 738–744 – CLL 1337 – drawbacks 17 – ISRs 1338 – drug selection, hybridomas 25–26 – NCIWG 1336 – efficacy and safety 954–956 MInT. See MabThera International Trial – vs. EGFR. See epidermal growth factor (MInT) receptor (EGFR) 2172 Index

monoclonal antibodies (mAbs) (contd.) – for tumor therapy. See tumor therapy –ELISA.See enzyme-linked immunosorbent – UMIN-CTR and WHO 752 assay (ELISA) – Western blotting/immunohistology 21 – epitope and affinity 21 mononuclear phagocytic system (MPS) 1744 – expansion and freezing, hybridoma clones monosome vs. ribosome display 401 30–31 MOR103 1027, 1028 – fast approval 1268–1270 MORAB-022 1027 – FDA and/or EMEA 751 mouse family chronology – FIM clinical studies 1272–1280 – heavy chain variable genes (VH) 220 – flow cytometry 27, 28 – light chain variable genes (Vλ and Vκ) 220 – fragmentation, monoclonal IgG antibodies MPS. See mononuclear phagocytic system 32 (MPS) – function screening 30 MS. See multiple sclerosis (MS) – Hodgkin’s lymphoma 759–760 mucosal addressin cell adhesion molecule-1 – hybridoma technology 18–19 (MadCAM-1) 939, 1127, 1128–1131 – 125I-iodine-labeled second-step multiple myeloma and acute leukemias 1359 antibodies/protein A 26 multiple sclerosis (MS) –IGF-1R.See insulin-like growth factor type I – alemtuzumab 940–941 receptor (IGF-1R) – CARE-MS I and II 1351–1352 – immunization. See immunization, – description 939–940, 1377 monoclonal antibody – IFN beta-1a 1350–1351 – immunohistology and immunocytology – ITP 1350 28–29 – lymphocyte repertoire 1349 – investigator sponsored trials, academic – mAbs 941 settings 753 – mitoxantrone treatment 940 – labeling 32 – MSFC 1351 – ‘‘magic bullets’’ 17 – natalizumab 940 – mass culture and purification 31 – ocrelizumab 941 – membrane-bound and secreted forms – primary progressive 1347 19–21 – progressive relapsing 1347 – myeloma cell lines. See myeloma cell lines – relapsing remitting 1347 – onartuzumab 773–774 – secondary progressive 1347 – oregovomab 753 – T-cell pool 1349 – ovarian cancer. See ovarian cancer – TNFR1 inhibition 940 – pemtumomab 775 – transitional 1 B cells 1348–1349 – pharmaceutical trials, oncology 752 – treatments 1347 – phase 3 clinical trials 737 multiple sclerosis functional composite – phase 1 clinical trials, immunological (MSFC) 1351 disease 929–930 muromonab cluster of differentiation 3 – phase 2 clinical trials, immunological (M-CD3) disease 931–933 – action mechanisms 1648 – pivotal trials 1271–1272 – cardiac transplant recipients 1659, – racotumomab 774 1660–1661 – rapid market access 1270–1271 – cytokine release syndrome. See cytokine – RCC. See renal cell carcinoma (RCC) release syndrome (CRS) – regulatory validation, development program – diagrammatic representation 1646 1266 – efficacy 1654–1655, 1657–1658 – rilotumumab 773 – human T cells activation 1650 – scientific advice, EU 1264 – immunogenicity 1650–1651 – T-cellular non-Hodgkin’s lymphoma – immunosuppression, infections 758–759 1670–1671 – target modulation mechanisms 954 – interactions 1651–1652 – transgenic mouse and phage display – liver transplant recipients 1659 technologies 751 – mAbs production 1646–1647 Index 2173

– murine mAb 1646 – EGFR 762–763 – neoplasia 1671 – esophageal and gastric cancer 1684–1685 – pharmacodynamics 1649 – glioma 1682–1683 – pharmacology 1647 – head and neck 1679–1682 – plasma concentrations 1648–1649 – immunoglobin G 832 – renal–pancreas transplant recipients 1656 – NSCLC. See non-small-cell lung cancer – surface antigens 1648 (NSCLC) – therapeutic use 1652–1656 – pancreatic cancer 1685–1686 – withdrawal from market 1672 – pediatric glioma 1684 myasthenia gravis (MG) 1984–1985 nivolumab (anti-PD1) 772 myeloma cell lines NN-8210 1169 – antibody without antigen 22 NN-8226 994 – LOU/C strain, rat myeloma 23 NN-8765 (IPH2201; Novo Nordisk licensed – mouse interspecies hybridomas 23 from Innate Pharma) 1098 – nonproducer lines 23 NN-8828 Novo Nordisk from BMS MZLs. See marginal zone lymphomas (MZLs) (Zymogenetics) 995 nomenclature n – application information 1287 N-/O-glycosylation sites – elements, name 1283 – β-sheet structure, antibodies 95 – stems and infixes 1284 – consensus pattern – target/disease class infix 1284–1286 asparagine-X-serine/threonine 95 – USAN modified designations 1286–1287 – drug/radionuclides 95 non-antibody scaffolds ‘‘naked’’ gene delivery systems 750 – advanced mammalian expression systems namilumab 1027 437 naptumomab estafenatox (5T4) 768–769 – artificial binding proteins 441, 442 natalizumab – artificial binding proteins vs. antibodies – approved indications 2105–2107 438, 439 – description 2104 – bacterial expression systems 437 – multiple sclerosis (MS) 2104 – biomolecular characteristics, medical use – safety 2105 442, 443 natural killer cell group 2A (NKG2A) – biopharmaceutical drug development 1097–1098 programs 436 NCT00747344 (Pearl) 2074 – bivalency 441 necitumumab 762 – clinic 461–463 Neisseria meningitides infection 1167 – in clinical development 442, 446–447 neoplasia 1671 – companies, commercial performance since neovascularization. See angiogenesis 2006 442, 444–445 neurological disorders/demyelinating disease – conventional Escherichia coli expression 1612 systems 440 neutrazumab 1168, 1169 – dense and complex IP issues 437 neutrophil gelatinase-associated lipocalin – genetic libraries 435 (NGAL) 453 – in vivo and in vitro, 439–440 NGAL. See neutrophil gelatinase-associated – innovative biopharmaceutical compounds lipocalin (NGAL) 436 NI-0101 (Novimmune) 1150–1151 – non-Ig scaffold proteins 438 NI-0501 (Novimmune) 1000 – poly-ethylene glycol (PEG) 441 NI-0701 (Novimmune) 1021, 1022 – Pseudomonas exotoxin 441 NI-0801 (Novimmune) 1021 – scaffold proteins. See scaffold proteins NI-1401 (Novimmune/Roche-Genentech) – sequence-/consensus-guided design 435 991 – single domain immunoglobulins. See single nimotuzumab domain immunoglobulins – allergic reactions 832 – size comparison 438, 439 – description 1679 – therapeutic application 442 2174 Index

non-approved diseases – CDC activity 1701–1702 – AR 1811–1812, 1813 – CDRs 1697 – MCAS 1814 – chemotherapy, Bcl-2 and MDM2 inhibitors – urticaria/angioedema 1812, 1813 1712–1713 – VIT 1813–1814 – clinical experiences 1715 non-Hodgkin’s lymphoma (NHL) – in CLL 1722 – aggressive (DLBCL) 1588 – CLL11 trial 1722–1723 – CD20-targeted immunotherapy – in cynomolgus monkeys, B-cell depletion 1580–1581 1713–1714 – epidemiology 1579 – direct cell death induction 1702–1704 – response rates, alemtuzumab 1357–1358 – elbow-hinge engineering 1698 – responses classification 1359 – epitope recognition 1699–1701 – rituximab 1357 – ex vivo whole blood B-cell depletion – standard therapy 1580 1708–1709 non-small-cell lung cancer (NSCLC) – flow cytometry, reagents 1697 – aflibercept 836 – glycoengineering 1704–1706 – combination therapy 1510–1511 – in vitro NK cell and neutrophil ADCC and – figitumumab 767 macrophage ADCP activity 1706–1708 – HGF–MET pathway 838 – nonclinical pharmacology studies 1714 – IGFRs 799 – putative mechanism of action 1696 – ipilimumab 772 – type II CD20 antibody 1698–1699 – monotherapy 1510 – in xenograft models 1709–1712 – necitumumab 762 ocrelizumab 903–904, 941, 1120 – non-squamous 833 ocular diseases – optimal duration of therapy 1688–1689 – AMD 944–945 – patient selection 1687–1688 – uveitis 943–944 – pharmacodynamic evaluation 1689–1690 ofatumumab – progression-free survival (PFS) 829 – anti-CD20 constructs development 1734, – racotumomab 774 – apoptosis 1748 – safety 1690 – B-cellular non-Hodgkin’s lymphoma noncleavable thioether linkers 354–355 753–754 nonclinical testing, mAbs – C3b deposition and complement receptors – components 1250–1251 1745 – pharmacology and pharmacokinetic studies – CD20 interactions 1735–1736 1252–1253 – cell lines and CLL cells 1739–1742 – test species 1251–1252 – CLL monotherapy 1753 – toxicology 1254–1255 – complement control proteins 1735 nonmyeloablative conditioning regimens – as confounding factor 1745–1746 – allogeneic engraftment 1363 – development and characterization 1737 – CMV reactivation 1362 – dose requirements 1743–1744 – GvHD prophylaxis 1362 – epitope characterization 1737–1739 – total body irradiation (TBI) 1361–1362 – FC for CLL, combined chemotherapy nonsteroidal anti-inflammatory drugs 1757–1758 (NSAIDs) 942, 945, 1452, 1567, 1571, – FL monotherapy 1753–1756 1572, 2031, 2033 – lenalidomide, combined chemotherapy novel antibodies 707–708 1758–1759 NSCLC. See non-small-cell lung cancer – mononuclear phagocytic system (MPS) (NSCLC) 1744 nurse shark IgN 248–249 – mouse models 1746–1747 – neutrophils 1745 o – O-CHOP for FL, combined chemotherapy obinutuzumab 1758 – B-cellular non-Hodgkin’s lymphoma – physical, immunochemical and functional 754–755 characteristics 1736 Index 2175

– pivotal trial for CLL 1756–1757 OPN-305 (Opsona) 1146–1147 – rheumatoid arthritis 1760–1761 opsoclonus myoclonus syndrome (OMS) – RTX-refractory FL 1759–1760 1984 – type I CD20 mAbs, cytotoxicity mediated oregovomab 769–770 1735 organ transplantation–graft rejection oligoclonal antibodies 951–953 – cocktail formulations 1292 Orthoclone OKT3. See muromonab cluster of – effector functions 1292 differentiation 3 (M-CD3) – FDA/regulatory considerations otelixizumab 1082, 1083 1295–1296 ovarian cancer – fragment combinations 1293 – farletuzumab (MORAb-003) 769 – in vivo oligoclonal immune response – oregovomab 769–770 1292 oxelumab (Genmab) 1093 – natural immune response 1291–1292, ozoralizumab 314, 505–506, 972–973 1293 – preparations 1292 p – quality control issues 1292 palivizumab, RSV disease – uses/applications 1293–1294 – adverse events (AEs) 1843–1845 – varieties 1292 – Alaska native infants 1842 olokizumab 869, 987, 2024 – amino acids A105 1830–1831 omalizumab – antigenic sites and neutralization epitopes – administration 1806, 1807 1829 – adverse effects. See adverse effects, – cell-line stability 1834, 1835 omalizumab –CHD.See congenital heart disease (CHD) – allergic asthma 1159 – cotton rats, lungs 1832–1833 – anti-IgE mAb, humans 1787 – description 1825 – assessment, therapeutic response – downstream processing 1833 1809–1810 – FDA approval 1834 – beneficial effects 1796, 1797 – immunoaffinity-purified F protein – cell distribution 1785–1786 1831–1832 – contraindications 1804, 1805, 1806 – indications and usage 1839–1840 – cost 1811 – mAb1129 1829–1830 – dosage 1806, 1807–1808 – MARMs 1829 – drug interactions 1810 – MCB and WCB 1833 – early and late-phase asthmatic responses – mortality 1825 1793–1794 – motavizumab 1845 – exacerbation rate 1796, 1797 – newborns 1840–1841 – IgE affinity 1160 – pathogenesis 1825–1826 – indications 1804, 1805 – phase 3 trials 1835–1836 – monitoring of therapy 1810 – plaque-reduction assay 1832 – onset of action, anti-immunoglobulin E – population demographics 1840 effect 1808 – premature infants. See premature infants, – pharmacodynamics 1802 palivizumab – pharmacokinetics 1802 – preventive treatment 1202 – phase III randomized double-blind clinical – REACH program 1841 trials 1794–1796 – risk factors 1825 – pregnancy and lactation 1810–1811 – RSV-IVIG 1829 – preparation 1805 – scale-up comparability tests 1834, 1835 – safety and efficacy, rhuMAb-E25 – serum concentration 1842–1843 1792–1793 – serum neutralizing antibodies 1828 – treatment duration 1808–1809 – Swedish recommendations 1841–1842 OMS. See opsoclonus myoclonus syndrome – virion, proteins and genome (OMS) 1826–1827 onartuzumab 773–774 pancreas transplantation 1387–1388 2176 Index

pancreatic cancer – generic and biosimilar producers 731 – cetuximab 797 – innovative companies 730–731 – ganitumab 766 – intellectual property rights 706 – MT-110 808 – investment 705 – MUC5AC 790 – methodology 710 – nimotuzumab 763 – modifications, antibody 709–710 panitumumab, mCRC – monitoring 725 – antibody combination therapy 1863–1864 – National Phase stage, costs 722 – approval 1858 – novel antibodies. See novel antibodies – clinical trials 1860 – out-licensing 731 – description 1855 – overlapping 710–711 – development 1856–1857 – ownership 723 – EGFR 1855–1856 – partnered discovery 730 – first-line therapy with FOLFOX 1862 – Patent Cooperation Treaty (PCT) 720–721 – head and neck cancer 1864 – prior art 718 – KRAS, BRAF and PIK3CA 1857–1858 – priority year 720 – monotherapy 1859, 1861–1862 – production systems 718 – production, galenics and pharmacokinetic – provisional/priority applications 719, 720 properties 1858–1859 – public disclosures 720 – safety, pharmacokinetics and activity 1859 – ‘‘regional phase’’ route 721 – second-line therapy with FOLFIRI – royalty stacking 715 1862–1863 – specification 720 – xenograft mouse model 1857 – start-up companies 716 panning – term extensions 723–724 – phage display and monoclonal binders 46, – therapeutic applications 708–709 47 – third-party observations 725–726 – protease digestion 48 – time scales and costs 719 Panton-Valentine leukocidin (PVL) 1199 – transactions. See transactions, patents Parkinson’s disease (PD) – unitary 722 – active immunotherapy–clinical 1221 – unsolved patent issues and litigation threat – active immunotherapy–preclinical 1221 715 – description 1220–1221 PCNSL. See primary central nervous system – passive immunotherapy, full-length lymphoma (PCNSL) antibody 1221 PD-0360324 (Pfizer) 1024, 1025 – passive immunotherapy, intrabodies pediatric Crohn’s disease 1603 1221–1222 pediatric glioma 1684 pateclizumab 977–978 pediatric ulcerative colitis 1609 patents pegaptanib 1178 – academic institutions, inventors 722 PEGylation – annual renewal fees 722 – anti-TNF nanobodies 329 – antigen and antibody format 717–718 – description 328 – attacking 726 – lysine/cysteine amino acids 328 – claims 706 – microbial expression levels 329 – commercial success 705 – renal and hepatic pathways 329 – dominant 716 pemtumomab 775 – drug companies 705 pentostatin 1922–1923 – due diligence 732 pentostatin, mitoxantrone, rituximab (PMR) – exclusivity 724–725 1923 – fee for service, CRO 729–730 pentoxifylline 1668–1669 – freedom to operate. See freedom to operate peptide linkers 356 analysis peripheral T-cell lymphoma (PTCL) 1426 – functional enhancements 718 pertuzumab – funding 731–732 – ADCC pathway 1874 – generation, antibodies 716 – adjuvant chemotherapy 1876–1877 Index 2177

– adverse events 1877 PMR. See pentostatin, mitoxantrone, – anthracyclines 1878 rituximab (PMR) – biomarkers 1877–1878 PMX-53 1167 – Calu-3 and KPL-4 xenograft models 1874 polyclonal antibodies – cardiac dysfunction 1876 – adjuvants 1299 – cardiac safety profile 1879–1880 – description 1296 – dimerization inhibitors 1874 – FDA/regulatory considerations 1295–1296 – efficacy and safety 1875 – immunogen 1298–1299 – HER2-positive breast cancer 1871 – production 1297–1298 – mAbs trastuzumab 502, 2048 – recombinant 1302–1303 – mechanisms, trastuzumab resistance – route of injection 1300 1871–1873 – therapeutics 1301–1302 – pathological complete response (pCR) posttransplant lymphoproliferative disorder 1878 (PTLD) 1976–1977 – PI3K/Akt inhibition 1874 preclinical development – single-agent 1875–1876 – anti-drug antibodies (ADAs) 696 – trastuzumab emtansine (T-DM1) – CMC comparability exercise 694 1878–1879 – FDA biosimilar draft guidelines 696 pexelizumab 1167 – in vivo non-clinical strategy 695 PF-04236921 (Pfizer) 988, 989 – non-human primates 696 – stepwise approach 694, 695 phage display preclinical studies, CARs – comparison, recombinant antibody selection – animal models 755–756 systems 43, 44 – CAR transfected effector cells 750–751 – human hybridomas 43 – effector functions, CAR gene-modified – hybridoma technology 43 effector lymphocytes 751 – in vitro selection process 45 – memory function, redirected T cells – in vitro technologies 43 752–755 – libraries. See libraries – ‘‘naked’’ gene delivery systems 750 – panning rounds, M13K07 46 – retroviral gene transfer into T lymphocytes – peptide::pIII fusion protein 45 748–750 – phage T7 and phage Lambda 45 Prediction of ImmunoGlobulin Structure – phagemid system 45 (PIGS) 217, 218 – sdAbs 319 premature infants, palivizumab – selection and screening 46–47 – prevention, recurrent wheeze 1837–1838 – vectors. See vectors, phage display – RSV-related hospitalization 1836–1837 phage libraries primary central nervous system lymphoma – combinatorial antibody libraries 107 (PCNSL) 1978 – guided selection 107 primary cutaneous CD30-positive – HFS and HFA 107 lymphoproliferative disorders – murine CDRs 107 – brentuximab, treatment 1435 phagemid system 45, 48 – lymphomatoid papulosis (LyP) 1433 phagocytosis 278 primary mediastinal B-cell lymphoma pharmacodynamic evaluation, NSCLC (PMBCL) 1689–1690 – CHOP-like CT 1957 PHOENIX-1 (NCT00267969) 2072–2073 – DA-EPOCH-R 1957–1958 PHOENIX-2 (NCT00307437) 2073 – description 1916 pitrakinra (Aerovance) 947, 1002 – MACOP-B and VACOP-B 1957 placental growth factor (PLGF) primary systemic therapy (PST) 2048 – breast cancer progression 823–826 pro-protein convertase subtilisin kexin – signal transduction 827 (PCSK)-9 – VEGF 1177 – alirocumab 858–859 PMBCL. See primary mediastinal B-cell – description 852 lymphoma (PMBCL) – evolocumab 853–857 2178 Index

pro-protein convertase subtilisin kexin Pseudomonas fluorescens 564 (PCSK)-9 (contd.) psoriasis – knock-out (KO) mouse studies 853 – characteristics 937, 1533 – LDL-C 853 – experimental autoimmune production systems encephalomyelitis (EAE) 2071 – antibody fragments 561 – IL-12 and IL-23 role 2071 – eukaryotic expression systems. See – infliximab 1607–1608 eukaryotic expression systems – keratinocytes, overproduction and immature – examples, expression systems 582, 583 migration 2071 – functional immunoglobulin G (IgG) – plaque 1533 antibodies 561 – and psoriatic arthritis 937–938 – glycosylation sites 561 – systemic agents 2071 – prokaryotic expression systems. See – T-cell activation 1533–1534 prokaryotic expression systems – T-cell migration and extravasation 1534 progression-free survival (PFS) 1426 – T-cell reactivation 1534–1535 prokaryotic expression systems psoriatic arthritis (PsA) 1571–1572, – advantages and disadvantages 562 1606–1607, 2074–2075 – Bacillus species 564–565 PTLD. See posttransplant lymphoproliferative – cell-wall-less L-form, Proteus mirabilis 562 disorder (PTLD) – Escherichia coli 562–564 putative backmutations – Pseudomonas fluorescens 564 – anti-Tac humanization 102 prophylactic trimethoprim/sulfamethoxazole – CDR residues 102–103 1922 – description 102 protein characterization and quality control – ‘‘hybrid variable’’ regions 103 testing – VH of antibody ABL364 103 – carbohydrate heterogeneity 648 PVL. See Panton-Valentine leukocidin (PVL) – contaminants 650 – impurities 648–650 q – overall structural confirmation 648 QAX576 (Novartis) 1004–1005 – physicochemical properties 647 QBX258 (Novartis) 1003 – potency 650 QGE031 (Novartis, Roche–Genentech) – purity 647–648 1161–1162 protein-engineered antibodies quality control testing 651, 652–653 – clinical toxicity 152 Quality Target Product Profile (QTPP) – combined protein-and glycoengineering. See 686–687 Fc engineering quaternary structure, IgG-Fc – computational design algorithms and – inflammatory cascades activation 175 high-throughput screening 154 – ‘‘overlapping nonidentical sites’’ 175 – engineered Fc portions 155 – polyclonal IgG cleavage 174 –FcγRs activation 153–156 – rheumatoid factor (RF)-like autoantibody – hOKT3γ1(Ala-Ala) 152 174 – human IgG isotypes to cellular Fc receptors – staphylococcal protein A (SpA) 174 151 – streptococcal protein G (SpG) 174 – mutant Fc library 153 – X-ray crystal analysis 174–175 – mutating amino acid 297 (N297A) 152 quilizumab 1162 – mutations 152–153 – rat anti-human CD3 antibody (YTH 12-5) r 152 RA. See rheumatoid arthritis (RA) – selected engineered IgG1 Fc variants 154 rabbit reticulocyte 400 – solvent-exposed amino acid residues 153 racotumomab 774 – unmodified human IgG4 151 radioimmunoconjugates (RAIT) – Xmab5574 (MOR208) 156 – lintuzumab-radiolabeled – yeast display system 153 (huM195-radiolabeled) 806–807 pseudogene (P) 211, 233, 245 – therapeutic radioisotopes 806 Index 2179

– 90Y-epratuzumab (IMMU-102) 806 receptor gene-modified effector lymphocytes radioimmunotherapy (RIT) 546 – bispecific antibodies and 286–288 receptor tyrosine kinase (RTK) 830 – clinical studies using 1590 recombinant antibody selection systems 43, – in mantle cell lymphoma 1588–1589 44 – primary adverse event 1586–1587 recombinant bispecific antibody molecules – principles 1581 – antigen-binding site and IgG fusion – therapeutic advantages 1582 275–276 radiolabeled antibodies – asymmetric heterodimerization domains – arcitumomab 2124–2126 276–278 – besilesomab 2131–2132 – diabodies (Db) 272–274 – 111In-capromab 2126–2129 – genetic engineering 271 – fanolesomab 2132–2134 – single-chain diabodies (scDb) 272, 274 – 111In-imicromab 2129–2130 – single-chain variable fragment 272 – satumomab 2123–2124 – single-domain antibodies and alternative – sulesomab 2134–2137 scaffolds 272 RAIT. See radioimmunoconjugates (RAIT) – tandem scFv molecules (taFv) 272, 273 ramucirumab (VEGF-R) 764 – therapeutic applications 274 ranibizumab – variable domain 272–274 –AMD.See age-related macular degeneration recombinant cytotoxic fusion proteins (AMD) – advantages 375 – anti-VEGF effect 1891–1894 – anti-Lewis Y-directed immunotoxins 375 – CDR 1883 – anti-mesothelin SS1P (SS1-dsFv-PE38) – CRVO and BRVO 1886 377 – DME 1886, 1889 – BL22 (RFB4(dsFv)-PE38) 377 – molecular weight 1883–1884 – cytokine release syndrome 375 – myopic CNV. See choroidal – cytotoxic T and NK cells 378 neovascularization (CNV) – disulfide-stabilized Fv fractions (dsFvs) – recombinant antibodies 1883 374–375 RANTES 1021 – immunoRNases 377–378 rapid automated protein purification – immunotoxins, within phase I/II clinical technology (RAPPT) 627 trials 375, 376 rapid formulation development 635 – LMB-2 375–377 raxibacumab – single chain Fv (scFv) fragments 374 – animal models 1902–1903 recombinant human soluble tumor necrosis – animal rule 1901–1904 factor receptor 1669–1670 – anthrax attacks 1899 recombinant scFv-CPG2 fusion protein – anthrax toxins. See anthrax toxins – description 479 – antibiotic combination studies 1904 – MFECP1 and bis-iodo phenol prodrug 480 – ATRs 1899–1900 – MFECP, Pichia pastoris 480 – description 1899 – phage antibody technology 479–480 – dosing 1906 – SW1222 colon carcinoma xenografts 480 – health and human services (HHS) 1899 regorafenib 832–833 – HGS 1902 regulatory considerations, mAbs development – human safety 1905–1906 – ADCs 1236 – indication 1906–1907 – approved mAbs and Fc-fusion proteins – molecule generation and in vitro 1234–1235, 1237, 1238 pharmacology 1901 – cell line qualification 1240–1242 – monotherapy studies 1903–1904 – chimeric mAbs 1235 – nonclinical safety 1905 – comparability 1247–1248 – safety and anthrax 1900 – human mAbs 1236 RCC. See renal cell carcinoma (RCC) – immunogenicity 1255–1257 REAL. See Revised European American – nonclinical testing 1249–1255 Lymphoma (REAL) – product stability 1245 2180 Index

regulatory considerations, mAbs development – infliximab 1603–1605 (contd.) – initiation 936 – quality by design 1248–1249 – interleukin 6 (IL-6) signaling 506 – quality control testing 1242–1244 – juvenile idiopathic arthritis, clinical studies – reference standard 1245–1246 1574–1575 – safety test, feasibility clinical trials – monotherapy long-term extensions 2028 1246–1247 – MTX treatment 1569, 2027 – statutory authorities 1237–1239 – NI-0101 (Novimmune) 1150–1151 – TSE 1244–1245 – ofatumumab (OFA) 1760–1761 – viral clearance and inactivation studies – phase 3 studies 1569 1246 – propagation 936 relapsed/refractory indolent B-cell lymphoma – psoriatic arthritis 1571–1572 1927–1930 – radiographic progression 2030 renal cell carcinoma (RCC) – synoviocytes 936 – girentuximab (CA IX) 767–768 – TCZ 2025, 2026 – naptumomab estafenatox (5T4) 768–769 – TLR signaling 1146 renal transplantation – TNF antagonist 2029–2030 – basiliximab vs. daclizumab 1382 –TNFα 505 – basiliximab vs. lymphocyte-depleting agents –TNFα-blocking drugs 936 1379 – tocilizumab combined therapy 2028, 2029 – calcineurin inhibitor-sparing protocols – ulcerative colitis 1573–1574 1381–1382 ribosome display – daclizumab 1379–1380 – advantages 399 – IL-2R monoclonal antibodies vs. placebo – antibody generation 402 1378–1379 – construction 400–401 – steroid-sparing protocols 1380–1381 – eukaryotic, rabbit reticulocyte 400 renal–pancreas transplant recipients 1656 – vs. monosome 401 resins and ligands 626 – prokaryotic, E. coli S30 399–400 reslizumab 879–881, 882–883 RICOVER-60 trial 1954 respiratory syncytial virus (RSV) rilotumumab 773 – MEDI-493 1152 RIT. See radioimmunotherapy (RIT) – palivizumab. See palivizumab, RSV disease rituximab – sdAbs 324 – autoimmune disorders 1979–1985 – TLR4 1149 – B-cell lymphoma. See B-cell lymphoma, restin 829 rituximab resurfacing/veneering, humanization – CD20 antigen, properties 1910–1911 104–105 – in combination with bendamustine Revised European American Lymphoma 1926–1927 (REAL) 1915 – mechanism of action 1911–1913 rheumatoid arthritis (RA) – pharmacokinetic (PK) studies 1913–1914 – ACR20 2025 – production, design and structure – ACT-RAY trial 2026–2027 1909–1910 – alemtuzumab 1359–1360 – subcutaneous (SC) rituximab formulation. – ankylosing spondylitis 1572–1573 See rituximab SC –anti-TNFα VHHs, Ablynx 505–506 rituximab in combination with CHOP – Arana Therapeutics 506 (R-CHOP) 1925 – bDMARDs 2027–2028 rituximab in combination with CHVP-IFN – biologic therapy 2025, 2026 1926 – canakinumab 1454 rituximab in combination with CVP (R-CVP) – DMARDs 936–937 1924–1925 – GlaxoSmithKline 506 rituximab in combination with ifosfamide and – GO-FORWARD, GO-AFTER and etoposide (R-IE regimen) 1978 GO-BEFORE studies 1570–1571 rituximab in combination with MCP (R-MCP) – inflammatory biomarkers 1569 1925–1926 Index 2181 rituximab maintenance therapy – individual extended loops. See individual – chemotherapy induction 1941–1942 extended loops – description 1937, 1938–1939 – rigid secondary structure interface – monotherapy induction 1937, 1940–1941 457–461 – overall survival hazard ratios (HRs) SCCHN. See squamous cell carcinoma of head 1943–1944 and neck (SCCHN) – previously untreated FL patients 1943 scFv. See single chain Fv (scFv) – relapsed/refractory follicular lymphoma sclerostin 1942 – animal models 859–865 – relapsed/refractory indolent B-cell – bone density measurement 865 lymphoma 1942–1943 – osteoblastogenesis, inhibitor 859 rituximab monotherapy – romosozumab 865–866 – relapsed indolent B-cell lymphoma – SOST gene complex 859 1934–1935 SCRs. See structurally conserved regions – untreated patients with FL 1933–1934 (SCRs) rituximab SC sdAbs. See single-domain antibodies (sdAbs) – development 1993 SDR. See specificity-determining residue – PK bridging 1986 (SDR)-transfer – PK, safety and efficacy results 1986, second and third signals, CARs 529–530 1987–1989 selectins 1136–1137 – research questions 1986, 1990 semaphorins – SABRINA (BO22334) 1992 – expression 1086 – SAWYER (BO25341) 1992–1993 – humoral and cellular immunity 1085 – SparkThera (BP22333) 1986, 1991 – inflammatory disease therapy 1085 romosozumab – plexins 1085 – CTX and P1NP 866 – VX-15 1086 – phase III studies 866, 867–868 sequence families – postmenopausal osteoporosis 865 – heavy chain variable genes (V ) 221 – treatment 865 H – human family chronology. See human rontalizumab 997 family chronology ‘‘RosettaAntibody3’’ 217 – light chain variable genes (Vλ and Vκ) RSV. See respiratory syncytial virus (RSV) 221–222 RTK. See receptor tyrosine kinase (RTK) – mouse family chronology. See mouse family s chronology SA237 986, 987 – subgroups and 218–219 SABRINA (BO22334) 1992 sequential rituximab salvage therapy 1331 – CHOP CT 1923 SAN-300 1132–1133 – fludarabine 1964 SAR156597 (Sanofi) 1003 – FND 1923 SAR252067 (Sanofi, licensed from KHK) sialic acid binding immunoglobulin-type 1095 lectins (SIGLECs) 904 SAR-113244 (Sanofi) 1018 sialylation, IgG-Fc oligosaccharides sarcoidosis 1318 – amino acid residues 184 sarilumab – ASGPR 184 – cytokine-mediated inflammatory signaling – autoantibody-initiated inflammation 869 185 – MTX 870 – galactose residues 184 – phase III studies 870, 871–872 – inflammatory cascades 185 satumomab (OncoScintⓇ) 2123–2124 sifalimumab 996 SAWYER (BO25341) 1992–1993 SIGLECs. See sialic acid binding scaffold proteins immunoglobulin-type lectins (SIGLECs) – contiguous hypervariable loop region. See single-chain CARs 524–525 contiguous hypervariable loop region single-chain diabodies (scDb) 272, 274 2182 Index

single chain Fv (scFv) sirukumab (CNTO136) – antibody format 46 – human anti-IL-6 mAb 870 – assembly PCR 58 – MTX therapy 870, 873 – V gene subfamilies 58 – phase III trials 873, 874 – Yol linker and Gly-Ser linker 48 sJIA. See systemic-onset juvenile idiopathic single-domain antibodies (sdAbs) arthritis (sJIA) – ability and stability 324 Sjogren’s¨ syndrome 1984 – affinity maturation 321 Skin toxicity 1861 – albumin binding. See albumin binding SLE. See systemic lupus erythematosus (SLE) – albumin-binding 311 small lymphocytic lymphoma (SLL) – bi-/tri-specific molecules 311 1915–1916, 1936 – bi-specifics and targeted payloads 326–328 SMZL. See splenic marginal zone lymphoma – biopharmaceuticals 312 (SMZL) – Camelidae (nanobodies)/human frameworks solanezumab 907–908 314 solid organ transplantation – clinical assets 314, 315–316 – alemtuzumab immunosuppressive – companies 312, 313 properties 1364 – conventional mAbs/HCAbs/IgNARs 312, – and IL-2R-based therapy 1377–1378 313 – kidney and pancreas 1364 – cryptic and conformational epitopes 323 – MMF 1365 – diagnostic application 325–326 soliris (eculizumb) – Fc-fusion. See Fc-fusion – clinical efficacy data 1269 – HCAbs 311 – clinical package 1269 – HIV-1-integrase, TVNH and GFP 320 soluble antigens – in vitro compartmentalization and ribosome – antibody characteristics 126 display 320–321 – ELISA 126 – imaging 332–334 – epitopes 126–127 – immune library generation 317 – keyhole limpet hemocyanin (KLH) 126 – immune repertoires 320 – methods and technologies 127 – modularity 324 soluble mediators –na¨ıve library generation 317 – chemokine inhibitors 1015–1023 – natural immunoglobulin repertoire, camels – cytokine inhibitors 969–1015 312 – growth factor inhibitors 1023–1028 – PEGylation. See PEGylation somatic gene therapy, bispecific antibodies – phage display 319 – adenoviral vectors 292 – pharmacokinetics/biodistribution 328 – bispecific chemical conjugates 292 – polyethylene glycols (PEGs) 311 – conditionally replicative adenoviruses – pulmonary administration 324 (CRAds) 293 – radioisotope-based imaging 311 –DNAin vivo transfer 291 – structural differences 322 – gene transfer vehicle 292 – synthetic library generation 317–318 – recombinant 292 – target space 321 somatic hybridization – tissue penetration 325 – antibody-secreting cells 268, 269 – transgenic animals 318–319 – enzyme-linked immunosorbent assay – yeast and bacterial display 319–320 (ELISA) 269 single domain immunoglobulins – fluorescence-activated cell sorting (FACS) – Bence–Jones dimers 449 269 – CDR loop 448 – heavy and light chain pairing 269 – ‘‘heavy-chain’’ antibodies 449 – heterologous heavy chain pairing 269 – Ig novel antigen receptors (IgNARs) 449 sonepcizumab 810–811, 1179, 1180–1181 – light and heavy chains 448 source (donor) sequence analysis – research tools and protein therapeutics 448 – canonical residues 93 – single-chain (sc) Fv fragments 448–449 –CDRs.See complementarity determining – X-ray structural analysis 449 regions (CDRs) Index 2183

– interface packing residues. See interface – characterization 1452 packing residues – IL-1 and IL-6 1452 – N-/O-glycosylation sites 95 – phase III trials 1453–1454 – rare framework residues 94–95 – treatment 1454, 1455 SparkThera (BP22333) 1986, 1991 systemic lupus erythematosus (SLE) specificity-determining residue (SDR)-transfer – AMG 729 1117 – anti-V-region antibodies 106 – BAFF levels 1118 – CDR-grafted mAbs 105 – belimumab 1405 – murine mCOL-1 105 – rituximab 1116, 1120, 1982 sphingosine 1-phosphate (S1P) 1178–1180 systemic-onset juvenile idiopathic arthritis splenic marginal zone lymphoma (SMZL) (sJIA) – rituximab therapy 1935–1936 – designed international trial 2031–2032 – splenectomy 1916 – intention-to-treat analysis 2031 SPR. See surface plasmon resonance (SPR) – radiologic evaluation 2031 squamous cell carcinoma of head and neck – TCZ treatment 2030 (SCCHN) – cetuximab 1509 t – combination therapy 1509–1510 T-and B-cell epitopes 106 – grade 3 toxicities 1509 T-cell depletion and graft rejection prevention – monotherapy 1509 – campath-1 family 1360 – panitumumab 1864 – lymphocytes 1361 – radiotherapy 1509 T cell inhibitors structurally conserved regions (SCRs) – anti-CD3 1081–1083 –averageα-carbon coordinates 96 – anti-CD4 1083–1085 – and templates 96 – anti-CD100 1085–1086 Study of Transitioning from Alendronate to –anti-TcellRαβ 1079–1081 Denosumab (STAND) T-cell prolymphocytic leukemia (T-PLL) – BMD and bone turnover 1525 1355–1356 – CTX-I levels 1525 T cell receptors – side effects 1525–1526 – and antibodies 521–522 STX-100 1014–1015 – antigen-specific 1086 subcutaneous (SC) rituximab formulation. See – immunoglobulin 522–523 rituximab SC – mAbs 1080 subgroups assignment, tools 213 – MHC-restricted CD4+ T helper cells 1079 sulesomab (LeukoscanⓇ) 2134–2137 – αβ TCR 1080, 1081 surface plasmon resonance (SPR) T-cellular non-Hodgkin’s lymphoma – antibody affinity 129 758–759 – ‘‘avidity effects’’ 130 TAB-08 1088 – Biacore system 130 tabalumab 899, 1119 – charge-coupled device (CCD) camera 131 TALENs. See transcription activator-like – evanescence wave 129 effector nucleases (TALENs) – physical process 128 TAMs. See tumor-associated macrophages – sensors 129–130 (TAMs) – total internal reflection (TIR) 129 tandem scFv molecules (taFv) synthetic library generation 272–273 – description 317 target antigen selection, ADC therapy – human antibody scaffolding 318 – CD22 expression in B-cell neoplasias – natural antibody repertoires 318 1547–1548 – negatively charged solubilizing amino acids – CD33 in AML 1546–1547 318 target/disease class infix – risks, immune response 317–318 – single letter 1284 – submicromolar affinity, sdAbs 317 – source infix 1285–1286 systemic juvenile idiopathic arthritis (sJIA) – tumor-specific infixes 1285 – ACR50 response 1454, 1456 – USANC 1284 2184 Index

taxanes, trastuzumab in combination – molecular cloning and recombinant – docetaxel monotherapy 2045–2046 expression 4 – paclitaxel 2045 – natalizumab (TysabriⓇ) 10 – phase III trial 2047 – new therapeutic agents 6 TGFβ inhibitors – novel alternative production systems 6 –anti-αVβ6 integrin 1014–1015 – novel molecular designs 11 – antiproliferative and proapoptotic effects – passive and active vaccination 1, 2 1011, 1012 – recombinant human IgG therapeutics 5 – description 1011 – specificity issues 6 – fresolimumab 1013 – systems employed, human antibodies 4, 5 – immunosuppressive role 1013 thrombocytopenia 1331 – isoforms 1011 thrombospondin 1 (TSP-1) – LY2382770 (Eli Lilly) 1013 –HIF-1α 830 – metelimumab (CAT-192) 1012 – p53 tumor suppressor gene 830 TH1 cytokines thymic stromal lymphopoietin (TSLP) – anti-IFN-α 996–998 1008–1010 – anti-IFN-αβR 998 TKIs. See tyrosine kinase inhibitors (TKIs) – anti-IFN-γ 998–1000 TNFR-associated factor (TRAF) 1418–1419 – anti-IL-1 979–982 tocilizumab (TCZ) – anti-IL-6 987–989 – Castleman’s disease 2032 – anti-IL-17 989–991 – CRP 2032–2033 – anti-IL-18 982–984 –IL-6.See Interleukin 6 (IL-6) – anti-IL-20 993–994 – monotherapy 2025, 2026 – anti-IL-21 994–995 – rheumatoid arthritis. See rheumatoid – anti-IL-23 992–993 arthritis – anti-IL-6R 986–987 –sJIA.See systemic-onset juvenile idiopathic –anti-LTα 976–978 arthritis –anti-TNFα 970–974 TOL-101 (Tolera Therapeutics) 1080–1081 – anti-TNFR1 975–976 toll-like receptors (TLRs) – anti-TWEAK 978–979 – anti-TLR2 1146–1147 – IL-6 inhibitors 984–986 – anti-TLR3 1147–1149 TH2 cytokines – anti-TLR4 1149–1151 – anti-IL-10 1007–1008 – description 1145–1146 – anti-IL-13 1003–1005 – inhibitors 1146–1151 – anti-IL-31 1010–1011 – TLR2 1146 – anti-IL-4 and anti-IL-13 1000–1002 – TLR3 1147–1149 – anti-IL-5R/IL-5 1005–1007 – TLR4 1149–1150 –anti-IL-4Rα 1002–1003 tositumomab – anti-TSLP 1008–1010 – CD20 2116–2117 therapeutic antibodies – nonhematologic side effects 2117 – anti-CD3 antibody 4 – production 2116 – antibody structure 2–3 – response rate 2117 – biosimilar antibodies 10 – risks 2117 – cancer and immune-mediated disorders 2 – therapeutic regimen 2117–2118 – cell surface markers and soluble molecules tralokinumab 1003, 1004 7 transactions, patents – clinical studies 2012 7 – commercial success 726 – combination therapies 11 – description 726 – in European Union/United States 7, 8 – licensing 727–728 – immune defense 1 – sale 728–729 – lateral chain theory 2 – university/small biotechnology company – mogamulizumab, afucosylated IgG1 11 727 – molecular and immunological processes transcription activator-like effector nucleases 10 (TALENs) 451, 576, 577–578, 608 Index 2185 transgenic animals 318–319 – in tumor treatment. See tumor treatment Ⓡ transgenic rodents triomab trAb family – BAC integration 81 –anti-CD20× anti-CD3 lymphomun – construction, human Ig transloci. See 1484–1488 human Ig transloci construction – anti-EpCAM × anti-CD3 catumaxomab – designer zinc finger endonucleases, 1474–1481 endogenous Ig loci. See zinc finger – anti-GD2 × anti-CD3 ektomab 1488–1490 (endo)nucleases (ZFNs) – anti-HER2/neu × anti-CD3 ertumaxomab – DNA rearrangement 77 1482–1484 – embryonic stem (ES) cells 77 – CASIMAS trial 1476 – expression comparison, human and – malignant ascites treatment 1474–1481 chimeric IgH loci. See human and – pharmacokinetic analysis 1477 chimeric IgH loci – SECIMAS study 1476 – FDA-approved therapeutic monoclonal – time-to-next therapeutic puncture (TTP) antibodies 77, 78 1475 transmissible spongiform encephalopathies tumor-associated macrophages (TAMs) 828 – active immunotherapy 1225 tumor control ratio (TCR) 1709 – disease and target 1224–1225 tumor growth inhibition (TGI) 1710 – passive immunotherapy 1225 tumor therapy transmissible spongiform encephalopathy – antibody engineering 17 (TSE) 1244–1245 – bispecific antibodies 35 trastuzumab emtansine 763–764, – CDC and ADCC 35 1878–1879 – enzyme prodrug activation 441 trastuzumab monotherapy – epithelial differentiation antigens 33–34 – chemotherapy regimens 2043 – human monoclonal antibodies 35–36 – median survival 2043 – leukocyte differentiation antigens 33 – response rates 2044 – therapeutic effects 34–35 trastuzumab resistance tumor treatment – alternative ErbB ligands 1873 – anti-EpCAM antibody titers 1472 – description 1871, 1872 – autologous human ex vivo systems 1468 – HER2 interaction 1873 – catumaxomab-mediated concerted attack – membrane-associated glycoprotein MUC4 1469 1871 – CLL patients 1472 – p95HER2 expression 1872 – cytokine secretion and tumor cell – PI3K-AKT-mTOR signaling pathway elimination 1469 1872–1873 – ELISPOT analysis 1472, 1473 tregalizumab 1084–1085 – EpCAM and HER2/neu expression profile trifunctional antibodies (trAb) 1471 – affinity and ion-exchange chromatography – Fc region, role 1470 1467 – gastric and ovarian cancer 1471 – anti-drug antibodies (ADAs) 1466 – intraoperative catumaxomab application – biomarkers treatment 1490–1491 1471 – bispecific CrossMab antibodies 1466–1467 – peritoneal carcinomatosis (PC) 1471 – H/H chain assembly 1467–1468 – polyclonal T cells 1468 – human IgG-like bsAb formats 1466–1467 – stem cell transplantation (SCT) 1472 – immunogenicity 1466–1467 – T cell activation markers 1468 – low target antigen expression 1473–1474 – TAA-specific binding 1468 – mAb chimerization 1466 – TAA-specific MHC class I-restricted CD8+ T – mouse/rat hybrid-hybridomas 1467 cells 1471 – phase II trial (SECIMAS) 1466 – therapy and autoimmune diseases 288 – quadroma technology 1467 – trAb-stimulated T lymphocytes 1471 – triomab antibody concept 1466 – trastuzumab with chemotherapy – triomabⓇ trAb family. See triomabⓇ trAb 1470–1471 family – tri-cell complex 1468 2186 Index

tumor treatment (contd.) – VEGF-A 2089 – tumor-reactive antibodies 1471 vastatin 829 – vaccination-like effects 1470–1472 vatelizumab 1134 tumstatin 829–830 VAY736 1119 tyrosine kinase inhibitors (TKIs) 2048 vectors, phage display – in alphabetical order 48, 49–56 u – amber stop (TAG) codon 48, 57 UF/DF. See ultra/diafiltration (UF/DF) – Erwinia caratovora 48 ulcerative colitis 1573–1574, 1608–1609 – Fab fragments 48 ultra/diafiltration (UF/DF) 622 – Hyperphage/Ex-phage 57 upstream processing. See also commercial – lacZ and gIII promoter (gIII) 48 manufacturing processes – pSEX81/pHAL14 48 – cell culture. See cell culture vedolizumab 900–901, 1129 – description 604 VEGF. See vascular endothelial growth factor – expression systems. See expression systems (VEGF) – holistic model 604–605 veltuzumab 1120–1121 – MCB and WCB 604 venom immunotherapy (VIT) 1813–1814 urticaria/angioedema 1803, 1812, 1813 VH and VL 494 US biosimilars 684 VHH 492, 493 USAN Council (USANC) 1283 viral diseases and anti-infectious monoclonal ustekinumab antibodies – ACCEPT (NCT00454584) 2073 – CCR5 1203 – action mode 2070 – CMV 1203–1204 – Crohn’s disease. See Crohn’s disease – HCV 1204 – DLQI scores 2074 – HIV infection 1202–1203 – meta analyses, long-term use 2078 – immunoassays 1206 – multiple sclerosis 2077–2078 – influenza 1204–1205 – NCT00747344 (Pearl) 2074 – mAbs 1201–1202 Ⓡ – ongoing observational studies 2083 – Pfizer 1203 – PHOENIX-1 (NCT00267969) 2072–2073 – RSV 1202 – PHOENIX-2 (NCT00307437) 2073 – SARS 1206 – psoriasis. See psoriasis VIT. See venom immunotherapy (VIT) – studies with no results 2079–2082 VNAR 492, 493 uveitis VX-15 1086 – adalimumab (HumiraⓇ) 1314–1316 – autoimmune 943 w – description 943 Waldenstrom’s¨ Macroglobulinemia (WM) – immunosuppressive drugs 943 1936–1937 – TNF-blocking therapy 943–944 web resources – antibody V domain humanization v 246–247 vascular addressin protein-1 (VAP-1) – IGHG CH amino acid positions. See IGHG 1134–1135 CH amino acid positions vascular endothelial growth factor (VEGF) – IMGT data 212 – antibodies 835 – Kabat data 211–212 – biological effects 830 – only-heavy-chain antibodies 247–249 – cancer therapy 830 WM. See Waldenstrom’s¨ Macroglobulinemia – chemotherapeutic agents 831 (WM) – fusion constructs 835–836 – intracrine VEGFR1/VEGF signaling 831 x – ligand 833–835 xenograft models – resistance mechanisms 836 – of AML 1550 – RTK 830 – F(ab) 2 fragments conjugated to CPG2 479 – tumor vasculature 831 – human cancer 347 Index 2187

– multiple human cancer cell lines 839 – dosing 1584 – obinutuzumab 1709–1712 – First-Line Indolent Trial (FIT) investigators – in SCID mice 1121 1587 – frontline chemotherapy 1589–1590 y – indications 1588 yeast – in lymphoma, therapeutic advantages 1582 – and bacterial display 319–320 – in mantle cell lymphoma 1588–1589 – endogenous AOX promoter 566 – NHL 1579, 1580 – eukaryotic folding and secretion apparatus – preclinical results 1585 565 – preparation 1582–1584 – Fc-receptor binding, antibodies 568 – radioimmunotherapy 1581 – fermentation process 565 – stem cell transplantation 1590–1592 – GlcNAc and galactose residues 567 – uses 1587–1588 – immunoglobulin binding protein (BiP) chaperone 568 z – Kex2 protease 567 zalutumumab 762 – ManII and GnTII 567 zalutuzumab 832 – O-glycosylation 568 zanolimumab 758–759, 1083–1084 – P. pastoris 566 ZFNs. See zinc finger (endo)nucleases – pharmaceutical production 566 (ZFNs) – proteolytic degradation 567 zinc finger (endo) nucleases (ZFNs) – recombinant antibody expression 566 – detrimental deletions 83 – Y. lipolytica and K. lactis 566 – DNA repair pathways 577 – yeast-expressed scFv-Fc fusion proteins – double-strand breaks, target sites 82, 83 568–569 – homolog recombination, nucleases 576 yttrium-90 ibritumomab tiuxetan (ZevalinⓇ) – knockout lines, fully silenced Ig loci 82 – absolute neutrophils count (ANC) 1586 – mutations/knockout animals 82 – adverse events 1586–1587 – sequence-recognition and cleavage function, – aggressive (DLBCL) NHL 1588 FokI 82 – chelators 1583 – and TALENs 577 – clinical therapeutic efficacy 1585–1586