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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5703_Библиотеки_им_академика_М_И_Перельмана
.pdf
Cytomegalovirus (CMV), 195
Cytotoxic drugs, 354
Cytotoxic payloads, 101
Cytotoxic T lymphocytes (CTLs), 106, 247, 318,
336e337
D
Daratumumab, 133e134
Deadly Choices: How the Anti-Vaccine Movement
Threatens Us All (Offit, Paul A.), 214
Decay accelerating factor (DAF), 374e375
Decision-making, 185
Definitive preclinical studies, 415
Delivery method, justification of, 432
Delta-retroviruses, 266
Dendritic cells (DC), 207, 427
Deoxyribonucleic acid (DNA), 185
Dependoparvoviruses, 264
Depots, 136
Deerisking strategies, 241
therapeutic vaccines, 245
for vaccines, 240e241, 244e245
vaccines with adjuvants, 245
Desired pharmacology, 210e211
Development challenges, cellular therapies, 321e339
Developmental and reproductive toxicology (DART),
70, 74, 195, 281e282, 354, 356e358, 384e385,
387, 433
Developmental toxicity, 433
nonclinical vaccine development, 233e234
Dexamethasone, 298
Differentiated pluripotent stem cell (PSCs), 406e407
Diffuse large B-cell lymphoma (DLBCL), 42e43
Digital drop polymerase chain reaction (ddPCR), 417
Dinucleotide variants (DNV), 417e418
Disease modeling, 406e407
Disease/injury animal model, 430
Disruptive insertions, 299e300
Disseminated intravascular coagulopathy (DIC), 293
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC),
262
Dogs, 331e332
Donor pluripotent stem cell (PSCs)-derived cells, 428
Donor screening/testing requirements, 410e412, 411t
Dorsal root ganglia (DRG), 293
Dose extrapolation, considerations for, 436e437
Dose, justification of, 431e432
Dose range-finding (DRF) studies, 100e101, 110
Dosing frequency, 433
Dosing regimen, 40e41
Double stranded (ds)-breaks, 434
Downstream process, 271e272
Doxorubicin, 376
Drug induced liver injury (DILI), 292
Drug Master File (DMF), 195
e196
Drugs, 9, 70e71, 430
assays, 161e162
development process, 61e62
exposure assays, 161e163
product, 209 e210
Drug substance (DS), 271
Dual-acting Fab (DAF), 26
Dual affinity retargeting molecule (DART), 24e25
Dual-targeting antibodies, 43e48
Dual variable domain immunoglobulin (DVD-Ig)
format, 27
Duchenne muscular dystrophy, 284
Duobody, 26
Durvalumab, 384
E
Ebola virus disease (EVD), 230
Edited cells, 428e429
Effective dose (ED), 276e277, 279, 431e432
Effector functions, 20
Effector modified antibodies, 102e104, 104t
Electrochemiluminescence (ECL) method, 154,
156e157
Embryo-fetal development (EFD), 76e81, 356e357,
368
Embryoefetal study, 78
Embryonic stem cells (ESCs), 314e315, 401e403
Emergency use authorization (EUA), 50
Emicizumab, 45
Endogenous amino acids, 81
Endogenous human proteins, recombinant analogs
of, 387e390
Endogenous receptor ligands for central nervous
system (CNS) delivery of biotherapeutics,
47e48
EnGeneIC Delivery Vehicles (EDV), 27
Engineered protein scaffolds, recombinant formats
using, 24e27
Engineered T cell Receptor therapy-harvested T cells,
316
Engraftment, 427
Enhanced cardiotoxicity, 377
Enhanced pre-and post-natal development (ePPND),
78e81
Enhancer insertion, 299e300
Enthusiasm, 258
Environmental risk assessment, 234e235
Enzyme-linked immuno-sorbent assays (ELISAs), 154,
247
Enzyme-linked immunosorbent spot (ELISpot)
assays, 247
Index456
Enzymes, 351
Epcoritamab, 42e43
Epidermal growth factor (EGF), 133e134
Epidermal growth factor receptor (EGFR), 41, 44e45,
265, 366e367
Epilepsy, 406
Epithelial cell adhesion molecule (EpCAM), 36
Epsilon-retroviruses, 266
EpsteineBarr virus (EBV), 317
ErbB2, 43e44
ErbB3, 43e44
Erythropoietin (EPO), 108, 140
European Bank for induced Pluripotent Stem Cells
(EBiSC), 410
European Commission (EC), 284
European Federation of Pharmaceutical Industries
and Associations (EFPIA), 195e196
European Medicines Agency (EMA), 88e89, 113e116,
184e185, 228
European Partnership for Alternative Approaches to
Animal Testing (EPAA), 10e11
European public assessment reports (EPARs), 195
European Union and European Economic Area
countries (EU/EEA), 184
Ex vivo gene therapy, 259te261t
Exaggerated pharmacology, 426
Expanded neurohistopathology evaluation (ENHP),
294
Expansion cohort trial designs, 287
Exubera, 133
F
Faricimab, 46e47
Fatal GT-related hepatotoxicity in clinical trials, 291
Febrile responses, 244
Female cynomolgus monkeys, 368
Fertility and early embryonic development (FEED),
77, 358
Fibroblast growth factor receptor 1 (FGFR1), 265
Filtration, 136e139
First dose effect induced by monoclonal antibodies
(mAbs), 112e116
First-generation vaccines, 185e189
First-in-human (FIH), 67, 195
clinical trial, 86e89, 273
dosing, 151e152
enabling nonclinical toxicology studies, 278e279
nonclinical safety assessment package, 87e88
studies, 150
Flow cytometry assay, 332
Fludarabine, 327
Fluorescence in situ hybridization (FISH), 271
Fluorescent activated cell sorting (FACS), 270e271
Formalin-inactivated respiratory syncytial virus
(FI RSV) vaccine, 242
Foxn1 gene, 423
Fragment-based molecules, 24e25
Functional assays, 248
Fungal infections, 202e204
Fusion protein, 11e12
Fusogens, 267
G
Gamma-glutamyl transferase (GGT), 292
Gamma-retroviruses, 266
Gasdermin E (GSDME), 332
Gene editing, 338e339, 433
techniques, 318e319, 328
tools, 274e275
Gene efficiency factor (GEF), 286e287
Gene expression, 100
Gene therapy (GT), 8
delivering, 258e268, 259te261t
nonintegrating viral vectors, 263e266
adeno-associated vectors (AAV), 264e266
adenoviral vectors (AdV), 263e264
integrating viral vectors, 266e268
therapeutic applications, 268
nonviral vectors, 261e262
products, 258
viral vectors, 262e263, 262f
General de-risking strategies for vaccines, 242e244
General toxicology, 356
Genetic ablation, 385
Genetically engineered mouse (GEM) model,
274e275
Genetically immunocompromised models, 423e425
Genetically modified organisms (GMOs), 234e235
Genetically modified T cells, 316
Genetic toxicity, 431e434
Genome editing, 408e409
Genomic RNA (gRNA), 49
Genotoxicity, 81e84, 235, 282e283, 358e359, 387
assessment, 434
and carcinogenicity, 249
of human leukocyte interferon, 389
studies, 249
Germline transmission, 282e283
Gestation days (GD), 74e75, 368
GlaxoSmithKline (GSK) Vaccines, 199e200
Global Alliance for Vaccines and Immunisation
(GAVI), 199e200
Global regulatory guidance, 437e438
Global Vaccine Data Network (GVDN), 216e217
Glucagon-like peptide 1 (GLP-1), 7
Glutamate dehydrogenase (GLDH), 292e
293
Index 457
Glycoprotein L (gL), 195
Good Clinical Practice (GCP), 161e162
Good Documentation Practices, 232e233
Good Laboratory Practice (GLP), 87e88, 161e162,
192e193, 273e274, 321, 421
conditions, 231e232
toxicity study, 232e233
toxicology study, 279
Good manufacturing practice (GMP), 273e274
GPR108, 265
Graft versus host disease (GVHD), 424
models for, 335e336
and rejection associated with allogeneic engineered
T cells, 335e336
Granulocyte colony-stimulating factor (G-CSF), 140
GRNOPC1, 438e439
Growth hormone (GH), 136
Guillain-Barré syndrome (GBS), 216
Gutless’ adenovirus (AdV), 264
Gyros system, 158
H
Haemophilia, 45e46
Half-life extended (HLE) bispecific T-cell engager,
26e27
Harvard Stem Cell Institute, 410
Harvested tissues, 145
Health Authorities (HAs), 228
Healthy naive animal, 430
HEK293 cells, 271
HEK293t cells, 271
Hematologic toxicity, 117e122, 118te119t
AMG X case study, 121
Bevacizumab case study, 120
LY2541546 (antisclerostin) case study, 120e121
mAbY. 1 case study, 121e122
omalizumab case study, 121
Hematopoietic stem cells (HSCs), 268, 299
Hematopoietic stem cell transplantation (HSCT), 333
Heparan sulfate glycosaminoglycans (HS-GAGs),
263e264
Heparan sulfate proteoglycans (HSPG), 265
Hepatic metabolism, 136e139
Hepatitis C virus, 109e110
Hepatocellular carcinoma (HCC), 300
Hepatocyte growth factor receptor (HGFR), 265
Hepatotoxicity, 291e293
Herceptin, 139e140
Herd protection, 213
Herpes Simplex Virus Type I (HSV1), 14
Hexamers, 143e144
High content imaging system, 322e324
High-dose selection, 68e69
Highest nonseverely toxic dose (HNSTD), 34e35, 151
History of Vaccines, The, 180
Homologous protein, 64e66
Host resistance assays, 111e112
Human acid-alpha glucosidase (GAA), 294e295
Human cell-based assays, 244
Human diseases, animal models of, 274e275
Human embryonic stem cells (hESCs), 321e322,
401e403
derived retinal pigment epithelium (RPE) cells, 315
Human epidermal growth factor receptor (HER),
366e367
HER2, 374 e375
proteins, 366e367
Human equivalent dose (HED), 88e89, 151,
276e277
Human health impacts of vaccines, 193
Human immune system (HIS), 424
Human immunodeficiency virus, 266e267
Human immunogenicity, 108e109
Human leukocyte antigen (HLA) matching, 327
Human pharmacokinetics (PK) projections, 151
Human serum albumin (HSA), 25
Human-specific markers, 428
Human trials, pioneers in translating to, 438e440
Humanized mice, 424e425
Huntington’s disease, 406
Hybrid Pharmacology Toxicology studies, 422
Hybridoma fusion approaches, 23e24
Hypersensitivity reactions (HSR), 73, 116
Hyperthermia, 235
I
Immune cells, 329e330
Immune checkpoint inhibitors (ICIs), 117e120
Immune complex disease (ICD), 73, 120
Immune effector cell-associated neurotoxicity
syndrome (ICANS), 293e294, 328
Immune reactivity, 297
Immune rejection, 325e328
Immune responses, 241, 246
Immune system, 8
activation, 107
arms of, 180e184
Immuno-ablation models, 424
Immunoassays (IAs), 152e159, 249
Immunocompromised models, 429e430
Immunodeficient mouse models, 423
Immunogenic potential, 33
Immunogenicity, 33e34, 62, 71e73, 295e299,
360e363
assays, 232e233
assessments, 7 1, 164e166
Index458
impact on pharmacokinetics (PK) and
biodistribution, 145e146
Immunoglobulin (Ig) antibodies, 296
Immunoglobulin E (IgE), 318
Immunoglobulin G (IgG) -like molecules, 26
Immunoglobulins, 380
Immunohistochemical (IHC) methods, 116e117, 145
Immunomodulation, 110
Immunostimulation, 383
Immunostimulatory activity, 109e110
Immunostimulatory biotherapeutics, 112
Immunosuppressants in nonclinical studies, 298e299
Immunosuppressive biotherapeutics, 111e112
Immunosuppressive regimens, 424
Immunotherapy, 13, 316, 350
Immunotoxicity, 359
evaluation of, 110e116
parameters, 68
Immunotoxicology evaluation, 68
Immunotoxin fusion proteins, 11e12
Impedance-based assay, 332
Induced pluripotent stem cells (iPSCs), 314e315, 401,
403
Infectious diseases, 200
vaccines for, 201e205
Inflammatory responses, 379
Informed consent forms (ICFs), 288
Inhibitory antisense oligonucleotides (ASOs), 12
INitial Targeted Engagement for Regulatory Advice
on CBER ProducTs (INTERACT) meeting,
405e406
Initial toxicology studies, 369e370
Injury animal model, 430
Innate immune system, 180e181, 296
Inner cell mass (ICM), 401e403
Insertional mutagenesis, 282e283, 299e300, 337e339
In silico evaluations, 243
In silico expression data, 100
Institutional animal care and use committee
(IACUC), 410e412
Institutional review board (IRB), 288, 410e412
Insulin, 59
Insulin-like growth factor I (IGF-I), 133e134
Intellectual property (IP), 198
Interferon (IFN-a), 109e110, 387e388
Interferon (IFN) beta, 387e388
Interferon-g (IFN-g), 207, 318, 387e388
Interferons (IFNs), 109e110, 387e388
Interleukin 1 beta (IL-1b), 244, 318
Interleukin (IL-12) case study, 109
Interleukin 2 receptor gamma (IL2rg), 319e320
Interleukin-6 (IL-6), 244
Internal standards (IS), 159e161
International Acquired immunodeficiency syndrome
(AIDS) Vaccine Initiative (IAVI), 199e200
International Conference of Drug Regulatory
Authorities (ICDRA), 59
International Consortium for Innovation and Quality
in Pharmaceutical Development, 9e10
International Council for Harmonisation (ICH), 154
core battery tests, 430e431
ICH M3 (R2) Nonclinical Safety Studies for the
Conduct of Human Clinical Trials for
Pharmaceuticals, 351
ICH S5 (R3), 88e89, 358
ICH S6 (R1) guideline, 88e89, 351, 383
ICH S9, 88e89, 354e355
guidance, 351
Q&A, 356e357
recommendations, 355
International Network of Special Immunization
Services (INSIS), 216e217
Intracellular proteins, 325
Intramuscular (IM) administration, 133
Intravenous (IV) administration, 133
Intravenous immunoglobulin, 333
Inverted terminal repeats (ITRs), 264e265
Investigational New Drug (IND), 64, 320
In vitro
assays, 100, 244
coculture models, 332
models for biomarker assessment, 332
safety assessments, 96
technologies, 108e109
toxicology testing, 406e407
In Vitro Fertilization (IVF) treatments, 437
In vivo
approaches, 30e 31
drug exposure, 132
gene therapy (GT) products, 258
nonclinical studies, 70
pharmacokinetic/pharmacodynamic (PK/PD)
studies, 38
pharmacology, 35
studies, 100e101, 377e378
technologies, 108e109
Ipilimumab, 377e383
K
Ketamine, 380
Knob-into-hole technology, 26
Krupple-like factor 4 (KLF4), 321e322
L
LAG-3, 385, 387
Late life onset (LLO), 74
Index 459
Lentiviral vectors (LVs), 258, 337
Lentivirus, 266
Leukemia, 337e338
Ligand Binding Assay Bioanalytical Focus Group
(LBABFG), 154
Ligand-binding assays, 246e247
Limulus amebocyte lysate (LAL) assay, 244
Lineage Cell Therapeutics, 438e439
Lineage specific markers, 325
Lipid nanoparticle (LNP), 230
Liquid chromatography coupled to mass
spectrometry (LC-MS), 159e161
Liver enzymes, 243
Liver function tests (LFTs), 243
Liver injury data, 292e293
Loading dose approach, 72e73
Local tolerability, 435
Long-term B-cell depletion, 333
Long-term follow-up (LTFU), 441
Long-term immunosuppression, 424
5
0
long terminal repeat (LTR), 267e268
Low-density lipoprotein (LDL) receptor, 47e48,
136e139
Low-density lipoprotein receptor 1 (LRP1), 48
Luciferase-mediated bioluminescence imaging (BLI)
assay, 332
Luteinizing hormone (LH), 149e150
LY2541546 (antisclerostin) case study, 120e121
Lymphocryptovirus (LCV), 112
Lymphokine-activated killer (LAK), 109
Lysosomal degradation, 202
M
mAbY.1 case study, 121e122
Machine learning (ML) approaches, 11
Macrophage colony-stimulating factor (M-CSF), 140
Magnetic resonance imaging (MRI), 429
Major histocompatibility complex (MHC), 104e106,
181, 326, 336e337
Major histocompatibility complex class II (MHC II),
181
Male NZW rabbits, 372e373
Manufacturing of pluripotent stem cell (PSCs) -based
products, 419
Manufacturing scalability, 409e410
Manufacturing scale, 409e410
Marketed biologics, nonclinical development of, 364
avastin, 369 e387
herceptin, 374e377
ipilimumab, 377e383
monoclonal antibodies (MAbs), 366e367
for oncology indications, 364te366t
rituximab, 367e369
Marketing Authorization Application (MAA), 184,
320
Massachusetts Human Stem Cell Bank, 410
Master cell bank (MCB), 271, 413
Master clinical protocols to support multiple drugs
or multiple patient subpopulations, 287e288
Master protocol, 288
Matrigel, 321e322
Maximal tolerable dose (MTD), 38, 277, 425
Maximum feasible dose (MFD), 277, 425, 431e432
Maximum recommended safe starting dose (MRSD),
88e89, 151
MECOM, 299
Medicines and Healthcare products Regulatory
Authority (MHRA), 195
Meganucleases, 408e409
Melanoma antigen-encoding-A3 (MAGE-A3)-derived
peptide, 336e337
Meningoencephalitis, 245
Mesenchymal stem cells (MSCs), 401
Meso Scale Discovery (MSD), 156e157
Messenger RNA (mRNA), 12
Metabolism, 144
and biodistribution, 144e145
Method of administration for nonclinical studies
pluripotent stem cell (PSCs)ebased therapies,
421e422
viral vector gene therapies (GT), 274
Mice, 331e332
Microarrays, 243e244, 413
Microbial pathogens, 111e112
Micro RNA (miRNA), 12
Minimum anticipated biological effect level
(MABEL), 34e35, 88
e89, 97, 151
Minimum efficacious dose (MED), 275, 419e420
Misconception, 68e69
Model informed drug discovery and development
(MID3), 146
Modified molecules, disposition of, 148e149
Molecular mimicry, 242
Monkey neurovirulence test (MNVT), 236
Monkey toxicity studies, 379
Monoclonal antibodies (mAbs), 20e21, 66e67, 74e75,
101, 132, 139e140, 350e351, 363, 366e367
fragments and constructs, 134e136
TGN1412 case study, 113e116
therapies, 101e102, 103f
tumor lysis syndrome (TLS), first dose effect and
cytokine release syndrome (CRS), 112e116
Monocyte activation test (MAT), 244
Monovalent biopharmaceuticals (MVBs), 21
Morphological assays, 418
Mosquitoes, 234e235
Index460
Mosunetuzumab, 35e36
Multiorgan dysfunction, 329
Multiple drugs, master clinical protocols to support,
287e288
Multiple patient subpopulations, master clinical
protocols to support, 287e288
Multiple PD-1/PD-L1 pathway blockers, 384e385
Multiple reaction monitoring (MRM), 159
Multiple regulatory guidance documents, 319
muMAb4D5, 374
Murine surrogate (muS110), 38
Muromonab-CD3, 111
Mutations, 143e144
Mycobacterium tuberculosis, 112
Myelodysplastic syndrome (MDS), 299
Myeloid differentiation primary response 88 (MyD88)
protein-dependent pathways, 296
N
Nanobody. See Single-domain antibody (sdAb)
National Academy of Science, The (NAS), 410e412
National Institutes of Health (NIH), 285
National Regulatory Authority (NRA), 184
Native proteins, 144
Natural killer (NK) cells, 207, 316, 332, 423
Necropsies, 232e234
Neisseria meningitides, 193
Neonatal Fc receptor (FcRn), 20
Neurotoxicity, 293e294
animal models for, 331e332
cytokine release syndrome (CRS), 329e332
models for, 331e332
utility of biomarkers for predicting, 331
Neurovirulence, 236
Neutralization assays, 248
Neutralizing antibodies, 247
New approach methodologies (NAMs), 10, 100
New chemical entities (NCEs), 426e427
New molecular entities, 21e23
New Zealand White (NZW) rabbits, 371
Next generation sequencing (NGS), 413
Nivolumab, 384
Non-cell-based allergy immunotherapeutic
treatments, 207
Nonclinical data
to clinical application translation, 436e437
translation of nonclinical data to clinical trial dose
selection, 88e89
Nonclinical development, 21
challenges, 35
combination therapeutics, 49e50
severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) antibody cocktail, 49e50
dual-targeting antibodies, 43e48
anti-ErbB2/ErbB3, 43
anti-HER3/EGFR, 44
anti-TfR bispecific antibody, 48
bispecific antibodies of endogenous receptor
ligands, 47e48
coagulation disorder, 45e46
ocular disease, 46e47
general challenges and considerations, 28e35
effector function, 29e30
immunogenicity, 33e34
molecular properties, 32e33
pharmacokinetics (PK), 32
species selection, 30e31
starting dose, selection of, 34e35
target, expression, regulation, and distribution of,
28e29
tissue cross-reactivity (TCR) study, 31e32
understanding target biology, 29
of marketed biologics, 364
monovalent biopharmaceuticals (MVBs), 21
of oncology biologics, 351
pluripotent stem cell (PSCs)ebased therapies,
419e435
polyvalent biopharmaceuticals (PVBs), 21e23
scientific rationale, 21e23, 22f
programs, 30
T celledependent bispecific antibody (TDB)
biotherapeutics, 35e43
blinatumomab (MT103), 38e42
catumaxomab, 36e38
epithelial cell adhesion molecule (EpCAM)
-targeting, 36
pharmacological activity and formation of
antidrug antibodies (ADAs), 42e43
technology and formats, 23e27
chemical cross-linking and hybridoma fusion
approaches, 23e24
fragment-based molecules, 24e25
immunoglobulin G (IgG) -like molecules, 26
recombinant formats using engineered protein
scaffolds, 24e27
single-chain variable fragments (scFv), formats
based on, 24e25
viral vector gene therapies (GT), 273e283
Nonclinical evaluations, objectives of, 352
Nonclinical models, 242
Nonclinical program, 67, 376
Nonclinical safety
assessment, 245
differences in nonclinical safety assessment of
vaccines and biopharmaceutical drugs, 248e249
programs, 58e59
Index 461
Nonclinical safety (Continued )
studies, 240
evaluation, 278e283
program considerations, 87e88
Nonclinical species for toxicology testing, 7e8
Nonclinical studies, 297, 319e320
with biologics, 354e355
with cellular therapies, 316e317
and principles of study design, cancer, 355e359
selection of test article for, 273e274
viral vector gene therapies (GT), 274
Nonclinical testing programs, 192e193, 210e211
Nonclinical toxicity
studies, 227e228, 231
testing, 228
Nonclinical toxicology studies, 62, 240, 321
Nonclinical vaccine development
biodistribution, 234
developmental toxicity, 233e234
environmental risk assessment, 234e235
genotoxicity and carcinogenicity, 235
neurovirulence, 236
regulatory guidelines, 228e230
alternate approaches, 230
repeat-dose toxicity evaluation, 231e233
safety pharmacology, 235
Non-Hodgkin’s lymphomas (NHLs), 40e41,
112e113
No observed adverse effect level (NOAEL), 13,
34e35, 85e86, 88, 97, 151, 227e228, 233, 240,
279, 355, 386, 419e420, 429
No-observable-effect level (NOEL), 85e86, 355
Noncommunicable diseases (NCD), 206
Noncompartmental methods, 147
Nonhuman primates (NHPs), 58e59, 68, 109e110,
151, 231, 236, 245, 280, 331e332, 351e353
Nonintegrating viral vectors, 263e266
Noninvasive imaging modalities, 429
Nonobese diabetic (NOD) mice, 423
NOD/SCID/IL-2rgKO (NSG) mice, 324
NOD/SCID/gCnull (NOG) mice, 324
severe combined immunodefi
ciency, 319 e320
Nonviral systems, 262
Nonviral vectors, 258e268
Normal tissues, target expression in, 32e33
Novel biopharmaceuticals, 81, 240e241
absorption, 132e140
bioanalytics, 152e166, 153t
assays, 161 e166
biomarkers, target engagement, 163e164
drug exposure, 161e163
immunoassays (IAs), 154e159, 155fe156f
immunogenicity assessment, 164e166
liquid chromatography coupled to mass
spectrometry (LC-MS), 159e161, 160f
method development guidances and regulations,
154
methods and platforms, 154e161
distribution and elimination, 132e140
monoclonal antibodies (mAbs) fragments and
constructs, 134 e136, 135t, 137te138t
target-mediated processes, 136f, 139e140
therapeutic proteins and peptides, 136e139
immunogenicity and impact on pharmacokinetics
(PK) and biodistribution, 145e146
metabolism and biodistribution, 144e145
nonclinical to clinical translation, 150e152
first-in-human (FIH) dosing, 151e152
human pharmacokinetics (PK) projections, 151
pharmacokinetics (PK) and biodistribution, 140e144,
142f
pharmacokinetics and pharmacodynamics (PK/PD)
methods, 146e150
model types and examples, 149e150
molecule types, representative for, 148e149
Novel chemical entities (NCEs), 235
Novel screening technologies, 117
O
Ocular disease, 46e47
age-related macular degeneration, 46e47
Office of Therapeutic Products (OTP), 184, 284e285,
403
Office of Tissues and Advanced Therapies (OTAT),
284e285
Office of Vaccines Research and Review (OVRR), 184
Off-target toxicity, 332e334
“Off-the-shelf” therapies, 326
Off-tumor toxicity, models for, 332e334
Omalizumab case study, 121
Omnitrope, 12
Oncology biologics, 351, 356e358, 390e391
Oncology indications, 35
Oncology vaccines, 245
Oncolytic viruses (OVs), 14
Oncophage vaccine, 207
On-target toxicity, 332e334
off-tumor toxicity, models for, 333e334
Opdualag, 387
Oppenheimer effect, 440
Opsonophagocytic assays (OPA), 248
Optical coherence tomography (OCT), 439e440
Organ-on-a-chip, 58e59
Organ transplant rejection, 111
Organogenesis, 79
Ornithine transcarbamylase, 291
Index462
P
Pancreatic islet cells, 315
Panitumumab-based bispecific T-cell engager
antibodies (P-BiTE), 41
Parasitic diseases, 204e205
Parkinson’s disease, 406
Pathogen-associated molecular patterns (PAMPs),
180e181
Pathway analysis, 99
Patient interventions, 297
Pattern recognition receptors (PRRs), 291
Pegylated recombinant human megakaryocyte
growth and development factor (PEG-MGDF),
108
PEGylation, 143
Pembrolizumab, 384
Peptide-major histocompatibility complex (pMHC)
antigens, 336e337
Peripheral blood mononuclear cells (PBMCs),
110e111, 247, 319e320, 335e336
Pertuzumab, 6
Pharmaceutical candidates, nonclinical studies of, 61t
Pharmaceutical Research and Manufacturers of
America (PhRMA), 193e194
Pharmaceuticals, 429
Pharmacodynamics (PD), 132, 149, 360e363, 426
activity, 108
assessments, 246
of biologics, 363
endpoints, 43, 386
information, 68
marker, 61e62
methods, 146e150
studies, 38, 368
therapeutic index (TI) and exaggerated
pharmacology, 426
viral vector gene therapies (GT), 276e278
Pharmacokinetics (PK), 32, 132, 140e144, 195,
360e363, 375, 426e428
assessments, 246
biodistribution, 427e428
of biologic therapeutics, 362
drug interaction studies, 376
engraftment, 427
immunogenicity impact on, 145e146
information, 68
methods, 146e150
studies, 38, 277
viral vector gene therapies (GT), 276e278
Pharmacologically active dose (PAD), 34e35, 88e89,
151, 286
Pharmacologic efficacy assessments, 275e276,
425e426
mechanism of action, 426
study design, dose selection and justification,
425e426
Pharmacologic ef
ficacy studies, 276
Pharmacologic immunostimulation, 109
Pharmacologic studies, 422
Pharmacology, 280
Pharmacovigilance, 194
Phase I advanced cancer clinical trials, 356
Phenotypic assays, 418
Phenylketonuria (PKU), 300
Physeal dysplasia, 370e371
Physiologically based pharmacokinetic (PBPK)
modeling, 147e148, 151
Picomolar (pM) detection, 155e156
PiggyBac transposons, 338e339
Pivotal IND-enabling pharmacology study, 277
Plasma membrane, 264
Plasmodium falciparum, 204e205
Platelet derived growth factor (PDGF), 265
Platform approach, 230
Pluripotency and potential for tumorigenicity, 415
Pluripotent stem cells (PSCs), 314e315, 322e324, 400,
406e407, 428e429
based cellular therapy products, 437
based therapeutics, 403, 439e440
based therapies, 420
clinical studies of pluripotent stem cell (PSCs)-
derived therapeutic candidates, 438e441
number of clinical trials for pluripotent stem cell
(PSC)-based products, 439t
pioneers in translating to human trials, 438e440
reflection on clinical investigations to date and
looking forward, 441
decisions, 407e419
cell line characterization, 412e413
cell line selection, critical decisions in, 410e412
manufacturing process, 407e410, 408f
manufacturing scale, 409e410
product characterization, 413e419
raw materials, 409
testing, 409
definitions, regulations, and therapeutic applications,
401e407
applications, 406e407
human embryonic stem cells (hESCs), 401e403
induced pluripotent stem cells (iPSCs), 403
regulations, 403e406
therapeutic applications, 406
global regulatory guidance, 437e438
ethical and political issues, 437e438
nonclinical development, 419e435
biodistribution, 427e428
Index 463
Pluripotent stem cells (PSCs) (Continued )
bioluminescence, 429
chemical immunosuppression models, 424e425
clinical application, 436e437
clinical considerations and endpoints, 436e437
delivery method, justification of, 432
disease/injury animal model vs. healthy naive
animal, 430
dose, justification of, 431e432
dose extrapolation, considerations for, 436e437
engraftment, 427
general toxicity, 431e433
genetic toxicity, 433e434
genetically immunocompromised models, 423e425
human-specific markers, 428
immuno-ablation models, 424
justification for route and method of
administration for nonclinical studies, 421e422
local tolerability, 435
magnetic resonance imaging (MRI), 429
pharmacodynamics (PD) and pharmacokinetics
(PK), 426e431
pharmacologic efficacy assessments, 425e426
positron emission tomography (PET), 429
principles of, 419e420
reporter genes, edited cells, and Y chromosomes,
428e429
reproductive and developmental toxicity, 433
safety pharmacology, 430e431
selection of animal models and/or species for
nonclinical studies, 422e425
selection of test article for nonclinical studies and
key manufacturing considerations, 420e421
single-photon emission tomography (SPECT), 429
special considerations for species and model
selection for assessment of toxicity, 429e430
study design and endpoints, 432e433
test system, justification of, 432
toxicity assessments, 431e435
tumorigenicity assessment, 434e435
product attributes based on source of cell-based
therapies, 402t
resource documents for, 404te405t
Polyethylene glycol (PEG)-lipid conjugate, 262
Poly(lactide-co-glycolide)-block-poly(ethylene glycol)
-block-poly(lactide-co-glycolide)
(PLGAPEG-PLGA triblock copolymer), 6
Polymerase chain reaction (PCR), 158e159
Polyvalent biopharmaceuticals (PVBs), 20e23
scientific rationale, 21e23, 22f
Positron emission tomography (PET), 429
Potency assays, 273, 418
Potential carcinogenicity, evaluation of, 84
Pre-and postnatal development (PPND), 77, 356e357,
368, 372
Preintegration complexes (PIC), 266
Pre-Investigational New Drug (Pre-IND), 405e406
Preliminary critical quality attributes (CQAs),
272e273
Preliminary embryo-fetal development (pEFD), 78
Prescription Drug User Fee Act (PDUFA), 284e285
Primary mechanism of action (PMOA), 403
Priority Medicines (PRIME), 230
Private partnerships (PPPs), 199e200
Probabilities of success (POS), 194
Producer cell line selection, 270e271
Product characterization, 272e273, 413e419, 416t
kinetics, chromosomal stability, differentiation
status, and cellular attributes, 417e418
pluripotency and potential for tumorigenicity, 415
potency assays, 418
product lot release specifications, 419
threshold for residual stem cells, 416e417
Product development process, 418
Product lot release specifications, 419
Product-specific assessment (PSA), 358e359
Program for Appropriate Technology in Health
(PATH), 199e200
Programmed cell death Ligand 1 (PD-L1), 384
Programmed cell death protein 1 (PD-1) genes, 337,
384e385
Progressive multifocal leukoencephalopathy (PML),
367
Promoter insertion, 299e300
Proof-of-concept (POC) studies, 273e274, 423
Prophylactic vaccines, 13, 240
Proposed cell line provenance checklist, 411t
Protein pharmaceuticals, 33, 433
Pure red cell aplasia, 108
Q
Q&A Guidance, 358
Quadromas, 23e24
Quality attributes, 272e273
Quantitative polymerase chain reaction (qPCR), 417
Quantitative real-time polymerase chain reaction
(qRT-PCR), 163, 325
Quantitative systems pharmacology (QSP), 150
R
Radioimmunoassays (RIAs), 155e156
Ramifications, 99
Randomized controlled trials (RCTs), 288
Raw materials, 409
Reactogenicity, 243e244
Real time polymerase chain reaction (RT-PCR), 325
Index464
Real-world data (RWD), 288
control subjects, placebo groups, and use of,
288e289
Receptor binding domain (RBD), 49, 267
Receptor-mediated endocytosis (RME), 134
Receptor-mediated transcytosis, 48
Receptor occupancy (RO), 110
Recombinant
analogs of endogenous human proteins, 387e390
roferon-A, 388e390
deoxyribonucleic acid (DNA), 3e4, 58
growth factors, 108e109
(nonantibody) protein therapeutics, 107e110
proteins, 83
recombinant cytokines, 109e110
interferon (IFN-a) case study, 109e110
interleukin (IL-12) case study, 109
technology, 23
Recombinant human IL-12 (rhIL-12), 109
Reduce, Refine, Replace (3R) initiatives, 100, 424e425
Regenerative Medicine Advanced Therapy (RMAT),
284e285
Regenerative Patch Technologies (RPT), 439e440
Regulatory guidelines, nonclinical vaccine
development, 228e230
Regulatory landscape, 283e286, 284t
Regulatory strategy, 61e62
Regulatory T cells (Tregs), 377
Relatlimab as combination immunotherapy,
development of, 385e387
Removab, 36
Repeat-dose IV studies, 370
Repeat-dose toxicity evaluation, 231e233
Repeat-dose toxicity studies, 67
Repeat-dose toxicology studies, 360e362
Repeated dose toxicity studies, 433
Reporter genes, 428e429
Reproductive toxicity, 433
Reprogramming techniques, 403
Research and development (R&D), 180
Residual pluripotent stem cell (PSCs), 415
Residual stem cells, 416e417
Respiratory syncytial virus (RSV), 242
Retinal pigment epithelium (RPE), 315, 439
Retro viral vectors, 337
Retrogenix Cell Microarray Technology, The, 334
Retroviruses, 266, 282
Reverse cumulative distribution curve, 212
Reverse-mediated transcytosis (RMT), 47e48
Risk-benefit analysis, 441
Rituximab, 6, 116, 133e134, 139e140, 366e369
Rodent/rabbit reproductive toxicity, 75
Rodent species, 280, 423
Roferon-A, 388e390
Route of administration (ROA), 271
e272
for nonclinical studies
pluripotent stem cell (PSCs)ebased therapies,
421e422
viral vector gene therapies (GT), 274
Routine toxicity endpoints, 71
Ruthenium (Ru), 156e157
S
Safety margin calculations, 249
Safety pharmacology, 235, 356, 430e431
assessments, 386
endpoints, 68
Safety risk assessment, 434
Salmonella typhimurium, 376
Screening process, 63e64
Secondary internalization receptors, 265
Self inactivation (SIN), 267e268
Sensitive assays, 417
Serratia marcescens, 206e207
Serum bactericidal antibody (SBA), 248
Serum concentration, 133e134
Serum therapy, 3e4
Severe acute respiratory syndrome coronavirus-2
(SARS-CoV-2), 49e50
Severe combined immunodeficiency disorder (SCID),
267e268, 290, 423
Severely debilitating/life-threatening diseases
(SDLT), 74, 357
Shedding of recombinant viral vectors, 278
Short-duration toxicology studies, 248e249
Sickle cell disease (SCD), 299
Simian immunodeficiency virus (SIV) DNA vaccines,
377e378
Single-chain variable fragments (scFv), 24e25
Single-domain antibody (sdAb), 24e25
Single-dose acute toxicology studies, 375
Single nucleotide variants (SNV), 417e418
Single-photon emission tomography (SPECT), 429
Single reaction monitoring (SRM), 159
Single stranded (ss) DNA, 318
Small activating RNA (saRNA), 12
Small interfering RNA (siRNA), 12
Small molecule drugs, 6, 363
Smallpox, 193
Specialty toxicology assessments, 356
Species selection, 8, 61e66
Specificity of drug assay, 148
Specific pathogen-free (SPF) animals, 112
Specific safety pharmacology studies, 381
Spinal cord injury, 406
Spinal muscular atrophy (SMA), 291
Index 465
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