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349 a AAC, See Antibody-Antibiotic Conjugate Acid-Labile Linkers, 51, 59 Index A αhuCD11a-LXR, 327 AAC, see Antibody-antibiotic conjugate αhuCD11a-PDE4, 328 Acid-labile linkers, 51, 59 αmuCD11a-PDE4, 329 acMMAE, see Antibody-conjugated MMAE AmbrX’s technology, 123–124 Activatable dual variable domain (aDVD) American Society of Hematology (ASH), 35 antibody, 284, 287–288 Aminoacyl-tRNA synthetase (aaRS), 252–253 Activated leukocyte cell adhesion molecule AML, see Acute myeloid leukemia (ALCAM), see CD166 PDCs Anaplastic large cell lymphoma (ALCL), 107 Acute lymphoblastic leukemia (ALL), 62 Anthracyclines, 201–203 Acute myeloid leukemia (AML), 3, 193 Antibody-antibiotic conjugate (AAC), 329–331 Adcetris, 33, 107, 332 Antibody-conjugated MMAE (acMMAE), ADC-IO combinations 92–93 clinical trials, 30–34 Antibody-dependent cell-mediated PBDs, 25–29 cytotoxicity (ADCC), 49, 269 preclinical data, 29 Antibody/drug-conjugated micelle (ADCM) rationale, 29–30 technology, 234 reported data, 35–36 Antibody prodrugs tubulysin, 25–26 acidic tumor microenvironment, 285–286 ADC payloads differential pH-sensitivity, 284–285 anthracyclines and camptothecin, 201–203 issue of off-target toxicity, 282–283 Bcl-xL, 202–204 linker/payloads, 282–283 conjugation reaction, 188 linker/toxins, 283 cytosolic microtubules, 205–206 PDC (see Probody Drug Conjugates) DNA-damaging payloads, 192–201 protease activatability, 284–285 essential cellular processes, 188 protease antibody formats, 287–289 non-oncology, targeted delivery, 206–209 proteolysis, 286–287 RNA polymerase, 204–205 Anti-CD70 ADC SGN-75, 86 spliceosome, 204 Anti-fibrin ADCs, 305–306 tubulin, 189–192 Antigen ultra-potent payloads, 188 internalization and recycling, 340–341 Ado-trastuzumab emtansine, 33, 58–59 physiological function, 341–342 See also Trastuzumab-emtansine (T-DM1) tissue and cell types, 339–340 AFCA-branched-PEG-(SN-38)3 ADC, 305 Antigen-negative (Ag-) cells, 81 Alanine aminotransferase (ALT), 62 Antigen-positive (Ag+) cells, 81 © Springer International Publishing AG, part of Springer Nature 2018 349 M. Damelin (ed.), Innovations for Next-Generation Antibody-Drug Conjugates, Cancer Drug Discovery and Development, https://doi.org/10.1007/978-3-319-78154-9 350 Index Anti-HER2 agents, 107 NHP, 295–296 Anti-inflammatory effect, 322 T cell proliferation and activation, 292 Aspartate aminotransferase (AST), 62 Chemistry, manufacturing and controls (CMC) Atezolizumab (Tecentriq®), 33 assessments, 103 Auristatin, 49, 54, 131, 132 Chemotherapy, 3–5 Auristatin F-HPA, 226–227 Classical Hodgkin lymphoma (cHL), 33 Autologous stem cell transplant (ASCT), 107 Clear cell renal cell carcinoma (ccRCC) Azide, 120 subtypes, 304 Clinical trial assay (CTA), 110 Clinical trial in a mouse, 6 B Combo, 23 Bacterial transglutaminase (BTG), 257 Companion diagnostic (CDx), 106–108 B cell lymphoma (BCL), 64, 200 Complement-dependent cytotoxicity (CDC), 49 4-Benzoyl-L-phenylalanine (BPA), 260 Complete responses (CRs), 22 Bergman cyclization, 193 Conjugation technologies Bioconjugation, 2 bispecific antibody therapeutics, 134–135 Biologic license application (BLA) conventional Cysteine chemistry, 117–118, submissions, 102–103 127–128 Bispecific antibodies (BsAbs) examples, 116 Blinatumomab, 268 extracellular ADCs/EDCs, 134 catumaxomab, 268 Fleximer (Mersana), 131 format selection, 270–271 glucuronide, 131 internalization and lysosomal trafficking, Hydraspace (SynAffix), 131 271–276 native antibodies, 116–120 molecular formats, 269–270 native glycan modification/removal, 116, 125 selectivity, 276–277 pharmaceutical industry/academia, 115 Bivatuzumab mertansine, 53 preclinical and clinical arena, 133 BMS-936561, 65 probodies, 134 Brentuximab vedotin (BV), 17–18, 21, 33, 106 pyrophosphate diesters, 131 Bulk drug subtance (BDS), 145 quaternary amine, 131 BxPC3 model, 4 site specific technologies (see Drug Bystander effect, 301 antibody ratio) sulfonates, 131 toxic payloads, 128–130 C Contract manufacturing organization Calicheamicin, 25, 50, 59, 193–194 (CMO), 137 Camptothecin, 201–203 Conventional chemistry, 117 The Cancer Genome Atlas (TCGA), 47 Critical quality attribute (CQA), 122 Carbonic Anhydrase IX (CAIX), 304–305 Cross-masking antibody approach, 284, 288 Cardiac glycoside (CG), 206 CT26, 25 CD4+ T cells, 23–25 CTLA4, 20 CD8+ T cells, 23–26 64Cu-MM-302, 233 CD11c, 27 Cyclic adenosine monophosphate CD27, 33 (cAMP), 327 CD30-expressing tumor cells, 107 Cytotoxic T lymphocytes (CTLs), 26–29 CD39, 15 CD45+ cells, 27 CD63, 275 D CD73, 15 Damage-associated molecular patterns CD86, 27 (DAMPs), 14, 312 CD91, 14 DAR, see Drug antibody ratio CD166 PDCs Dendritic cells (DCs) characterization, 293–294 auristatins and maytansinoids, 20 in vivo efficacy, 293–295 BV, 21 Index 351 DC:tumor cell co-cultures, 20–21 Engineered cysteine conjugation technology, direct activation, 18, 20 123, 247, 250–251 in vivo, 20 Enhanced permeability and retention (EPR) maturation, 18 effect, 232 microtubule assembly, 18 Enzymatic conjugation technologies, 117–120, warheads, 18 125–126 Depolymerization, 18 Enzyme formylglycine, 120 Diffuse large B cell lymphoma (DLBCL), 34 EphA2, 25–29 Disulfide linkers, 51 Epidermal growth factor receptor (EGFR), 109 Disulfide-stabilized Fv (dsFv), 284, 287 Eucode, 120 DNA alkylation, 196–198 Expressed peptide ligation (EPL), 260 DNA damaging payloads Extracellular drug conjugates (EDCs), 206 calicheamicin, 193–194 Extracellular matrix (ECM) dividing and non-dividing cells, 192 anomalies in pH, 307 duocarmycins, 198–201 FNs, 307–309 mouse xenograft models, 192 TnC, 308–309 PBDs, 194–198 tumor-specific proteins, 307 uncialamycin, 194 DNA topoisomerase I inhibitors, 50 Dolastatins, 20 F Dose-limiting toxicities (DLTs), 57, 195, 283 Fc receptor (FcRn) pathway, 62 Drug antibody ratio (DAR), 6, 50 F-hydroxypropylamide (auristatin F-HPA), clinical trials, 121 226–227 conventional lysine and cysteine Fibroblast Activation Protein α (FAPα), 306 technologies, 121–122 Fibronectins (FNs), 307–309 DS characterization, 116 First in human (FIH) dose selection, 103–104 engineered cysteine technology, 123 First In Patient (FIP), 146 enzymatic conjugation, 117–120, 125–126 Folate receptor (FR), 334–335 glycan targeted conjugation, 124 Folate receptor-β (FR-β), 335 in-process issues, 121 Follicular NHL, 34 mAbs, 132–133 Food & Drug Administration (FDA), 100 maytansine and auristatin, 165 Formyl glycine (fGly), 258–259 PK and TI, 116 Formylglycine-generating enzyme (FGE), UAA, 123–124 258–259 Drug substance (DS), 116 Fourth extracellular domain (ECD4), 165 Drug substance intermediates (DSI), 129 Duocarmycins anti-CD19 ADC, 199 G anti-CD70 duocarmycin ADC, 199–200 Gemtuzumab ozogamicin, 106 CBI/pharmacophore, 198 Genentech, 197 CD33, 200–201 Genotype-Tissue Expression (GTEx), 47 electrophilic cyclopropyl moiety, 199 GITR ligand fusion protein (GITRL FP), 26 SYD985, 200 Glembatumumab vedotin, 34 DXd, 175 Glucocorticoid-induced leucine zipper DXd(2), 175 (GILZ), 324 Glucocorticoid-induced TNFR-related protein (GITR), 26 E Glucocorticoid receptor (GR) modulators, E. Coli (ReCODE™), yeast and mammalian 206–207 (EuCODE™) technology, 253–255 Glutathione (GSH), 301–302 EDV technology (EnGenIC), 134 Glycan targeted technologies, 124 EMILIA, 169 Glycine-glycine-phenylalanine-glycine Endoplasmic reticulum (ER), 17 (GGFG), 222 Enfortumab vedotin, 34 GlycoConnect, 118 352 Index Glycoprotein non-metastatic melanoma I protein B (gpNMB) expression, 54 ICH S6 (R1), 101–102 Glycotransferase, 256 ICH S9, 101–102 GMP, 121, 124, 136, 139, 141, 148 Illumina’s Human BodyMap 2.0, 47 Good laboratory practice (GLP) study, 103 Immune-deserts, 13 Guidance for Industry: In Vitro Companion Immunogenic cell death (ICD) Diagnostic Devices, 108 anti-cancer immunity, 13 ATP, 15 CRT, 14–15 H gold-standard functional assay, 13 Heavy chain (HC) mispairing, 269 HMGB1, 15–16 Hematopoietic stem cell transplantation immune-modulating properties, 17–19 (HSCT), 62 immunological memory, 13 Hemoglobin-haptoglobin (Hb-Hp) complex, induction, 16–17 322 long-term T cell memory, 14 Hepatic veno-occlusive disease, 62 type I IFN, 16 HER2 Immunoglobulin superfamily (IgSF), ADC components, 165–166 341–342 antibody binding, 164 Immunohistochemistry (IHC), 48 cell surface and recycling endosomes, 272 Immunoliposomes (ILs), 232–233 cleavable linker, 171–172 Immunologically “cold” tumors, 13 extracellular domains, 164 Immunomedics Dock-and-Lock technology, increased drug loading, 176–177 134 internalization, 177 Immuno-oncology (IO) agents, 2–3 mechanism of action, 166–167 ADC payload classes (see ADC-IO non-competing antibodies, 272–273 combinations) novel drug-linkers, 174–176 APC by tubulin-depolymerizing ADC site-specific conjugates, 172–173 (see Dendritic cells; Trastuzumab solid tumors (NCT02576548), 274 emtansine) therapy, 178–179 checkpoint inhibitors, 13 trastuzumab-MCC-DM1, 167–172, 178 mechanism of ICD (see Immunogenic cell Herceptin, 107 death) High DAR ADCs Innovations antibody-targeted nanotherapeutics, antibody, linker and payload, 2 231–234 challenges, 3–7 biodegradable polyacetal polymer carrier motivation, 2–3 (see High drug-loaded ADCs) technology development, 7–9 cytotoxic activity, 217 tools, 2 drug load technologies, 217–220 Inotuzumab-ozogamicin, 93 hydrophilicity, 225 Internalization and lysosomal degradation payloads, 216–217 expression profile, 271 PEG-based bioconjugation technology, HER2, 272–274 221–225 increased avidity/overall affinity, 271–272 High drug-loaded ADCs receptor clustering and cross linking, Dolaflexin®, 226–231 274–275 Fleximer®, 226 therapeutic index, 275–276 HPMA-based ADCs, 227, 231 Investigational Device
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