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 Exemption (IDE), 109 Highest non-severely toxic dose (HNSTD), 104 Investigational New Drug (IND) application, Histidine switches, 285 102–104 HMGB1, 15–16 Investigative Use Only device (IUO), 109 Hodgkin lymphoma (HL), 17 In vitro-in vivo correlation (IVIVC), 77 Hydrazino-iso-Pictet-Spengler (HIPS) In vitro PK-PD models ligation, 258–259 bystander effect, 80–81 Hypoxia inducible factor 1 (HIF1α), 285 cell-level disposition model, 78 Index 353

description, proposed utility, and dataset Maleimidodiaminopropionic acid (mDPR), 224 requirements, 75–77 Maximum tolerated dose (MTD), 57, 59, 91, mathematical models, 77 144–145, 282–283 model structure, 77–78 MCA205, 25 platform type cell-level, 78–79 Microtubule-disrupting agent monomethyl semi-mechanistic models, 79–80 auristatin E (MMAE), 310–311 set of simulations, 78 Microtubule inhibitors, 49–50 smcc-DM1 based linkers, 78–79 Minimum effective dose (MED), 145 stability, 77 Mirvetuximab soravtansine, 34 system-specific properties, 77 MMP9, 288 In vivo PK-PD models MN antigen, 304–305 oncology indications, 87 Model-based drug development (MBDD), 74 patient populations, 90 Modeling and simulation (M&S) plasma/serum pharmacokinetics, 81–83 approaches, 75 TD model, 89–91 Molecular heterogeneity, 6–7 trastuzumab-resistant mouse xenografts, Monoclonal antibody (mAb), 300 87–88 Monomethyl auristatin E (MMAE), 17–18, TSC, 88 107, 165 tumor distribution model, 88–89 Monomethyl auristatin F (MMAF), 49, 165 tumor model, 78, 84–85 Mucic acid polymer conjugate of whole-body disposition, 86–87 camptothecin (MAP-CPT), 234 Ipilimumab (Yervoy®), 33 Multidrug resistance (MDR) exporters, 224 Mushroom tyrosinase, 120

J Jun N-terminal kinase (JNK), 18 N Nanotherapeutics ADCM technology, 234 K cancer treatment, 231–232 Kadcyla, 107 dendrimers, 234 See also Trastuzumab-emtansine (T-DM1) drug delivery systems/nanocarriers, 231 Kinesin spindle protein (KSP) inhibitors, 205 ILs, 232–233 Krogh cylinder tumor model, 85, 87 NaPi2b (SLC34A2), 54 Natural amino acids engineered cysteines, 247, 250–251 L selenocysteine, 251–252 LAMP-3, 275 Neutropenia, 55, 57–58, 94 Large cell neuroendocrine carcinoma N-(2-hydroxypropyl) methacrylamide (LCNEC), 196 (HPMA), 225 LC-MS/MS-based Human Proteome Map N-hydroxysuccinimide (NHS) ester, 322 (HPM), 47 Nivolumab (Opdivo®), 33 Leucine-rich repeat containing G protein-­ Nodular regenerative hyperplasia (NRH), 62 coupled receptor 5 (LGR5), 50 Non-Hodgkin lymphoma (NHL), 33, 59, Light chain (LC) approach, 270 302, 304 Linker-cytotoxic agent, 55–57 Non-human primate (NHP) cynomolgus Liver X Receptor (LXR), 325–327 monkeys, 295–296 Lymphocyte function-associated antigen-1 Non-internalizing ADCs (LFA-1), 207–208 activity and selectivity, 311–312 biological activity, 302, 304–306 clinical responses, 300 M ECM, 307–311 MAAA-1181, 175 L19, F8 and F16 antibodies, 309–311 Maleimide and caproic acid (MC), 330 mAbs, 300 Maleimide linker, 127, 128 mechanism of action, 301–303 354 Index

Non-natural amino acids P EuCODE™ technology, 253–255 p-aminobenzyl quaternary ammonium salt OCFS technology, 255–256 (PABQ), 330 p-AcF, 252 para-acetylphenylalanine (p-AcF), 252 p-AzF, 252 para-azidophenylalanine (p-AzF), 252 recombinant antibodies, 252–253 Pathogen-associated molecular patterns strain of, 252 (PAMPs), 14 Non-oncology ADC Patient derived xenograft (PDX) models, αCD11a-LXR, 325–327 4, 175, 274 αCD11a-PDE4, 327–329 Patient selection, 6 αCD30-vedotin conjugate, 332 Payloads αCD45-Saporin (SAP) conjugate, 331 antibody conjugation chemistry, 338 αCD70-Budesonide Conjugate, 324 linker design and chemistry, 338–339 αCD163-Dexamethasone conjugate, mode of action, 337–338 322–324 pharmacology and toxicity, 336–337 αCXCR4-dasatinib conjugate, 325–326 PEG-based bioconjugation technology αCXCR4-tacrolimus conjugate, 333 benefit of, 225 αS. aureus-antibiotic conjugate, 329–331 CPT, 222–223 αTNF-steroid conjugate, 332–333 DNA topoisomerase I (Topo I) inhibitor, antigen selection, 339–342 221–222 folate conjugates, 334–336 linkers and cytotoxic payloads, 221 payload selection, 336–339 platinum(II), 224–225 siRNAs, 334 Seattle Genetics, 222–224 Non-target-mediated toxicities transglutaminase-mediated conjugation, conjugation chemistry, 55–56 222–223 hematological effects, 55, 57–60 Pembrolizumab (Keytruda®), 33 independent of, 55 Peripheral neuropathy (PN), 63, 94 linker-cytotoxic agent, 55–57 Personal protection equipment (PPE), 136 liver, 60–62 Phage Elisa for Selection of Reactive Thiols ocular, 64 (PHESELECTOR), 250 peripheral/generalized edema, 64–65 Pharmacokinetics (PK) and peripheral neuropathy, 63 pharmacodynamics (PD) models serosal effusion, 64–65 clinical development, 91–94 Non-T cell-inflamed tumors, 13 decision making, 75 MBDD, 74 M&S approaches, 75 O preclinical development (see In vitro Objective response rates (ORRs), 90 PK-PD models; In vivo PK-PD models) Ocular toxicity, 64 receptor-mediated internalization, 74 Oncology Pharmacology, 4 anti-infective ADC, 207–208 Phenylalanine-lysine (Phe-Lys), 327 anti-inflammatory ADCs, 206–208 Phosphodiesterase 4 (PDE4), 207–208, 327–329 siRNA, 209 Poly-1-hydroxymethylethylene On-target toxicities, 53–55 hydroxymethylformal (PHF), 226 Open cell free synthesis system (OCFS) Population PK-PD model, 93 technology, 255–256 Precision medicine, 110 O-phosphoseryl-tRNASec kinase (PSTK), 252 Preclinical studies, 4–6 Ovarian cancer (OC), 34, 230, 274 Premarket approval (PMA) program, 108–109 Overall response rate (ORR), 54 Premarket authorization (PMA), 109 Overall survival (OS), 30, 93, 169 Probody drug conjugate (PDC), 8 OX40 ligand fusion protein (OX40L FP), 26 anti-Jagged Probody therapeutic, 290–293 Index 355

CD166, 292–296 Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs), characterization, 293–294 194–198 therapeutic index, 289 Probody therapeutics, 289, 290 Process development and manufacturing Q accelerated approval, 152–153 Quality-by-Design (QbD) approach, 142 activities and sequence, 147 analytical development and Reference Material, 146 R CDMO and CMO offering, 137–139 RC48, 171 conjugation (see Conjugation technologies) Regulatory CQA, 119–120, 148–149 expedited pathways, US, 104–106 cytotoxicity, 143–145 FDA, 100 development timelines, 146 FIH dose selection, 103–104 early process development, 147 nonclinical evaluation, 100–103 outsourced development, 139, 141 patient selection strategy, targeted agents, outsourcing manufacturing, 138–140 106–110

platform approach, 151–152 Regulatory T cells (Tregs), 21 QbD approaches, 147–148 Renal cell carcinoma (RCC), 200 regulatory agencies, 142 Rovalpituzumab tesirine, 65 requirements, 122, 136 stages, 114–115 SUT, 136–138 S “tool box” approach, 149–151 Sacituzumab govitecan, 222 toxicology material, 146 Safety Prodomain, 289–290 determinants (see Toxicity) Programmed cell death protein-1 (PD-1), Probody™ therapeutics, 65–66 13, 21–22, 33 therapeutic index, 65 Programmed death-ligand 1 (PD-L1), Sec insertion sequence (SECIS), 252 21–22, 33 Seco-duocarmycin-hydroxybenzamide-­ Progression-free survival (PFS), 90 azaindole (DUBA), 174 Prolactin receptor (PRLR), 275 Second extracellular domain (ECD2), 165 Prostate-specific membrane antigen Selenocysteine, 251–252 (PSMA), 191 Severe combined immunodeficiency disease Protease activatable antibody formats (SCID), 221

activatable trivalent antibodies, 284, 287 Severely toxic dose to 10% (STD10), 103–104 aDVD, 284, 287–288 Short-interfering RNA (siRNA), 209 cross-masking antibody approach, 284, 288 Single use technologies (SUT), 136–138 probody therapeutics, 289, 290 Sinusoidal endothelial cells (SECs), 62 XTEN platform, 284, 288 Sinusoidal obstruction syndrome (SOS), 62 Protease-cleavable linkers, 51 Site-specific antibody drug conjugates Pyrrolobenzodiazepine dimers (PBD), 176 challenges, 261 auristatins and maytansinoids, 26 clinical development, 245–246 colloidal factors, 133 clinical trials, 121 CTLs, 26–29 comparison methods, 247–249 CT26 tumor-bearing mice, 26 conventional lysine and cysteine DNA-damaging agents, 50 technologies, 121–122 immunocompetent BALB/c mice, 25–26 cysteine re-bridging, 259–260 immunodeficient mice, 26 cytotoxic chemotherapeutic drugs, 244 limitations, 25 DS characterization, 116 Renca model, 27, 29 engineered cysteine technology, 123 warheads, 25 enzymatic conjugation, 117–120, 125–126 356 Index

Site-specific antibody drug conjugates (cont.) Topoisomerase I inhibitors, 175 enzymatic ligations, 256–259 Total trastuzumab (TTmAb), 92 glycan targeted conjugation, 124 Toxicity groups, 247 conjugation technology, 52–53 in-process issues, 121 cytotoxic agent, 49–50 inter-chain disulfide bonds, 245 linkers, 51 monoclonal antibodies, 132–133, non-target-mediated effects (see Non-­ 241–244 target-­mediated toxicities) natural amino acids, 247, 250–252 target antigens, 47–48 non-natural amino acids, 252–256 targeting antibody, 48–49 off-target toxicities, 262 target-mediated toxicities, 53–55 on-target activity, 262 Toxicodynamics (TD) model, 89–91 photoactive protein Z, 260 Translocation of calreticulin (CRT), 14–15 PK and TI, 116 Trastuzumab-emtansine (T-DM1) SAR, 246 CD4+ and CD8+ T cells, 23–25 SPR, 246 combination therapy, 22–23 UAA, 123–124 companion diagnostic, 107 Small cell lung carcinoma (SCLC), 196 components, 171–172 Small interfering RNA (siRNA), 334 conjugation, 52 Small-molecule drug conjugates first line metastatic positive breast (SMDCs), 191 cancer, 170 SMCC-DM1, 54 hematological effects, 59 Sortase A, 258 induction of ICD, 22–23 Sortase-tag expressed protein ligation non-breast positive malignancies, 171 (STEPL), 260 orthotopic Her2+ Fo5 breast cancer Sprague-Dawley rats, 57–58 models, 22 Squamous cell carcinoma of the head and neck PD-1, 21–22 (SCCHN), 33 preclinical development, 167–168 Steroids, 332–333 rat and monkey, plasma PK, 82–83 Strain-promoted alkyne azide cycloadditions resistance and potential impact, 172, 178 (SPAAC), 259 second line metastatic positive breast Structure-activity-relationship (SAR), 246 cancer, 168–169 Structure-property-relationship (SPR), 246 whole-body disposition, 87 Sym-004, 272 Trastuzumab-SPP-DM1, 167 Systemic anaplastic large cell lymphoma Trastuzumab-SSNPP-DM4, 167 (sALCL), 17 Triple-negative breast cancers (TNBCs), 221 “Triple negative” tumor xenografts, 191 Tub-tag labeling, 259 T Tubulin polymerization 4T1, 25 auristatins, 189–190 Tacrolimus (FK506), 333 blockage, 189 Target antigens, 47–48 maytansinoid, 192 Targeted delivery method, 323 polar functionalities, 192 Target-mediated drug disposition tubulysins, 190–191 (TMDD), 289 Tubulin tyrosine ligase (TLL), 259 Target-mediated skin toxicity, 53–54 Tubulysin payloads, 25–29 Target-mediated toxicities, 53–55 Tumor associated antigen (TAA), 276 Team Supply (TS), 146 Tumor associated macrophages (TAMs), 255 Tenascin C (TnC), 308–309 Tumor growth inhibition (TGI) datasets, 87 Therapeutic index (TI), 65, 90, 275–276, 289 Tumor initiating cells (TICs), 196 THIOMAB, 52–53, 123 Tumor microenvironment Thiomab-drug conjugates (TDCs), 82, 83 acidic, 285–286 Thio-succinimide linkages, 127–128 non-internalizing ADCs (see Non-­ Thrombocytopenia, 58–60 internalizing ADCs) Thymic stromal lymphopoietin (TSLP), 291 proteolysis, 286–287 Index 357

Tumor necrosis factor receptor (TNFR), 26 V Tumor Static Concentration (TSC), 88 Vadastuximab Talirine (SGN-CD33A), 127 2-compartment model, 82 ValAlaPABC linker, 196 Type I IFN, 16 Valine-citrulline (Val-Cit) dipeptide, 166, 302 Tyrosine kinase inhibitor (TKI), 6, 109 Valine-citrulline-p-aminobenzylcarbamate (val-cit-PABC) linker, 223 vc-MMAE, 57, 92–93 U Un-natural amino acid (UAA), 123–124 Untranslated regions (UTR), 252 X Urokinase plasminogen activator (uPA) XMT-1522, 227–230 systems, 286 XMT-1536, 54, 230 XTEN platform, 284, 288