Index. C Calicheamicin, 16, Campath, 93 Cantuzumab ravtansine, 131

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1 A Acid-cleavable hydrazone linkers, ADCs. See Antibody drug conjugates Adriamycin, 107 Analytical characterization, Analytical method, physicochemical characterization cell-based viability assays, chromatography, immunoassays, 44 ADC binding measurements, 45 ELISA antidrug antibodies, competitive, 47 conjugated antibody, 47, 48 formats and reagents, 48 generic total antibody, 46 semi-homogeneous, 46 specific total antibody, 46 mass spectrometry, ultraviolet visible spectrophotometry, 50 Ansamitocin, 16 Anti-body-dependent cellular cytotoxicity (ADCC), Antibody drug conjugates (ADCs) activity mechanism, 11, 12 antigen expression, 96 BR96-DOX conjugate, 14 clinical investigation, 4, 6 7 clinical trials auristatins (see Auristatins) calicheamicin, 14, DNA-targeting agents, 106 doxorubicin, 13, 107 duocarmycins, effectors structure, 101 linker types, 100 maytansinoids (see Maytansinoids) microtubule-binding agents, cytotoxic drugs, 13, 14 gemtuzumab ozogamicin, 14 history, immune response, 96 inotuzumab ozogamicin, 16 internalization mechanisms, 97 linkers, 10 brentuximab vedotin, 16 cleavable linkers, 13 dipeptide, 16 hydrazone, 15, 16 limitations, 14 noncleavable linkers, 13 stability, 13, MAbs, 10, maytansine, 17 metabolite, 97 MLN2704, 8 optimization of, 18 PSMA, 8 serum concentration, 96 structure, 10, 11, target cells, delivery, 94 targets, 4, 8, trastuzumab emtansine, 17 tumor localization, 97 G.L. Phillips (ed.), Antibody-Drug Conjugates and Immunotoxins: From Pre-Clinical Development to Therapeutic Applications, Cancer Drug Discovery and Development, DOI / , Springer Science+Business Media New York

2 370 Auristatins antimitotic agents, 104 dolastatin 16, 104 MMAE, 16, 105, 108 MMAF, 105, 109 tubulin inhibitors, 15, 16 Aurora-A kinase overexpression, 80 Avastin, 93 B B-cell malignancies treatment anti-cd19 antibodies, CD19 B lineage differentiation stages, 150 cytoplasmic domain, 149 mutations, 149 SAR3419 (see SAR3419) clinical trials ADC with rituximab, 142 CD70 expression, DCDT2980S, 141 inotuzumab ozogamicin, MDX-1203, 143 SAR3419, SGN-75, 143 preclinical ADC CD79b, epratuzumab-sn-38, hbu12, 143 MDX-1206, 143 Brentuximab vedotin (SGN-35), 16 activation of, 303 adverse events, 166 bystander killing, 304 cac10, 163 cycle I pharmacokinetics, 170 dose-escalation trial, 166, 168 dose-limiting toxicities, 168 mechanism of action, 163, 164 MMAE, 163 peripheral neuropathy, 166 phase I trial, pivotal studies, preclinical studies, 163, structure of, 163, 164 C Calicheamicin, 16, Campath, 93 Cantuzumab ravtansine, 131 CD56 immunoconjugates targeting, Lorvotuzumab mertansine antibody component of, chemical structure, 275, 276 clinical development of, cytotoxic payload component, 278 linker moiety and fi nal design, mechanism of action, in preclinical models, CD30-positive malignancies brentuximab vedotin (SGN-35) adverse events, 166 cac10, 163 cycle I pharmacokinetics, 170 dose-escalation trial, 166, 168 dose-limiting toxicities, 168 mechanism of action, 163, 164 MMAE, 163 peripheral neuropathy, 166 phase I trial, pivotal studies, preclinical studies, 163, structure of, 163, 164 TNFRSF8, 162 CDX-011 (glembatumumab vedotin, CR011-vcMMAE) clinical trials with in breast cancer, 216, 217 in melanoma, glycoprotein nonmetastatic B, human IgG2 monoclonal antibody, 212 structure, Cell-based viability assays, Chromatography, Cleavable disulfide linkers, Cleavable peptide linkers, Clinical pharmacology analytes, assay development, drug interaction, 33 drug-to-antibody ratio, 31 ECG evaluation, exposure-response analysis, 34 gemtuzumab ozogamicin, 28, 29 immunogenicity, 32 internalization, 29 metabolism, organ impairment, 34 pharmacokinetic comparability, 33 T-DM1 (see Trastuzumab emtansine)

3 371 Combotox, 4 Cytotoxic payloads potency, 98 solubility and membrane permeability, stability, 99, 100 D Docetaxel, Dolastatin-10, 104, Doxorubicin, 13, 107 Duocarmycins, E Enzyme-linked immunosorbent assay (ELISA), 31 antidrug antibodies, competitive, 47 conjugated antibody, 47, 48 formats and reagents, 48 generic total antibody, 46 semi-homogeneous, 46 specific total antibody, 46 Erbitux, 93 Erythropoietin-producing hepatocellular (Eph) EphA2 ectopic expression of, 244 in embryogenesis, 243 genetic deletion of, 243 human epithelial cancer, 243 monoclonal antibodies (mab), small molecule tyrosine kinase inhibitors, tumor overexpression pattern, 244 YSA and SWL, 245 MEDI-547 anti-epha2 antibody drug conjugate, 248, 249 dolastatin-10, immunoconjugate target, 246 lead identification, PC3 cells, 248, 249 P-glycoprotein (PGP), 250 structural organization, 241, 242 G Gemtuzumab ozogamicin, 14, 28, 29 Glycoprotein nonmetastatic B, Good laboratory practice (GLP) regulations, 26 H Herceptin, 93 Human epidermal growth factor receptor type 2 (Her2) anti-her2 immunotoxins, 320, 321 immunotoxins advantages, 320 B1D3/rGel, 335, 336 cell surface antigens, cytotoxic activity, functional activity analysis, 325 GrB, hepatotoxicity of, 335 intermediate-affinity antibodies, 334 linker design, RNases, 339 scfv affinity, scfv/rgel, antitumor activity, soluble Her2/neu antigen, therapeutic application, recombinant immunotoxins peptide linker designs, tumor-targeting scfv, 324 Trastuzumab DM1, 320 trastuzumab emtansine metastatic breast cancer ( see Metastatic breast cancer) preclinical studies, 182 structure, Hydrazone linkers, 118 I Immunoassays, 44 ADC binding measurements, 45 ELISA antidrug antibodies, competitive, 47 conjugated antibody, 47, 48 formats and reagents, 48 generic total antibody, 46 semi-homogeneous, 46 specific total antibody, 46 Immunotoxins antibody fragment, 8 bacterial exotoxins, 8 clinical development, 4, 5 fusion proteins, 8 Her2 advantages, 320 B1D3/rGel, 335, 336 cell surface antigens,

4 372 Immunotoxins (cont.) cytotoxic activity, GrB, hepatotoxicity of, 335 intermediate-affinity antibodies, 334 linker design, RNases, 339 scfv affinity, scfv/rgel, antitumor activity, soluble Her2/neu antigen, therapeutic application, plant toxin ricin, 8 protein toxins, 8 10 PSMA A5-PE40 and D7-PE40, melittin-like peptide 101, 265 MLN2704, 265 MMAE, 264 ricin A-chain, saporin, 264 targets, 4, 8 Inotuzumab ozogamicin, 16, International Conference on Harmonization (ICH) Guidance S9, 25 L Linkers, 13 antigen sink, 130 brentuximab vedotin, 16 cantuzumab ravtansine, 131 chemistries, 130 circulation and tissues, cleavable linkers, 17 design effect bystander cells, multidrug resistance cells, 128 dipeptide, 16 disulfide-containing linkers, 117 formats, 129 function of, 117 hydrazone linkers, 14, 15, 118 limitations, 14 maytansinoid conjugates, 129, 130 noncleavable linkers, 17 stability, 13, structures, 118 types acid-cleavable hydrazone linkers, cleavable disulfide linkers, cleavable peptide linkers, non-cleavable linkers, Lorvotuzumab mertansine antibody component of, chemical structure, 275, 276 clinical development of, cytotoxic payload component, 278 linker moiety and fi nal design, mechanism of action, in preclinical models, M Mass spectrometry, Maytansine, 17 Maytansinoids, 16 C3 ester side chain, 103 compounds, 103 cytotoxic activity, 102 disulfide cleavable, 103, 106 disulfide linkage, 102 DM4 disulfide cleavable, 103, 107 hindrance effect, 103 Maytenus ovatus, 102 microtubule dynamics, 104 non-cleavable, MEDI-547 anti-epha2 antibody drug conjugate, 248, 249 dolastatin-10, immunoconjugate target, 246 lead identification, PC3 cells, 248, 249 P-glycoprotein (PGP), 250 Metastatic breast cancer T-DM1 adverse events, cardiotoxicity profile, 196 docetaxel vs. trastuzumab, efficacy, 189 exploratory HER2 testing analyses, hepatic transaminases, 196 hypokalemia, 195 maximum tolerated dose (MTD), 183 pharmacokinetics, 183, 185, phase III studies, TDM4258g, 186 TDM4374g, 186, 187 thrombocytopenia, week dose schedule, 186 Monomethylauristatin E (MMAE) auristatins, 16, 105, 108 brentuximab vedotin, 163

5 373 ovarian cancer cell lines, 228, 229 protease-labile dipeptide linker, 228 valine citrulline linker, 264 Monomethylauristatin F (MMAF) conjugates of, 17, 105, 120, 236 cysteine residue, 105 non-cleavable linker, 127 SGN-75, 17 stable alkyl ketone linker, 228 MUC16 3A5 binding residues, 234 ADCC, aspartate transaminase (AST) over time, 236 CA125, 222, 230, 231 epitope mapping, 225, 226 expression level, immunohistochemistical (IHC) staining, 3A5 antibody, 226, 227 lysosomes, 228, 229 micro-array profile of, 222, 223 MMAE, 228, 229 monomeric binding affinity, 226, 228 MUC16 VC-MMAE vs. MC-MMAF, 232 neutropenia over time, 235 OC125, 222 oregovomab, 224 OVCAR-3 cells, 230 properties, in vivo dose ranging, 232, 233 N Neural cell adhesion molecule (NCAM). See CD56 NHL. See Non-Hodgkin s lymphoma Non-cleavable linkers, Nonclinical development, 25, 26 first-in-human studies, 25, 26 human starting dose, 28 ICH S9, SMD (see Small molecule drugs) Nonclinical Evaluation for Anticancer Pharmaceuticals, 25 Non-Hodgkin s lymphoma (NHL) anti-cd20, 144 CD22 expression, 140 CD70 expression, DCDT2980S, 141 inotuzumab ozogamicin, SAR3419, O Oregovomab, 224 Organ dysfunction studies hepatic impairment, QTc strategy, renal impairment, 69, 70 P Predictive biomarkers anti-apoptotic proteins, 81 assay platforms, Aurora-A kinase overexpression, 80 beta1-tubulin (TUBB), 80 circulating tumor cells isolation, 84 Ki-67 marker, 81 lysosomal activity, 79 microtubule-targeted agents, 80 mir-200c expression, new molecular entities, 83 preclinical efficacy models, 82 prevalence of, 83, 84 resistance phenomenon, target expression and internalization kinetics, TP53 mutations, 80 Prostate-specific membrane antigen (PSMA), 8 7E11, 259 expression in benign and malignant prostate tissues, 257, 258 cytoplasmatic staining, secretory cells, 257 duodenal brush border cells, 257 mrna level vs. real-time PCR, 257 prognostic factors, 257 prostatic intraepithelial neoplasia, 256 proximal renal tubules, 257 immunotoxins A5-PE40 and D7-PE40, melittin-like peptide 101, 265 MLN2704, 265 MMAE, 264 ricin A-chain, saporin, 264 radioimmunoconjugates 64 Cu-labeled mabs, 260 deimmunization, I-labeled mabs, Lu-DOTA-3/F11, 260

6 374 Prostate-specific membrane antigen (PSMA) (cont.) 177 Lu-labeled hu591, 262 ProstaScint imaging, Y-labeled huj591, 262 structure and function, 256 virotherapeutic agents, Protein toxins, 8 10 Q QTc strategy, R Rituxan, 93 S SAR3419 activity, preclinical models, anti-cd19 antibody component, clinical development, conjugation, 153 cytotoxic payload component, 153 linker component, 153 mechanism of action, 154 structure, schematic representation, 152 SGN-35. See Brentuximab vedotin Small molecule drugs (SMD) clinical pharmacology development, 33 clinical starting dose, 27 cytotoxic agent, 25, 27 efficacy and safety concerns, 29 embryofetal toxicity studies, 28 genotoxicity studies, 28 GLP regulations, 26 levels determination, 30 long-term toxicology studies, 28 mass balance study, 33 metabolism of, 30 moiety, nonclinical and clinical toxicities, 26 plasma protein binding, 30 renal/hepatic impairment study, 34 T Therapeutic protein drug interactions (TP-DI), Thrombocytopenia, 195 Trastuzumab emtansine (T-DM1), 17 activation of, bioanalytical strategy, bystander killing activity, catabolism and hepatobiliary clearance, clinical development, 65 cytotoxic potency of, 301 disposition, 63 dose escalation trial assessment, 61 exposure response analyses, 60, half-life of, 64 HER2-dependent tumor localization, 304, In-DTPA-trastuzumab, 305, 307 linear two-compartment model, 61, 63 lysine-smcc-dm1, 304, 306 metabolic fate, metastatic breast cancer (see Metastatic breast cancer) organ dysfunction studies hepatic impairment, QTc strategy, renal impairment, 69, 70 pharmacokinetic sampling schedules, 61, 62 pharmacokinetics profiles, 63 phase II study, population PK model, 61, preclinical studies, 182 steady state levels, 64 structure, structures of, 297, 298 TDM3569g, 61, 63 TP-DI, tumor uptake and catabolism, U Ultraviolet visible spectrophotometry, 50 V VB6-845 clinical experience with exploratory efficacy evaluation, immunogenicity, 362 pharmacokinetics, safety evaluation, 360 study design and dose escalation,

7 preclinical evaluation of animal model selection, 354, 356 immunogenicity in, Cynomolgus monkeys, 358 immunohistochemical staining, 353 in vitro specificity and cytotoxicity, in vivo efficacy, pharmacokinetics in, Cynomolgus monkeys, 357, 358 repeated-dose toxicology, Cynomolgus monkeys, single-dose toxicology, Sprague Dawley rats, 356 ribbon representation of, 351 T cell epitope-depleted form, Vectibix, 93