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TitleBiotherapeutics: Recent Developments using Chemical and Molecular Biology
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Document Text Contents
Page 1

Biotherapeutics
Recent Developments using Chemical and Molecular Biology

Page 2

RSC Drug Discovery Series

Editor-in-Chief:
Professor David Thurston, King’s College, London, UK

Series Editors:
Dr David Fox, Vulpine Science and Learning, UK
Professor Ana Martinez, Medicinal Chemistry Institute-CSIC, Madrid, Spain
Professor David Rotella, Montclair State University, USA

Advisor to the Board:
Professor Robin Ganellin, University College London, UK

Titles in the Series:
1: Metabolism, Pharmacokinetics and

Toxicity of Functional Groups
2: Emerging Drugs and Targets for

Alzheimer’s Disease; Volume 1
3: Emerging Drugs and Targets for

Alzheimer’s Disease; Volume 2
4: Accounts in Drug Discovery
5: New Frontiers in Chemical Biology
6: Animal Models for

Neurodegenerative Disease
7: Neurodegeneration
8: G Protein-Coupled Receptors
9: Pharmaceutical Process

Development
10: Extracellular and Intracellular

Signaling
11: New Synthetic Technologies in

Medicinal Chemistry
12: New Horizons in Predictive

Toxicology
13: Drug Design Strategies:

Quantitative Approaches
14: Neglected Diseases and Drug

Discovery
15: Biomedical Imaging
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
18: Proteinases as Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies:

Computational Techniques
and Applications

21: Designing Multi-Target Drugs
22: Nanostructured Biomaterials for

Overcoming Biological Barriers
23: Physico-Chemical and

Computational Approaches to
Drug Discovery

24: Biomarkers for Traumatic Brain
Injury

25: Drug Discovery from Natural
Products

26: Anti-Inflammatory Drug Discovery
27: New Therapeutic Strategies for

Type 2 Diabetes: Small Molecules
28: Drug Discovery for Psychiatric

Disorders
29: Organic Chemistry of Drug

Degradation
30: Computational Approaches to

Nuclear Receptors
31: Traditional Chinese Medicine
32: Successful Strategies for the

Discovery of Antiviral Drugs
33: Comprehensive Biomarker

Discovery and Validation
for Clinical Application

34: Emerging Drugs and Targets for
Parkinson’s Disease

35: Pain Therapeutics; Current and
Future Treatment Paradigms

36: Biotherapeutics: Recent
Developments using Chemical and
Molecular Biology

How to obtain future titles on publication:
A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.

For further information please contact:
Book Sales Department, Royal Society of Chemistry, Thomas Graham House,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: +44 (0)1223 420066, Fax: +44 (0)1223 420247,
Email: [email protected]
Visit our website at www.rsc.org/books

http://dx.doi.org/10.1039/9781849737159-fp001

Page 165

bAla-(D)Asp (8) and Pro-(D)Lys (9) resulted in ADCs that were essentially
inactive against the antigen containing cell lines and had no in vivo efficacy in a
tumor xenograft model. However, changing the peptide sequence to NorVal-
(D)Asp (10) or Asn-(D)Lys (11) resulted in ADCs that were exceptionally
potent both in vitro and in vivo. The latter sequence was incorporated into an
ADC that showed superior efficacy and safety to mcValCitPABC-MMAF (12)
in mouse models.

25
The development of these peptide-based linkers has been

largely driven by cell-based cytotoxicity assays and therefore the exact
mechanism of cleavage remains somewhat unclear. In fact, the above report
unfortunately does not present any conclusive evidence demonstrating that the
auristatin payload is released via proteolytic degradation. An additional
complication for the design of peptide-based cleavable linkers is the putative
role of enzymes other than cathepsin B in payload release, such as the work
described by Jeffrey showing that particular peptide-linked conjugates showed
excellent cellular potency but were not cathepsin B substrates.

24

Concurrent with the development of the peptide-based cleavable linkers, a
new class of disulfide-based cleavable linkers (Figure 6.4, 14 and 15) utilizing a
maytansinoid payload was emerging, primarily driven by the research efforts of
ImmunoGen. The early maytansinoid disulfide linkers were structurally related
to the first generation calicheamicin linkers, which incorporated a sterically
hindered disulfide that is cleaved intracellularly thereby releasing the thiol-
containing payload.

26,27
The release mechanism for these linkers relies on the

high intracellular glutathione concentration, frequently estimated in the
millimolar range, compared to the low micromolar levels of glutathione
typically found in plasma. Interestingly, this release mechanism seems to be
quite robust in spite of a report showing that the endocytotic pathway has a
strong oxidizing potential.

28
A recent report demonstrated that SPP-DM1 (14)

ADCs showed excellent cytotoxicity on a wide variety of antibody backbones,
even in cases such as anti-CD21 where the antigen is known to be poorly
internalized.

29
Unfortunately, this linker has also been shown to slowly release

its payload prematurely due to the presence of glutathione in plasma.
30,31

This
problem was partially ameliorated by the use of a modified linker, SPDB-DM4
(15), which incorporates additional steric hindrance near the disulfide. In
mouse xenograft models this linker provides a significant boost in efficacy over
SPP-DM1 that is attributed to improved in vivo stability of both the conjugate
and the resulting free payload.

27,32,33
Further studies have shown that

increasing the steric bulk around the maytansine-disulfide is a double-edged
sword. Increases in bulk have consistently showed improved stability and
exposure, but sometimes show decreased efficacy that is attributed to impaired
reductive release of payload.

33
As such, optimization of this linker requires

balancing high-stability and efficient release. A more thorough discussion of the
cleavage mechanism will be presented in sections 6.2.1 and 6.2.2.

Recent study of this linker has focused on noncleavable (thioether) variants
(vide infra) and on hydrophilic analogs. Zhao and colleagues have recently
reported the incorporation of hydrophilic moieties into the SPDB chain,
resulting in linkers such as 16 and 17. Interestingly, they found that the

Recent Advances in Antibody–Drug Conjugates 151

http://dx.doi.org/10.1039/9781849737159-00145

Page 166

sulfo-linker 17 has nearly equivalent potency against MDR (multi-drug resistant)
and non-MDR cell lines. In contrast, SPBD-DM4 (15) and PEG4-SPDB-DM4
(16) were observed to be 10–50 times less potent against the MDR cell lines.
Moreover, 17 was shown to be far more effective in a mouse xenograft study
against multidrug resistant COLO205-MDR tumors. The authors postulate
that the metabolites of 2-sulfo-SPDB-DM4 ADCs may be poor substrates for
MDR transporters such as P-glycoprotein (Pgp).

34
This hypothesis is based on

the frequently noted preference of Pgp for hydrophobic substrates. Inter-
estingly, it has been shown that metabolism of SPP-DM1 ADCs results initially
in a lysine-linked maytansinoid with subsequent slow cleavage of the
disulfide linkage (see section 6.4.1). In the case of 2-sulfo-SPDB-DM4, the

O
S

S
H
N

O
15, SPDB-DM4

O
O

O

N

O

N
H

OH

O

O

Cl
O

H

H

N
O

O

S
S

N
H

14
SPP-DM1

O

O
S

S
O

16, PEG4-SPDB-DM4

H
N

O4

O
S

S
H
N

O
17, 2-Sulfo-SPDB-DM4



H
N

O
18, SMCC-DM1

N

O

O

N
H

O

19, Peg4Mal-DM1

H
N

O4
N

OO

O

N
H
N

OSO3

SO3

O

O

S

20, 3-sulfoMal-DM1

S

S

O

O

O

S

21, BMPEO-DM1

N

O

O
O

N
3

O

O

S
O

Figure 6.4 Maytansine linkers.

152 Chapter 6

http://dx.doi.org/10.1039/9781849737159-00145

Page 329

Targeted Secretion Inhibitors (TSI),
234–9

TATA linkers, 254
tautomerization, 163
TBMB (1,3,5-tris(bromomethyl)-

benzene), 251, 252, 254
Template Assembled Synthetic

Protein (TASP), 276, 277
terminal deoxynucleotidyl transferase

(TdT), 117
tetanus

bacterial toxins non-cytotoxic,
234

epitope mimics, 271
glycoconjugate vaccines, 86
nicotine vaccine trials, 49
synthetic vaccines, 136
therapeutic antibody

generation, 108, 110
tetanus neurotoxin (TeNT),

225, 234
tetanus toxin (TT), 49, 52, 73, 76, 79,

82, 84, 86–7, 197
tetrahydroisoquinolines, 12
therapeutic antibody generation

cytokines, 109
deoxyribonucleic acid (DNA),

109–10
hydrophobicity, 113
IgG, 108, 111–3
influenza, 112
messenger RNA (mRNA), 110
monoclonal antibodies (mAbs),

106–9
murine, 106–8
polymerase chain reaction

(PCR), 109–10
tetanus, 108, 110
tumors, 108

therapeutic index, 145, 154
Theratope, 135
thermal stability, 122
thermodynamic recognition, 188
thiazolidinediones (TZDs), 8–9
thioester, 138, 141
thioester-mediated native ligation,

141

thioether, 76, 151, 153, 156, 165–7,
273

thiol-maleimide, 15, 275
thiomab-drug-conjugates (TDCs),

158, 160
thiomabs, 158
thrombin binders, 244, 288
thrombomodulin, 114
thymus, 20, 72, 80, 84–5
tick-born encephalitis virus (TBEV),

184, 194
toll-like receptors (TLRs), 1–6, 8, 70,

87, 109, 201
toxigenesis, 224
transactivation response (TAR), 184,

187
transamination reaction, 163
transcription factor, 8, 185
transcriptional gene activation

(TGA), 204–5
transcriptional gene silencing (TGS),

204–5
transcriptome, 203
transcutaneous, 55
transdermal nicotine patches, 38
transglutaminase 2 (TG2), 21–2, 164
transient systems, 114–5
transmembrane domains, 114
transmembrane sequence, 121
transsphenoidal resection, 240
trastuzumab, 107, 153–4, 160, 162,

164, 167
triazacylcophane (TAC), 118, 276,

277

tripartite antigen, 87
tris(carboxyethyl)phosphine (TCEP),

158, 159, 252
trisaccharide, 16, 79, 89
troglitazone, 8
Trojan horse, 146
Trypanosoma cruzi, 18, 70
trypsin-like serine proteases, 255, 257
tryptophan, 39
tuberculosis, 40
tumor necrosis factor, 138
tumor-associated carbohydrate

antigens (TACAs), 72, 86–7

315Subject Index

http://dx.doi.org/10.1039/9781849737159-00298

Page 330

tumors
ADC linker technology, 151–2
ADC metabolism, 165–9
ADC site specific, 157, 160, 162
antibodies as therapeutic agents,

106
bicyclic peptides, 256–7
carbohydrate vaccine

developments, 86–8
cell-cell communication, 12
pattern recognition receptors

(PRRs), 5, 8
therapeutic antibody

generation, 108
tymidine, 246
tyrosine, 9, 20, 73, 114, 163–4, 247

nitrotyrosine, 20
sulfotyrosine, 20

ultracentrifugation, 74
ultrafiltration, 74
undruggable genes, 178
University of California at Santa Cruz

(UCSC), 181
University of Connecticut, 51–2, 54
untranslated region (UTR), 180–1,

202, 203, 206–7
uracil DNA glycosylase (UNG), 117
urea, 44–5, 287
Urinary Incontinence, 238
urine, nicotine, 41
urokinase-type plasminogen activator

(uPA), 255–7
uronic acids, 75
uterotonic activity, 287

V-region sequences, 110, 117–9, 121
Vaccinia, 114
vanillotoxins, 287
varenicline, 39, 58
vascular endothelial growth factor

(VEGF), 16, 244, 247–8, 249, 288
VDJ genes, 117
vector tropism, 208
ventral tegmental area, 39
versutoxin, 286

vesicular stomatitis virus (VSV), 184,
194

Vibrio cholera
see cholera

vicinal hydroxyl groups, 76
Violaceae, 287
violet, 287
viral delivery systems, 114
viral miRNA (vmiRNA), 179, 182–4,

186, 194–5, 208
viral protease inhibitors, 58
virosomes, 87
virus-like particles (VLP), 48, 49,

50, 69
vitronectin, 245
VJ genes, 117
voltammetry, 48–9

Watson-Crick base pairing, 198, 201
West Africa, 287
West Indies, 287
West Nile Virus, 183
wheat germ, 235
whole cell vaccines, 69
wild-type phage, 243, 252, 254
willow bark, 141
willpower, nicotine abstinence, 38, 57
Wistar rats, 48
World Health Organization (WHO),

36, 76
wound healing, 12, 40

X-ray structures, 18, 231, 248, 250,
257, 267, 268–9

xenograft, 151–2, 256
XEOMIN (incobotulinumtoxin A),

230
Xgeva, 107

yeast, 110, 112–4, 243, 288
see also Candida sp.

yeast library, 113

Ziconotide, 286
Zwitterionic Polysaccharides (ZPS),

80, 84, 88

316 Subject Index

http://dx.doi.org/10.1039/9781849737159-00298

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