Approved ADC drugs list and the ongoing trails with hot ADC targets such as HER2, EGFR, TROP2, FRα, CLDN18.2,, c-Met, Nectin-4 and TF, with three targeting HER2 and two targeting CD22.

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A Look into Antibody–drug conjugates
(ADCs) Targets
Antibody-drug conjugates (ADCs) combine the advantages of high targeting of
antibody drugs and high activity of Payload in tumor tissues, providing better
efficacy than traditional antibody-based therapeutic agents and demonstrating
great clinical value.
ADC has become another popular field after the immune checkpoint inhibitors
represented by PD-1/PD-L1, and companies need to speed up the R&D
progress in order to seize the first-mover advantage. Reasonable selection of
targets is crucial if companies want to survive or even stand out.
R&D Status of ADCs
Currently, there are over 100 ADC drugs in various stages of development
worldwide, of which 14 have been approved for marketing, a dozen have
entered clinical phase III, and most are still in clinical phase I and preclinical
stages.
Among the 14 approved ADC drugs, 7 are for the treatment of hematological
tumors and 7 are for the treatment of solid tumors. There are 11 targets
involved, namely CD33, CD30, HER2, TROP2, BCMA, EGFR, CD19, CD22,
CD79b, Nectin-4 and TF, with three targeting HER2 and two targeting CD22.
The overall global market for ADC drugs has exceeded US$5 billion in 2021.
Drugs
(Company)
Trade
Names
Target
antige
ns
Approved
Countries
Approve
d Date
Approved
indications
Gemtuzumab
ozogamicin
(Pfizer)
Mylotarg
®
CD33 FDA/EMA/PMDA
2000/5/1
7;
2017/9/1
newly-diagnos
ed
CD33-positive
AML to include
pediatric
patients 1
month and
older.

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Brentuximab
vedotin
(Seagen)
Adcetris
®
CD30
FDA/EMA/PMDA/N
MPA
2011/8/1
9
R/R CD30
positive HL and
systemic ALCL;
in combination
with
chemotherapy
including the
treatment of
certain types of
PTCL and
previously
untreated stage
III or IV cHL.
Ado-trastuzum
ab emtansine
(Roche)
Kadcyla
®
HER2
FDA/EMA/PMDA/N
MPA
2013/2/2
2
adjuvant
treatment of
patients with
HER2-positive
early breast
cancer who
have residual
invasive
disease after
neoadjuvant
taxane and
trastuzumab-b
ased treatment.
Inotuzumab
ozogamicin
(Pfizer)
Bespons
a®
CD22
FDA/EMA/PMDA/N
MPA
2017/6/2
8
adults with R/R
B-cell
precursor ALL.
Moxetumomab
pasudotox
(AstraZeneca)
Lumoxiti
®
CD22 FDA/EMA
2018/9/1
3
adult patients
with R/R HCL
who have
previously
failed to
receive at least
two systemic
therapies
(including
purine
nucleoside
analogs).

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Polatuzumab
vedotin
(Roche)
Polivy® CD79B FDA/EMA
2019/6/1
0
in combination
with
bendamustine
plus rituximab
for the
treatment of
patients with
R/R DLBCL,
who have
received at
least two prior
therapies.
Enfortumab
vedotin
(Seagen)
Padcev®
Nectin-
4
FDA
2019/12/
18
locally
advanced or
metastatic
urothelial
cancer who
have previously
received
platinum
chemotherapy
and a
PD-L1/PD-1
inhibitor
Fam-trastuzu
mab
deruxtecan
(Daiichi
Sankyo)
Enhertu
®
HER2 FDA/EMA/PMDA
2019/12/
20
adult patients
with
unresectable or
metastatic
HER2-positive
breast cancer
who have
received two or
more prior
anti-HER2
based
regimens in the
metastatic
setting; locally
advanced or
metastatic
HER2-positive
gastric or
gastroesophag
eal junction

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adenocarcinom
a who have
received a prior
trastuzumab-b
ased regimen.
Sacituzumab
govitecan
(Immunomedic
s)
Trodelvy
®
Trop-2 FDA/NMPA
2020/4/2
2
patients with
unresectable
locally
advanced or
metastatic
TNBC who
have received
two or more
prior systemic
therapies, at
least one of
them for
metastatic
disease.

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Belantamab
mafodotin
(GSK)
Blenrep® BCMA FDA/EMA 2020/8/5
adult patients
with R/R MM
who have
received at
least four
treatments,
including
anti-CD38
monoclonal
antibodies,
proteasome
inhibitors and
immunomodula
tors
Cetuximab
sarotalocan
(Rakuten
Medical)
Akalux® EGFR PMDA
2020/9/2
5
unresectable
locally
advanced or
recurrent
HNSCC
Loncastuxima
b tesirine
(ADC
Therapeutics)
Zynlonta
®
CD19 FDA
2021/4/2
3
adult patients
with R/R large
B-cell
lymphoma after
two or more
lines of
systemic
therapy,
including
DLBCL not
otherwise
specified,
DLBCL arising
from low grade
lymphoma and
high-grade
B-cell
lymphoma

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Disitamab
vedotin
(RemeGen)
Aidixi® HER2 NMPA 2021/6/8
patients with
locally
advanced or
metastatic
gastric cancer
(including
gastroesophag
eal junction
adenocarcinom
a) who have
received at
least 2 types of
systemic
chemotherapy
Tisotumab
vedotin
(Genmab/Sea
gen)
Tivdak® TF FDA
2021/9/2
0
adult patients
with recurrent
or metastatic
cervical cancer
with disease
progression on
or after
chemotherapy,
which is the
first and only
approved
TF-directed
ADC therapy
Table 1. FDA Approved ADC Drugs, source: reference 1
Of the the ADC drugs under investigation, the more popular targets include
HER2, EGFR, CLDN18.2, TROP2, c-Met, CD19, PSMA, Muc1, BCMA and
PDL1, most of which are validated mature targets.

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Figure 1. The important target antigens from tumor cells (overexpressed and
driver genes) and tumor microenvironment (vasculature and stroma) are used
for the development of ADC. Source: reference 1
HER2-Directed ADCs
HER2, known as human epidermal growth factor receptor 2, is a receptor
tyrosine kinase on the surface of cell membranes that regulates cell
proliferation and differentiation. Currently, abnormal expression of HER2 is
found in breast cancer, ovarian cancer, gastrointestinal cancer, lung cancer
and non-small cell carcinoma.Tumors with high HER2 expression exhibit
strong metastatic and infiltrative ability, poor sensitivity to chemotherapy, and
are prone to recurrence.
Several HER2 ADC products are currently available, including Kadcyla,
Enhertu and Disitamab vedotin. And a number of next-generation
HER2-targeted ADCs are currently under investigation in clinical trials.
ADC
name
Ab Linker Payload
Ongoing
clinical
trialsa
SYD985 Trastuzumab
Valine-citrulline linker
Seco-DUBA
(DNA-alkyla
ting)
NCT03262
935
NCT04602
117
NCT04235
101
NCT01042
379
(cleavable)

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ZW49 ZW25 Cleavable
N-acyl
sulfonamide
auristatin
NCT03821
233
(microtubule
inhibitor)
PF-06804
103
Trastuzumab-d
erived Ab
Maleimidocaproyl-valine-
citrulline linker
(cleavable)
Aur-063801
01
NCT03284
723
MRG002 Anti-HER2 IgG1 N.A.
Monomethyl
auristatin E
CTR20181
778
NCT04492
488,
NCT04742
153
GQ1001 Anti-HER2 IgG NA NA
NCT04450
732
ARX788
Modified heavy
chain Ala114 of
anti-HER2 mAb
Amberstatin (AS269)
Dolastatin
monomethyl
auristatin F
(microtubule
inhibitor)
NCT03255
070
(non-cleavable)
A166 Trastuzumab
Valine citrulline peptide
(cleavable linker)
Duostatin-5
(microtubule
inhibitor)
NCT03602
079
XMT-152
2
HT-19
(anti-HER2
IgG1)
Cleavable hydrophilic
polymer
AF-HPA
(microtubule
inhibitor)
NCT02952
729
RC48-AD
C
Hertuzumab
(anti-HER2
humanized Ab)
Valine citrulline peptide
(cleavable linker)
Monomethyl
auristatin E
(microtubule
inhibitor)
NCT04329
429
NCT04280
341
NCT04311
034
NCT04714
190
NCT04073
602
NCT04264
936
NCT03556
345
NCT03500
380

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NCT03052
634
BDC-100
1
Trastuzumab Non cleavable linker
TLR7/8
inhibitor
NCT04278
144
FS-1502 Trastuzumab NA
Monomethyl
Auristatin F
NCT03944
499
GQ1001 NA NA NA
NCT04450
732
ALT-P7
Trastuzumab
biobetter HM2
Cysteine-containing
peptide
Monomethyl
auristatin E NCT03281
824
(microtubule
inhibitor)
Table 2. Pharmacological properties of anti-HER2 ADCs undergoing clinical
trials
EGFR-Directed ADCs
Epidermal growth factor receptor (EGFR), also known as HER1/ErbB1, is an
important signaling molecule for normal cell proliferation in humans, and its
overexpression can lead to tumorigenesis. A variety of solid tumor tissues of
epithelial origin, such as non-small cell lung cancer, colorectal cancer,
pancreatic cancer, kidney cancer, and bladder cancer, have high EGFR
expression and this group of patients has a poor prognosis.
The only EGFR ADC drug currently available is Cetuximab sarotalocan (also
known as RM-1929) which was approved by the Pharmaceuticals and Medical
Devices Agency (PMDA) of Japan. It is a novel ADC consisting of an
anti-EGFR chimeric monoclonal antibody, cetuximab, conjugated with
IRDye®700DX, a near-infrared photosensitizing dye. Three ADCs targeting
EGFR are under clinical investigations, including depatuxizumab mafodotin
(ABT-414), MRG003 and M1231. ABT-414 has been so far the most advanced
investigational EGFR-driven ADC that has reached phase III trials.
ADC mAb Payload Linker DAR
Clinical
phase
Company
ABT-414
Anti-EGFR
mAb
(ABT-806)
MMAF
Non-cleavable
mc linker
4 II/III AbbVie
MRG003
Anti-EGFR
mAb
MMAE
Cleavable vc
linker
n/a Ⅱ Miracogen
M1231
Bispecific
antibody that
targets MUC1
and EGFR
Hemiasterlin n/a n/a I
Sutro, EMD
Serono
Table 3. Summary of anti-EGFR ADCs in clinical investigation.

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Trop-2-Directed ADCs
Trophoblast cell surface antigen 2 (TROP-2) promotes tumor cell growth,
proliferation and metastasis mainly by regulating calcium signaling pathway,
cell cycle protein expression and reducing fibronectin adhesion. TROP-2 is
highly expressed in a variety of tumors, such as pancreatic, breast, colon,
bladder, oral squamous and ovarian cancers, and its high expression is closely
associated with shortened survival and poor prognosis of tumor patients.
Currently, Sacituzumab govitecan (Trodelvy) developed by Gilead Science is
the only available TROP 2 inhibitor in the market which is indicated for the
management of triple negative breast cancer and urothelial cancer.
Another important investigational drug, DS-1062 (datopotamab-deruxtecan),
has shown good efficacy in multiline therapy-resistant non-small cell lung
cancer, with at least 40% of patients experiencing 30% or more tumor
shrinkage and nearly 80% of patients having good tumor control.
Figure 2. TROP-2 ADC ongoing trails
Tissue-factor Directed ADCs

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Tissue factor (TF) is encoded by the F3 gene. It belongs to the cytokine
receptor protein superfamily and is expressed in subendothelial tissue and
leukocytes. During an abnormal expression, it is highly expressed in many
solid cancers, including pancreatic, lung, cervical, prostate, bladder, ovarian,
breast, and colon cancer.
The binding between factor VII (FVII) and TF generates an active TF:FVIIa
complex responsible for activating the coagulation extravasation cascade.
Physiologically, this pathway is induced by vascular injury, which leads to the
exposure of normally hidden TF-positive cells to the blood. In contrast, TF is
frequently expressed by tumor cells, including pancreatic, lung, cervical,
prostate, bladder, ovarian, breast, and colon cancer, and has been shown to
promote tumor growth, angiogenesis, metastasis, and thrombosis. Because of
the limited selective expression of TF on normal cells and increased
expression on malignant cells, it is currently being explored as a potential
target for mAbs, small TKIs and ADCs.
Tivdak (Tisotumab vedotin), developed jointly by Seagen and GenMab, is the
world's first TF ADC drug for adult patients with recurrent or metastatic cervical
cancer with disease progression on or after chemotherapy.
Figure 3. Tisotumab vedotin mechanism of action, source: Seagen official
website

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FRα-Directed ADCs
Folate Receptor alpha (FRα) belongs to FRs (composed of four isoforms α, β,
γ and δ) and is the same cysteine-rich glycolipid-anchored protein as the FRβ
isoform. FRα is encoded by the FOLR1 gene and is less expressed in normal
tissues, but overexpressed in most solid tumors such as mesothelioma
(72-100%), TNBC (35-68%), NSCLC (14-74%), ovarian cancer (76-89%), and
endometrial cancer (20-50%).
Figure 4. Cancers overexpressing folate receptor α (FRα) and concordant
expression of FRα in non-malignant tissues, Adapted from Scaranti et al.
2020.28
Compared with the current hot targets such as HER2 and Trop2, the
development of ADC drugs against the FRα target appears to be exceptionally
cool, with only six companies worldwide currently laying out in this track.
IMGN853 (MIRV, Mirvetuximab soravtansine), developed by ImmunoGen,
has entered the Phase III clinical phase and is currently the fastest developing
FRα ADC drug in the world. In addition, positive clinical results have been
achieved with MORAb-202 as well as STRO-002.
c-Met-Directed ADCs
c-mesenchymal-epithelial transition factor (c-MET) is a receptor tyrosine
kinase encoded by the proto-oncogene MET. It is currently the only known

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receptor with high affinity for its naturally occurring ligand, hepatocyte growth
factor (HGF). The c-Met signaling pathway is frequently activated by cancer
cells to promote tumor formation, aggressive growth and metastasis, and it is
aberrantly expressed or mutated in many types of solid tumors such as lung,
gastric, liver, breast, skin and colorectal cancers. At present, no c-Met ADCs
have been approved, and most of them are in early stage of development.
AbbVie's Telisotuzumab vedotin progressed the fastest, with its phase II
clinical results showing significant efficacy in treating patients with
EGFR-negative non-small cell lung cancer (ORR: 35.1%, mDOR: 6.9m), with
an ORR of 53.8% in patients with high c-Met expression and 25.0% in patients
with low expression. However, the ORR among EGFR-positive patients was
only 13.3%. In terms of safety, the incidence of grade 3 or higher
treatment-related adverse events was 53.8%, and three patients reported
possible treatment-related deaths.
Nectin-4-Directed ADCs
Nectin Cell Adhesion Molecule 4 (Nectin-4) is a type I membrane protein
expressed mainly in the placenta and weakly to moderately expressed in
normal human tissues such as skin, bladder, salivary glands, esophagus,
breast and stomach. Nectin-4 is overexpressed in a variety of tumor cells, such
as uroepithelial, breast, pancreatic, triple-negative breast and bladder cancers,
and it activates the PI3K/Akt pathway to promote tumor cell proliferation and
invasion.
Padcev is a first-in-class ADC drug that targets Nectin-4 by conjugating an
anti-Nectin-4 monoclonal antibody with the microtubule-disrupting agent
MMAE (monomethyl auristatin E).
Claudin18.2-Directed ADCs
The claudin18.2 (CLDN18.2) protein belongs to a family of Claudin integrin
membrane proteins found in the tight junctions of the epithelium and
endothelium. Claudin18.2 is normally buried in the gastric mucosa and cannot
be bound by antibodies in normal tissues. In contrast, the development of
malignant tumors leads to disruption of tight junctions, exposing the
Claudin18.2 epitope on the surface of tumor cells as a specific target.
Claudin18.2 is highly expressed in gastric cancer and is also expressed in
pancreatic, esophageal and lung cancers.
Among the Cladin18.2-targeting ADC drugs currently in development, the one
that is progressing faster is Zolbetuximab. Zolbetuximab has been shown to be
highly selective for CLDN18.2 both in vivo and in vitro, binds to cancer-specific
targets that are predominantly expressed in tumor cells and shows little or no
binding in healthy tissues.
Huateng Pharma is dedicated to being your most reliable partner to provide
chemical synthesis and high-quality PEG linkers for ADC drugs. We are

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committed to promoting the progress of your ADC discovery and development
projects.
Two of the latest ADCs to be approved, Trodelvy and Zynlonta, were
developed with PEG moiety as part of their linker technology to improve
solubility and stability in vivo.
Zynlonta, an FDA-approved drug targeting CD19, is used to treat relapsed or
refractory diffuse large B-cell lymphoma (r/r DLBCL), including patients treated
with stem cell transplantation and CAR-T cell therapy.
PEG linker for Zynlonta
Trodelvy® (sacituzumabgovitecan-hziy) is used for the treatment of adult
patients with unresectable locally advanced or metastatic triple-negative
breast cancer (mTNBC) who have received at least two prior systemic
therapies or at least one of them for metastatic disease.
Sacituzumab-govitecan (IMMU- 132) is coupled to SN-38 via a cleavable
maleimide linker with a short PEGylated unit.
PEG linker for Trodelvy
References:
1. Fu, Z., Li, S., Han, S. et al. Antibody drug conjugate: the “biological missile”
for targeted cancer therapy. Sig Transduct Target Ther 7, 93
(2022). https://doi.org/10.1038/s41392-022-00947-7

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2. Ferraro, E., Drago, J.Z. & Modi, S. Implementing antibody-drug conjugates
(ADCs) in HER2-positive breast cancer: state of the art and future
directions. Breast Cancer Res 23, 84
(2021). https://doi.org/10.1186/s13058-021-01459-y
3. Yu J, Fang T, Yun C, Liu X, Cai X. Antibody-Drug Conjugates Targeting the
Human Epidermal Growth Factor Receptor Family in Cancers. Front Mol
Biosci. 2022 Feb 28;9:847835. doi: 10.3389/fmolb.2022.847835. PMID:
35295841; PMCID: PMC8919033.
4. Cao, W., Xing, H., Li, Y. et al. Claudin18.2 is a novel molecular biomarker
for tumor-targeted immunotherapy. Biomark Res 10, 38
(2022). https://doi.org/10.1186/s40364-022-00385-1
5. Scaranti, M., Cojocaru, E., Banerjee, S. et al. Exploiting the folate receptor α
in oncology. Nat Rev Clin Oncol 17, 349–359
(2020). https://doi.org/10.1038/s41571-020-0339-5
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