This document summarizes approved and investigational HER2-targeted antibody-drug conjugates (ADCs). Currently, three HER2 ADCs are approved: T-DM1, T-DXd, and RC48. T-DM1 and T-DXd are both comprised of the antibody trastuzumab linked to cytotoxic payloads (DM1 for T-DM1 and DXd for T-DXd). RC48 uses a different HER2-targeting antibody linked to MMAE. Many other HER2 ADCs are in clinical trials, including SYD985 which recently had its BLA accepted by the FDA. While some HER2 ADCs have been approved or shown promise, others like TAA013

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Summary of Approved HER2 ADCs on The
Market & in Clinical Trials
Antibody-drug conjugates (ADCs) are emerging anti-cancer treatment agents that
combine the strong cytotoxicity of small molecule drugs with the specificity of monoclonal
antibodies (mAb). Studies have shown that human epidermal growth factor receptor-2
(HER2) is overexpressed in many tumors and is one of the most common target antigens
for ADCs.
Introduction of HER2
Human epidermal growth factor receptor-2 (HER2) is a transmembrane receptor for
tyrosine kinases and a member of the epidermal growth factor receptor (EGFR) family,
which also includes HER1, HER3 and HER4, each of which includes an extracellular
domain, lipophilic transmembrane region, intracellular domain containing tyrosine kinase,
and a carboxy-terminal region. All of these four members are essential for regulating cell
proliferation and differentiation through ligand-dependent active forms or independent
homodimers or heterodimers.
However, unlike the other three members, the extracellular domain of HER2 is the only
one that dimerizes with any of the other members in the activated state without binding
ligands and then triggers signaling pathways that regulate cell proliferation and survival,
including the PI3K/AKT, MAPK and JAK/STAT pathways, etc. (Figure 1).

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Figure 1. Overview of the HER2 signaling pathway. Source: Reference [1]
Currently, there is increasing evidence that HER2 is overexpressed in various cancers,
such as breast, gastric, lung, and ovarian cancers. In particular, up to 15-30% of breast
cancer patients carry HER2 gene amplification and overexpression. Therefore,
HER2 is considered a valuable prognostic factor for breast cancer and an effective
therapeutic target for the treatment of various HER2-positive cancers.
Approved HER2 ADCs
Currently, three HER2 ADC drugs are approved worldwide, T-DM1 (Kadcyla,
Trastuzumab emtansine), T-DXd (DS-8201, Enhertu, Trastuzumab deruxtecan）
and RC48
(Disitamab vedotin).
Name Antibody Payload DAR Linkage Indication Phase
Fam-trastuzumab
deruxtecan-nxki
Trastuzumab
(IgG1)
DM1 (Maytansine) 3.5 Lysine-SMCC
Metastatic
breast
cancer
Approved
Ado-trastuzumab
emtansine
Trastuzumab
(IgG1)
DXd
(Topoisomerase I
inhibitor)
8.0 Cysteine-maleimide
Metastatic
breast
cancer
Approved

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Disitamab
vedotin
Disitamab
(IgG1)
MMAE (Auristatin) 4.0 Cysteine-maleimide
Metastatic
urothelial
cancer
Phase
III/Approved
in China
Table 1. List of Approved ADCs, source: references [3]
T-DM1 (Kadcyla, Trastuzumab emtansine)
T-DM1, developed by Roche, was the first anti-HER2 ADC to receive FDA approval. It
consists of trastuzumab conjugated to the maytansine derivative DM1 via a thioether
linker. DM1 effectively inhibits microtubulin polymerization and blocks mitosis, which leads
to apoptosis.
Figure 2. Structure of Kadcyla. Source: https://doi.org/10.3390/ph13090245
In 2013, T-DM1 was approved by the FDA for the treatment of advanced HER2+ breast
cancer.
In 2019, T-DM1 was also approved for adjuvant (after surgery) treatment of people with
HER2-positive early breast cancer (EBC) who have residual invasive disease after
neoadjuvant (before surgery) taxane and Herceptin® (trastuzumab)-based treatment.
T-DXd (DS-8201, Enhertu, Trastuzumab deruxtecan）

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T-DXd was the second anti-HER2 ADC to receive FDA approval. DS-8201a has a
drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Meanwhile,
T-DXd uses DXd, a potent topoisomerase I inhibitor, as a carrier drug, which has
approximately 1000 times more antitumor activity than conventional chemotherapy drugs
and can effectively avoid cross-resistance. In addition, DXd has better cell membrane
permeability and can penetrate cell membranes into adjacent tumor cells to exert
potent bystander effects.
Figure 3. DS-8201 Structure, source: doi:10.1248/cpb.c18-00744
In 2019, T-DXd was approved by FDA for unresectable or metastatic HER2-positive
breast cancer following two or more prior anti-HER2 based regimens.
After that, T-DXd was successively approved for the treatment of unresectable or
metastatic non-small cell lung cancer (NSCLC) and HER2-positive gastric or
gastroesophageal junction adenocarcinoma.
At the 2022 ASCO Annual Meeting, the Phase 3 clinical results of T-DXd for HER2-low
metastatic breast cancer were announced, which received a standing ovation. According
to the study, T-DXd reduced the risk of disease progression or death by a whopping 50
percent, compared with conventional chemotherapy, in HER2-low metastatic breast
cancer, which opened a new era of breast cancer treatment. In August 2022, FDA

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approved T-DXd for the treatment of adult patients with unresectable or metastatic
HER2-low breast cancer.
In addition, DS-8201 is also in clinical trials for pan-cancer types, including colorectal
cancer, uterine cancer, biliary tract tumors, and pancreatic cancer, etc.
RC48 (Disitamab vedotin)
RC48 (Disitamab vedotin), developed by RemeGen, is an innovative HER2 ADC
comprising a novel HER2-directed monoclonal antibody, disitamab, conjugated to
monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. The antibody
disitamab targets different epitopes of the HER2 receptor and has a better molecular
affinity for HER2 targeting compared to trastuzumab. The mc-vc linker is stable and can
only be cleaved by cathepsin when RC48 is cytosolicized into the lysosome, thus
releasing a payload to kill tumor cells. The toxin MMAE is a synthetic derivative with anti
mitogenic effects.
Figure 4. Structure of Disitamab Vedotin, source: doi: 10.1080/10717544.2022.2069883
In 2021, RC48 received conditional marketing approval in China for the treatment of
patients with HER2-overexpressing locally advanced or metastatic gastric cancer
(including gastroesophageal junction adenocarcinoma) who have received at least two
systemic chemotherapy regimens.
HER2 ADCs Under Investigation
There are many HER2 ADCs in clinical trials for cancer treatment.

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Name Antibody Payload DAR Linkage Indication Phase
SYD985
Trastuzumab
(IgG1)
DUBA (Duocarmycin) 2.8 Cysteine-maleimide
Metastatic breast
cancer
FDA accepted
BLA 1/Phase III
ZRC-3256
Trastuzumab
(IgG1)
DM1 (Maytansine) - Lysine-SMCC
Metastatic breast
cancer
Phase III
MRG002 IgG1 MMAE (Auristatin) - Unknown
Advanced solid
tumors
Phase II
ARX788
Transtuzumab
(IgG1)
MMAF(Auristatin) 1.9 pAF-hydroxylamine-PEG4
Metastatic breast
cancer/gastric
cancer
Phase II/III
BDC-1001
Trastuzumab
(IgG1)
TLR7/8 agonist - Unknown
Metastatic breast
cancer/gastric
cancer
Phase I/II
A166
Trastuzumab
(IgG1)
MMAF (Auristatin) 2 Lysine site-specific
Metastatic breast
cancer
Phase I/II
FS-1502
Trastuzumab
(IgG1)
MMAF (Auristatin) 2.0 Cysteine-maleimide Breast cancer Phase I
SHR-A1201
Trastuzumab
(IgG1)
DM1 (Maytansine) - Lysine SMCC
Metastatic breast
cancer
Phase I/II
DP303c
Trastuzumab
(IgG1)
DP104n 2.0 Unknown Gastric cancer Phase II
BI-CON-02
Trastuzumab
(IgG1)
Unknown - Unknown
Metastatic breast
cancer
Phase I
ALT-P7
Trastuzumab
biobetter HM2
(IgG1)
MMAE (Auristatin) 2.0 Cysteine-maleimide
Metastatic breast
cancer
Phase I
DX126-262
DX-CHO9
(IgG1)
Tubulysin - Cysteine-maleimide
Breast/gastric
cancer
Phase I
ZW49 IgG1 Auristatin - Cysteine-MC
Metastatic
cancers
Phase I
HS630
Trastuzumab
(IgG1)
DM1 (Maytansine) - Unknown Breast cancer Phase I
B003
Trastuzumab
(IgG1)
DM1 (Maytansine) - Lysine-SMCC
Metastatic breast
cancer
Phase I

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SBT6050 IgG1 TLR8 agonist - Unknown
Advanced solid
tumors
Phase I/II
SHR-A1811 Unknown Unknown - Unknown
Advanced solid
tumors
Phase I/II
MT-5111 Unknown SLTA - Unknown
Advanced solid
tumors
Phase I
GQ1001 Unknown DM1 (Maytansine) 2.0 Unknown
Advanced solid
tumors
Phase I
Table 2. List of HER2 ADCs in Clinical Trails, source: reference [3]
SYD985 (Trastuzumab duocarmazine)
SYD985 is an ADC that targets HER2 and consists of the monoclonal antibody
trastuzumab and a cleavable linker known as
valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). The
antibody of SYD985 is able to bind to HER2 targets on the surface of cancer cells,
resulting in ADC internalization by the cells. Following hydrolytic cleavage of the linker, the
inactivated cytotoxin is activated, which induces DNA damage and ultimately tumor cell
death. In addition, uptake of the activated payload by neighboring tumor cells with lower
HER2 expression may improve the efficacy potential, the so-called bystander effect.
In July 2022, The FDA accepted a Biologics License Application (BLA) for SYD985 in
patients with HER2-positive unresectable locally advanced or metastatic breast cancer
(MBC) with the Prescription Drug User Fee Act (PDUFA) action date of May 12, 2023.
Meanwhile, on July 18, 2022, the EMA validated the marketing authorization application
(MAA) for SYD985 for the treatment of patients with HER2-positive unresectable, locally
advanced or metastatic breast cancer.
Both applications are progressing based on the results of the pivotal Phase 3 TULIP trial.
Per central review, trastuzumab duocarmazine achieved a median PFS of 7.0 months (95%
CI, 5.4-7.2) compared with 4.9 months (95% CI, 4.0-5.5) for physician’s choice of therapy
(HR, 0.64; 95% CI, 0.49-0.84; P = .002). The investigator-assessed median PFS was 6.9
months (95% CI, 6.0-7.2) for trastuzumab duocarmazine vs 4.6 months (95% CI, 4.0-5.6)
for physician’s choice of therapy (HR, 0.60; 95% CI, 0.47-0.77; P < .001).
ARX788

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ARX788 is a homogeneous and highly stable ADC with a similar mechanism of action to
T-DM1. It is comprised of an anti-HER2 mAb Herceptin® (trastuzumab) site-specifically
conjugated a potent tubulin inhibitor payload AS269 is a non-natural amino acid
incorporated into the antibody.
Results from a phase I trial of the safety, tolerability, and pharmacokinetics of ARX788
monotherapy in Chinese patients with advanced HER2 breast cancer showed a favorable
safety profile and a tumor treatment response in the target dose group following efficacy
evaluation.
On March 2023, positive clinical data were obtained from a randomized Phase 3 clinical
trial (ACE-Breast-02) of ARX788,. The trial enrolled 441 patients with HER2-positive
breast cancer who were refractory to prior treatment with paclitaxel and trastuzumab.
Eligible patients were randomized 1:1 to receive either the new experimental drug
ARX788 or the control drug lapatinib in combination with capecitabine. Results showed
that ARX788 significantly improved progression-free survival (PFS) in patients with
HER2-positive locally advanced or metastatic breast cancer.
Last December, Ambrx announced the data of ACE-Breast-03, a phase II clinical trial of
ARX788, which showed that among seven patients with advanced breast cancer with
evaluable efficacy, five achieved PR and tumor shrinkage of more than 60% in all cases. It
is worth mentioning that all seven patients had previously received T-DM1 treatment.
In this published Phase II/III clinical analysis, preliminary clinical data showed that
ARX788 was approximately 25% effective in patients who were resistant to DS-8201 for
12 months. In this regard, Ambrx's CEO believes that ARX788 may become the first
choice for DS-8201-resistant patients.
MRG002
MRG-002 is under clinical development by Shanghai Miracogen and currently in Phase II
for HER2 positive breast cancer. It is composed of a humanized anti-HER2 mAb
trastuzumab conjugated to MMAE via a cleavable vc linker.

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The high-affinity of trastuzumab specifically binds to HER2 antigen on the surface of
tumor cells, internalizes and releases the cytotoxic payload MMAE, which effectively
inhibits microtubule protein polymerization, thereby interfering with mitosis and exerts
tumor cell killing effects. The innovatively modified trastuzumab has a selectively high
level of fucosylation in the Fc region, resulting in a reduced Fc binding to CD16a
expressed on effector immune cells, minimizing potential killing of CD16a expressing
immune cells by MRG002 and therefore reducing potential adverse effects on patients.
In the multicenter phase II study of MRG002 for advanced HER2 low-expressing breast
cancer, results showed that of 18 patients with HER2 low-expressing breast cancer who
had previously failed standard first-line therapy, 5 had achieved PR on first efficacy
assessment. In a clinical study of patients with HER2-positive breast cancer after multiple
lines of therapy, an ORR of 55% was achieved in 55 patients with HER2-positive breast
cancer who had received a median of 5 lines of prior therapy, with a common adverse
effect of decreased neutrophils.
HER2 ADCs Failed in Clinic Settings
Though many HER2 ADCs approved, there are also many HER2 ADCs failed in clinical
settings.
Name Antibody Payload DAR Linkage Indication
TAA013
Trastuzumab
(IgG1)
DM1
(Maytansine)
3.5 Lysine-SMCC Metastatic breast cancer
XMT-1522 HT-19
Auristatin
F-HPA
(Auristatin)
12
Cysteine-fleximer
polymer
Breast/gallbladder/gastric
cancer
ADCT-502 Trastuzumab
SG3199
(PBD)
1.7
Cysteine
site-specific
Breast/bladder/gastric
cancer
MEDI4276 (Bispecific)
Trastuzumab&
39S
AZ13599185
(Tubulysin)
4
Cysteine
site-specific
Breast/gastric cancer
NJH395 Unknown
TLR7
agonist
Unknown Unknown Solid tumors
MM-302 F5 Doxorubicin Unknown Unknown Advanced solid tumors

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BAT8001 BAT0606 Maytansinoid 3.5 Cysteine-3AA Advanced solid tumors
DHES0815A Unknown PBD Unknown Unknown Breast cancer
Table 3. List of anti-Her2 ADCs failed in clinic settings, source: reference [3]
Conclusion
The approved HER2-targeted ADCs have significantly benefited cancer patients, and the
ones being currently investigated may provide even further benefit.
Biopharma PEG provides GMP standard PEG derivatives and bulk orders via custom
synthesis, offering the opportunity to match customers' special quality requirements. ADC
linkers with molecular weights, branching, and functional groups not listed in our online
catalog may be available by custom synthesis.
References:
[1] Najjar MK, Manore SG, Regua AT, Lo HW. Antibody-Drug Conjugates for the
Treatment of HER2-Positive Breast Cancer. Genes (Basel). 2022 Nov 8;13(11):2065. doi:
10.3390/genes13112065. PMID: 36360302; PMCID: PMC9691220.
[2] Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers:
Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748. doi:
10.1155/2014/852748. Epub 2014 Sep 7. PMID: 25276427; PMCID: PMC4170925.
[3] Xinling Zhang, Andrew C Huang, Fahai Chen, Hu Chen, Lele Li, Nana Kong, Wenting
Luo, Jianmin Fang, Novel development strategies and challenges for anti-HER2
antibody-drug conjugates, Antibody Therapeutics, Volume 5, Issue 1, January 2022,
Pages 18–29, https://doi.org/10.1093/abt/tbac001
[4] 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

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