Antibody drug conjugates (ADCs) are undoubtedly one of the hottest research areas in recent years. To date, there are 15 approved ADCs in the world, of which 13 have been approved by the FDA, one in China (Disitamab Vedotin) and one in Japan (Akalux).

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Summary of ADCs in Clinical Phase 3
Antibody drug conjugates (ADCs) are undoubtedly one of the hottest research areas in recent years. To
date, there are 15 approved ADCs in the world, of which 13 have been approved by the FDA, one in
China (Disitamab Vedotin) and one in Japan (Akalux).
Figure 1. FDA Approved ADCs [1]
Global sales of marketed ADCs exceeded $7 billion in 2022, and have already exceeded $5 billion in the
first half of 2023, with the full year expected to surpass $10 billion.
Table. Sales of Approved ADCs from 2020 ~ 2023H1
In the first half of 2023, two ADC drugs reached $1 billion in sales, Kadcyla and Enhertu. Based on
Enhertu's growth rate over the last two years (3,450% year-on-year in 2021 and 153.52% year-on-year in
2022), Enhertu is expected to surpass Kadcyla in sales this year.

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Besides approved ADCs, as of January 2023, close to 300 ADC drugs have entered the clinic, of which
92 have been discontinued due to toxicity or lack of efficacy, and 164 are in clinical drug development. As
for the drugs in clinical development, 93 are in clinical phase I, 38 are in clinical phase I/II, 17 are in
clinical phase II, and 15 are already in clinical phase II/III or III. [1]
Antigens targeted by clinically tested ADCs
The choice of the target antigen and selection of the monoclonal antibody are important parameters in
determining the efficacy, therapeutic window, and toxicity profile of ADCs. Target antigens should be
highly expressed in tumors, but low or even not in normal tissues, or at least limited to a given tissue type.
Currently, popular targets include CD family (CD33, CD30, CD22, CD79β, CD19), HER2, Nectin-4,
TROP2, BCMA, EGFR, etc.
Figure 2. Antigens targeted by clinically tested ADCs [1]
Linkers utilized by clinically tested ADCs
Linker design plays a critical role in modulating ADC stability in the systemic circulation and payload
release efficiency in the tumors, which thus affects ADC pharmacokinetic (PK), efficacy and toxicity
profiles.
Broadly speaking, linkers can be divided into two categories: cleavable or non-cleavable linkers. Of the
clinical ADCs, 54% use cleavable linkers, which represent the most utilized linker class. [1]
Cleavable linkers depend on physiological conditions in the cell to cleave the linker and can be further
subdivided into acid sensitive, protease sensitive or glutathione sensitive. Non-cleavable linkers form
irreducible bonds with amino acid residues of the mAb, and therefore should be more stable in the

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bloodstream, have longer half-lives, and lower off-target toxicity. Non-cleavable linkers require ADC
cleavage by the lysosome to release the payload.
Figure 3. Linkers utilized by clinically tested ADCs [1]
Payloads utilized by clinically tested ADCs
The payloads utilized in ADCs are highly potent cytotoxic drugs, exerting their effects on critical cellular
processes required for survival. Payloads fall into four major classes: 1) microtubule
inhibitors (maytansine derivatives (DM1/DM4) or auristatins (MMAE/MMAF)), 2) DNA-damaging
agents (SN-38 or DXd, 3) topoisomerase I inhibitors, and 4) targeted small molecules (SM).
Figure 4. Payloads utilized by clinically tested ADCs [1]

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ADCs In Clinical Phase 3
Below, a selection of ADCs in clinical phase 3 are listed.
Name Company Target Indications Status
Trastuzumab
duocarmazine
(SYD985)
Byondis HER2 HER2-positive breast cancer
FDA
declined
Patritumab
deruxtecan
(HER3-DXd)
Daiichi Sankyo HER3 NSCLC, breast cancer Phase 3
Datopotamab
deruxtecan
(Dato-DXd)
Daiichi Sankyo Trop-2 PD-L1+ TNBC, NSCLC, breast cancer Phase 3
Telisotuzumab
Vedotin
(ABBV-399)
AbbVie, Inc. c-Met NSCLC Phase 3
Depatuxizumab
mafodotin
(ABT-414)
AbbVie, Inc. EGFR Gliosarcoma Phase 3
Tusamitamab
Ravtansine
（SAR408701）
ImmunoGen,
Inc./Sanofi
CEACAM5 NSCLC Phase 3
FS-1502
LegoChem
Biosciences/复兴
HER2 HER2-positive breast cancer Phase 3
ARX788
Ambrx, Inc./Zhejiang
Medicine Co.
HER3 Brest cancer Phase 3
BAT8001 Bio-Thera Solutions HER2 HER2-positive breast cancer Phase 3
A166 Kelun-Biotech HER2
HER2-positive breast
cancer,Cholangiocarcinoma,bladder
cancer
Phase 3
SKB-264 Kelun-Biotech/Merck Trop-2 TNBC Phase 3
SHR-A1811
Hengrui
Pharmaceutical
HER2 Brest cancer Phase 3
DP303c
CSPC ZhongQi
Pharmaceutical
HER2
HER2-positive breast cancer, Ovarian
cancer, Gastric Cancer
Phase 3

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MRG002 Miracogen HER2
HER2-positive uroepithelial carcinoma,
Gastroesophageal junction cancer,
HER2-positive breast cancer
Phase 3
MRG003 Miracogen EGFR HNSCC Phase 3
Trastuzumab duocarmazine（SYD985）
SYD985 (trastuzumab duocarmazine) is a next-generation HER2 ADC developed by Byondis utilizing its
proprietary duocarmazine linker-drug (LD) technology ByonZine®. It is comprised of the anti-HER2
monoclonal antibody trastuzumab and a cleavable linker-drug called
valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). [2]
Figure 5. Structure of SYD985 [2]
On 16 May, 2023, The FDA has issued a complete response letter for a biologics license application (BLA)
for SYD985 as a treatment for patients with HER2-positive, unresectable, locally advanced or metastatic
breast cancer. In the CRL, the regulatory agency requested additional information that will require
additional time and resources that extend beyond the current evaluation period.
Patritumab deruxtecan（HER3-DXd，U3-1402）
Patritumab deruxtecan (HER3-DXd, U3-1402) is the world's first HER3 ADC developed by Daiichi Sankyo
and is currently being explored for indications such as breast cancer and non-small cell lung cancer.
HER3-DXd is derived by conjugating patritumab (U3-1287), a monoclonal antibody to the extracellular
structural domain of HER3, and deruxtecan, a cytotoxic topoisomerase I inhibitor, by a maleimide-GGFG
linker via a cysteine-sited coupling, with a DAR value of 8 (Figure 6).
Figure 6. Structure of HER3-DXd

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At ASCO 2023, Daiichi Sankyo further announced Part A results from a Phase 2 study of HER3-Dxd in
patients with HER2-negative metastatic breast cancer (MBC). The results showed an overall response
rate (ORR) of 35%, a clinical benefit rate (CBR) of 48%, a median duration of response (DOR) of 10.0
months, and a 6-month PFS rate of 60% in the overall population (Figure 7) [3].
Figure 7. Phase 2 study of HER3-DXd [3]
Recently, Daiichi Sankyo at the 2023 WCLC Congress presented the primary results of the pivotal phase
2 study HERTHENA-Lung01 of HER3-DXd for the treatment of patients with EGFR-mutated non-small
cell lung cancer. The results showed that a confirmed ORR of 29.8% was observed with HER3-DXd (5.6
mg/kg) in 225 patients with EGFR-mutated NSCLC, as assessed by blinded independent center review
(BICR), with 1 complete response(CR), 66 partial response(PR), and 99 stable disease (SD) with a DOR
of 6.4 months and a disease Control Rate (DCR) of 73.8%.
As of May 18, 2023, the median progression-free survival (PFS) was 5.5 months and the median overall
survival (OS) was 11.9 months (Figure 8) [4].

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Figure 8. HER3-DXd- HERTHENA-Lung01 results [4]
Datopotamab deruxtecan(Dato-DXd, DS-1062)
Dato-DXd, a targeted Trop-2 ADC co-developed by AstraZeneca and Daiichi Sankyo, couples a
recombinant humanized anti-Trop-2 IgG1 antibody with a topoisomerase I inhibitor (DXd) via a
tetrapeptide-based linker. The tetrapeptide-based linker releases DXd upon proteolytic processing by
lysosomal enzymes such as histone proteases.On average, the number of targets of the drug linker for an
antibody molecule is 4 (Figure 9) [5].
Figure 9. Structure of Dato-DXd [4]
Unlike Trodelvy, the first approved Trop-2 ADC for the treatment of breast cancer, AstraZeneca and
Daiichi Sankyo plan to apply Dato-DXd for the treatment of advanced non-small cell lung cancer.
At the 2023 ASCO Annual Meeting, AstraZeneca and Daiichi Sankyo presented results from a
(TROPION-Lung02) study of Dato-DXd for advanced NSCLC. The results showed that Dato-DXd in
combination with pembrolizumab or Dato-DXd in combination with pembrolizumab and platinum-based
chemotherapy had an ORR of 38% and 49%, a DCR of 84% and 87%, and a PFS of 8.3 months and 7.3
months, respectively, in the overall population of advanced NSCLC. In the first-line treatment population,
the ORR of Dato-DXd in combination with pembrolizumab or Dato-DXd in combination with
pembrolizumab and platinum-based chemotherapy was 50% and 57%, respectively, with a DCR of 91%
in both cases, and the median DORs have not yet been reached in either case [5].

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However, Dato-DXd is currently experiencing safety issues, and the results of the TROPION-Lung01 trial,
while meeting the clinical primary endpoint, showed serious safety issues, with not only the discovery of
interstitial pneumonitis, but also a grade 5 adverse event in which the patient died due to an adverse
reaction to the drug.
Huateng Pharma is dedicated to being your most reliable partner to provide chemical synthesis and
high-quality PEG linkers for ADC drugs. We are committed to promoting the progress of your ADC
discovery and development projects.
References:
[1] Maecker H, Jonnalagadda V, Bhakta S, Jammalamadaka V, Junutula JR. Exploration of the antibody-drug conjugate
clinical landscape. MAbs. 2023;15(1):2229101. doi:10.1080/19420862.2023.2229101
[2] ASCO Highlights 2023, DAIICHI SANKYO CO., LTD.
[3] https://www.daiichisankyo.com/files/news/pressrelease/pdf/202309/20230910_E3.pdf
[4] Daisuke Okajima et.al, Datopotamab Deruxtecan, a Novel TROP2-directed Antibody–drug Conjugate, Demonstrates
Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells, Mol Cancer Ther 2021;20:2329–40
[5] ASCO-IR-deck-June-2023.pdf (astrazeneca.com)