Kadcyla (ado-trastuzumab emtansine, T-DM1), a second-generation antibody-drug conjugate (ADC), is the most commercially successful ADC. It is the first ADC approved for solid tumors (breast cancer).

1. Biopharma PEG https://www.biochempeg.com
Kadcyla - Top-Selling Antibody Drug Conjugate
(ADC)
Kadcyla (ado-trastuzumab emtansine, T-DM1), a second-generation antibody-drug
conjugate (ADC), is the most commercially successful ADC. In 2021, the global ADC
market exceeded $5.2 billion, with Kadcyla sales reaching $2.17 billion.
Kadcyla was first approved by the U.S. Food and Drug Administration (FDA) in 2013, for
patients with HER2-positive, late-stage (metastatic) breast cancer. It is the first ADC
approved for solid tumors.
Introduction of Kadcyla
Kadcyla is a HER2-targeted antibody-drug conjugate that contains the humanized
anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a
maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl]
cyclohexane-1-carboxylate). An average of 3.5 DM1 molecules are conjugated to each
molecule of trastuzumab.
Figure 1. Structure of Kadcyla, source: reference [5]

2. Biopharma PEG https://www.biochempeg.com
DM1 is a maytansine derivative. Maytansine, first isolated from the bark of African shrub
Maytenus ovatus in 1972, is a potent microtubule-targeted compound that induces mitotic
arrest and kills tumor cells at sub-nanomolar concentrations. Therefore, this class of
cytotoxic drugs also belongs to the class of microtubule protein inhibitors, and the two
most commonly used in ADCs today are DM1 and DM4.
Clinical Efficacy and Market Performance of
Kadcyla
The latest FDA approval in 2019 was based on KATHERINE (NCT01772472), a
randomized, multicenter, open-label trial of 1486 patients with HER2-positive EBC who
had residual invasive disease in the breast and/or axillary lymph nodes following
neoadjuvant treatment with taxane + trastuzumab-based therapy.
The primary objective of the KATHERINE study is to evaluate, the effectiveness and
safety of adjuvant treatment with Kadcyla versus trastuzumab in patients after surgery.
The primary endpoint of the study is invasive disease-free survival (IDFS), which is the
time from randomization grouping to recurrence of invasive breast cancer or death from
any cause. Secondary endpoints included disease-free survival (DFS) and overall survival
(OS).
Patients were grouped 1:1 and received Kadcyla or Herceptin (trastuzumab), respectively,
as well as radiation and/or hormonal therapy according to local treatment guidelines. At a
median follow-up time of 40 months, patients in the Kadcyla group had a statistically
significant improvement in IDFS compared to the Herceptin group and a 50% reduction in
the risk of death or recurrence of invasive disease. At 3 years, 88.3% of patients in the
Kadcyla group were relapse-free compared to 77.0% in the Herceptin group.

3. Biopharma PEG https://www.biochempeg.com
Figure 2. Efficacy Results from KATHERINE
Figure 3. 3-year iDFS rates were 88.3% for KADCYLA vs 77.0% for Herceptin, references
[1]

4. Biopharma PEG https://www.biochempeg.com
The most common adverse reactions (ADRs) (≥25%) included nausea, fatigue, skeletal
muscle pain, bleeding, headache, elevated transaminases, thrombocytopenia, and
peripheral neuropathy, with most ADRs being mild to moderate grade 1 or 2 ADRs and
the incidence of severe ADRs >0.5%.
In 2021, Kadcyla had global sales of $2.18 billion, ranking as the most commercially
successful ADC. According to an ADC market size report by Nature Reviews Drug
Discovery, sales of Kadcyla are expected to be $2.3 billion in 2026, indicating limited
room for future growth.
Figure 4. Sales of ADC drugs
There are 2 main reasons for its limited room for future growth, one is the high pricing of
Kadcyla. The pricing of Kadcyla in USA is $3,709 /100mg, $5,929/160mg, which limits the
use of the drug for some patients.
On the other hand, biosimilars are coming to market one after another, further eroding
Kadcyla's share. In India, an analogue, Ujvira, has been approved for 20% of the price of

5. Biopharma PEG https://www.biochempeg.com
Kadcyla. ADCs with the same target, HER2, are also being developed and
commercialized, undoubtedly posing a threat to Kadcyla.
Kadcyla (T-DM1) Compared to DS-8201 & RC48
Globally, two ADC products targeting HER2 have been launched: Enhertu
(DS-8201) by Daiichi Sankyo and Disitamab Vedotin (RC48) by RemeGen Co.
Figure 5. Kadcyla (T-DM1) Compared to DS-8201 & RC48, source: reference [3]
1.Trastuzumab Deruxtecan（Enhertu，T-DXd，DS-8201）
 ▶ Company: Daiichi Sankyo / AstraZeneca
 ▶​ Target: HER2
 ▶​ Antibody: Humanized IgG1 monoclonal antibody Trastuzumab
 ▶​ Drug/payload: DXd (topoisomerase)
 ▶​ Linker: GFLG (tetrapeptide)

6. Biopharma PEG https://www.biochempeg.com
 ▶​ Indications: Breast cancer, gastric cancer, lung cancer, etc.
 ▶​ Status: Available in 2019
Enhertu consists of an anti-HER2 antibody, Trastuzumab, coupled to the cytotoxic drug
DXd via a linker, GFLG. The linker is a cleavable tetrapeptidyl linker (Gly-Phe-Leu-Gly
(GFLG)), which is not only stable but also can be specifically cleaved and has a strong cell
membrane permeability, allowing it to exert a "bystander effect".
Figure 6. Structure of Enhertu. Source: reference [2]
The cytotoxic drug employs DXd, a new DNA topoisomerase inhibitor that improves the
hydrophobic properties of the drug, allowing each antibody to be loaded with 7 or 8 DXd
molecules. The high DAR allows the efficacy of Enhertu to be considered 2 to 4 times
higher than previously approved marketed ADC drugs.
Enhertu was first approved for marketing in the United States in 2019 for the treatment of
HER2-positive metastatic breast cancer.

7. Biopharma PEG https://www.biochempeg.com
2. Disitamab Vedotin (Aidixi, RC48）
 ▶​ Company: RemeGen Co.
 ▶​ Target: HER2
 ▶​ Antibody: recombinant humanized IgG1 monoclonal antibody Hertuzumab
 ▶​ Drug/Payload: Duocarmycin / Seco-DUBA
 ▶​ Linker: MC-Val-Cit-PAB
 ▶​ Indication: Gastric cancer
 ▶​ Status: Available in 2021
Disitamab Vedotin, consists of a recombinant humanized HER2 IgG1 monoclonal
antibody coupled to MMAE via a cleavable linker. It is indicated for the treatment of
patients with locally advanced or metastatic HER2 overexpressing gastric cancer,
including adenocarcinoma of the gastroesophageal junction, who have received at least 2
systemic chemotherapies.
Figure 7. Structure of Disitamab Vedotin, source: Reference [3]

8. Biopharma PEG https://www.biochempeg.com
In June 2021, the National Medical Products Administration (NMPA) granted conditional
approval for Disitamab Vedotin.
As a novel agent, RC48 as monotherapy or adjuvant treatment in clinical practice for the
therapy of other cancer in the world, including UC, biliary tract cancer (BTC), non-small
cell lung cancer (NSCLC), and HER2+ and HER2-low expressing BC.
Anti-Her2 ADCs in Clinical Trials
Except for the three anti-Her2 ADC approved for marketing, there are more than 20 ADCs
have entered clinical testing. Among them, trastuzumab duocarmazine (SYD985) making
the best progress.

9. Biopharma PEG https://www.biochempeg.com
Figure 8. List of anti-Her2 ADCs in clinical trials or on the market, source: reference [4]

10. Biopharma PEG https://www.biochempeg.com
Trastuzumab Duocarmazine (SYD985)
 ▶​ Company: Byondis
 ▶​ Target: HER2
 ▶​ Antibody: Monoclonal antibody trastuzumab
 ▶​ Drug/Payload: MMAE (monomethyl auristatin E)
 ▶​ Linker: vc-seco-DUBA
 ▶​ Indication: Breast Cancer, Endometrial cancer
 ▶​ Status: Phase III
SYD985 is an investigational next-generation HER2 ADC that was previously granted
Fast Track Designation by the FDA in January 2018. In addition, its U.S. marketing
application was accepted by the FDA on July 12, 2022, with a PDUFA date set for May 12,
2023.
SYD985 consists of the monoclonal antibody trastuzumab and a cleavable linker-drug
called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA).
which is designed using Byondis' proprietary ByonZine technology platform - -
duocarmazine linker drug technology.

11. Biopharma PEG https://www.biochempeg.com
Figure 9. SYD985 formula, anti-HER2 trastuzumab conjugated to seco-DUBA via a
cleavable linker sensitive to cathepsin B. Source: reference [5]
On July 18, 2022, Byondis announced that the European Medicines Agency (EMA) has
validated the Marketing Authorization Application (MAA) for SYD985 in patients with
HER2-positive unresectable locally advanced or metastatic breast cancer (MBC).
The MAA for SYD985 is based on data from the pivotal phase III TULIP. The trial was a
randomized, multicenter, open-label clinical trial (n=436) comparing the efficacy of
SYD985 with physician's choice (PC) for the treatment of patients with HER2-positive
unresectable locally advanced or metastatic breast cancer. The primary endpoint is
progression-free survival (PFS).
Byondis presented preliminary results from TULIP3 at the ESMO 2021 Congress. The
results showed that SYD985 significantly improved PFS in patients with HER2-positive
unresectable locally advanced or metastatic breast cancer, with a PFS of 7.0 months in
the SYD985 group and 4.9 months in the PC group. In addition, the overall survival (OS)
in the group receiving SYD985 showed a trend of improvement with an HR of 0.83.

12. Biopharma PEG https://www.biochempeg.com
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] https://www.kadcyla-hcp.com/early-breast-cancer/efficacy/clinical-trial-results.html
[2] Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The Latest Research and Development into the
Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer
Therapy. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. doi:10.1248/cpb.c18-00744
[3] Shi F, Liu Y, Zhou X, Shen P, Xue R, Zhang M. Disitamab vedotin: a novel antibody-drug conjugates
for cancer therapy. Drug Deliv. 2022 Dec;29(1):1335-1344. doi: 10.1080/10717544.2022.2069883. PMID:
35506447; PMCID: PMC9090390.
[4] Zhang X, Huang AC, Chen F, Chen H, Li L, Kong N, Luo W, Fang J. Novel development strategies
and challenges for anti-Her2 antibody-drug conjugates. Antib Ther. 2022 Jan 27;5(1):18-29. doi:
10.1093/abt/tbac001. PMID: 35146330; PMCID: PMC8826051.
[5] Joubert, N.; Beck, A.; Dumontet, C.; Denevault-Sabourin, C. Antibody–Drug Conjugates: The Last
Decade. Pharmaceuticals 2020, 13, 245. https://doi.org/10.3390/ph13090245
Related Articles:
Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Review
HER2 Targeted Therapies In Breast Cancer
ADC Drugs Global Sales of 2021 and Future Prospects
The Bystander Effect of ADCs