Antibody-Drug Conjugates (ADCs) are drugs that conjugate monoclonal antibodies to different numbers of small molecules of cytotoxic agents (effector molecules) through chemical linkers. ADC combines the potent cytotoxicity of small molecule drugs with the selectivity of monoclonal antibodies and a favorable pharmacokinetic profile. Currently, 15 therapeutic ADCs received marketing approval. They target a variety of disease markers, of which HER2 and Trop2 are the most widely used targets for ADC drugs.
Hottest ADC Target - 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 (EGFR), HER3 and HER4. All four members regulate cell proliferation and differentiation through ligand-dependent or independent forms of homo- or heterodimerization activity. Unlike the other three members, HER2 is the only receptor that can form a dimer with any of the other members, thereby triggering a signaling pathway that regulates cell proliferation and survival. HER2-targeted therapy has significantly improved the prognosis of HER2-positive breast and gastric cancers..
Figure 1. Mechanism of action of HER2, source: reference 1
There are currently more than 30 ADC drugs targeting HER2 in the clinical phase worldwide, with three already approved for marketing.
▶ T-DM1 (Kadcyla) was the first FDA-approved HER2-targeted ADC drug for the treatment of advanced HER2+ breast cancer and was also approved for use in early-stage, high-risk patients with residual disease after neoadjuvant therapy.
▶ In 2019, T-DXd (DS-8201; ENHERTU) became the second approved HER2-targeted ADC drug that showed significant antitumor activity in patients with treatment-refractory HER2+ metastatic breast cancer.
▶ In 2021, RC48 (Disitamab Vedotin) was approved in China for the treatment of patients with locally advanced or metastatic HER2 overexpressing gastric cancer who have received at least two forms of systemic chemotherapy.
Figure 2. List of anti-Her2 ADCs in clinical trials or on the market, source: reference 1
Several anti-HER2-targeted ADCs at the forefront of development have demonstrated excellent antitumor activity in the treatment of breast cancer, and in addition, some of them have shown significant clinical benefit in other HER2-positive cancers.
▶ DS-8201 achieved significant improvements in the treatment of patients with metastatic breast cancer and HER2-positive gastric cancer. In the phase II clinical trial, patients with metastatic breast cancer achieved an objective response rate (ORR) of 60.9%, progression-free survival (PFS) of 16.4 months and overall survival (OS) of 12 months. Patients with HER2-positive gastric cancer also experienced significant clinical benefit from DS-8201, with an ORR of 43.2%, disease control rate (DCR) of 79.5% and PFS of 5.6 months. In HER2-mutant non-small cell lung cancer, the ORR was 72.7% and the median PFS was 11.3 months.
▶ RC48 also demonstrated superior clinical efficacy in the treatment of uroepithelial carcinoma (ORR 51.2%, OS 13.9 months, PFS 6.9 months), gastric cancer (ORR 18.1%, PFS 3.8 months, OS 7.6 months) and breast cancer (ORR 36.7%, SD 60.0%).
▶ DS-8201 and RC48 have also shown significant efficacy in treating patients with low Her-2 expression. In the HER2 IHC1+ or IHC2+ breast cancer staging trial, DS-8201a had an ORR of 37% and a DCR of 87%. In a multicenter phase II trial of HER2-negative uroepithelial carcinoma (IHC0 or IHC1+), RC48 had an ORR of 25% and a DCR of 75%.
▶ ARX788 has shown significant efficacy in treating patients with HER2-positive gastric cancer: 9 out of 20 patients (45.5%) received a PR. And in March 2021, the FDA has granted an orphan drug designation to ARX788 for the treatment of patients with HER2-positive gastric cancer.
Novel ADC Target - Trop2
Tumor-associated calcium signal transducer 2 (TROP2) is a glycoprotein that in humans is encoded by the TACSTD2 gene. It is a 36 kDa transmembrane protein consisting of 323 amino acids and four N-linked glycosylation sites.
High expression of Trop2 plays a key role in the growth of tumor cells and is associated with aggressive disease and poor prognosis. TROP2 was first described in 1981 as a protein highly expressed on the surface of trophoblast cells but later on revealed to play complicated roles in cancer cell growth, proliferation, migration, invasion and survival. Its overexpression was demonstrated in various tumor types and correlated with unfavorable prognosis and increased risk of metastasis, including breast, lung, urothelial, gastric, colorectal, pancreatic, prostatic, cervical, head and neck, and ovarian carcinomas.
Figure 3. TROP2 promotes tumor invasion and metastasis, source: https://www.cusabio.com/
Currently, only one Trop2 ADC has been approved for marketing worldwide, but several preclinical products are already advancing, and international transactions around Trop2 ADCs are in full swing. The future competitive landscape of the Trop2 ADC market is worth looking forward to.
Sacituzumab Govitecan/Trodelvy (Gilead/Immunomedics)
Sacituzumab Govitecan (Trodelvy), the only Trop2 targeted ADC drug currently approved for the treatment of triple-negative breast cancer (TNBC) and locally advanced or metastatic uroepithelial carcinoma (UC).
▶ An anti-Trop2 humanized IgG1κ mAb Sacituzumab；
▶ A hydrolyzable linker, with a short PEGylated unit.
▶ A topoisomerase I inhibitor, SN‐38, DAR=7.4. Among them, SN-38 is the bioactive metabolite of Irinotecan, which can effectively inhibit DNA synthesis and cause DNA single-strand breakage. Compared with microtubule inhibitors, SN-38 has a shorter half-life and is less likely to accumulate in vivo; at the same time, since the number of intracellular targets of microtubule inhibitors far exceeds that of DNA inhibitors, DNA inhibitors are expected to exert better cell killing effects with the same number of warheads entering the cell.
Note: PEG derivatives are one kind of the most widely used linkers in targeted therapy with many features, such as high-usage rate, targeting, regulating PH value, etc.Huateng Pharma offers a variety of PEG linkers to facilitate antibody-drug conjugate (ADC) development projects. All PEG linkers are of >95% purity and they are the basic building blocks for a successful ADC.
Figure 4. Trodelvy structure
DS-1062 (Daiichi Sankyo / AstraZeneca)
DS-1062 (Datopotamab deruxtecan, dato-DXd) is a Trop2 ADC co-developed by Daiichi Sankyo and AstraZeneca.
▶ An anti-Trop2 humanized IgG1 mAb Datopotamab;
▶ Cleavable cysteine linker;
▶ A topoisomerase I inhibitor, DXd，DAR=4. DXd is an innovative DNA topoisomerase inhibitor that is 10 times more active than Irinotecan (SN-38) and interferes with DNA replication, recombination and gene expression. However, DS-1062 is designed with only a DAR of 4, which is significantly lower than the DAR of 8 of DS-8201. Trop2 is also expressed in healthy cells, so the therapeutic-window is relatively narrow and the payload ratio needs to be reduced.
Figure 5. DS-1062 structure, source: Daiichi Sankyo website
DS-1062 is currently being developed for non-small cell lung cancer and triple negative breast cancer.
Advanced non-small cell lung cancer: the 6 mg/kg dose group of DS-1062 achieved an objective remission rate of 21%, with a disease control rate of 67% and a PFS of 8.2 months.
Advanced triple-negative breast cancer: initial objective remission rate (ORR) of 43% and disease control rate (DCR) of 95% in 21 evaluable patients treated with DS-1062 in a blinded, independent center evaluation.
Based on AstraZeneca/Daiichi Sankyo's exclusive advanced ADC technology, DS-1062 has promising clinical data and is expected to be a leader among Trop2 ADCs.
Decades of efforts from the academia and the industry have led to successful development of a variety of ADC therapies that benefit tens of thousands cancer patients. Now there are dozens of targets for ADC research. Except HER2 and Trop2, there are many other promosing ADC targets. It is believed that, more and more targets will be discoevered for ADC research.
 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.
 Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485
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