Antibody drug conjugate (ADC) research involves more and more targets, such as HER-2, Trop-2, Claudin-18.2, B7-H3 and B7-H4, etc. Trop-2 is a transmembrane glycoprotein. Its high expression is associated with the occurrence of many tumors and poor prognosis. It is a very popular ADC research target, second only to HER2.
Currently, only Gilead’s Trop-2 ADC drug Trodelvy has been approved for marketing in the world. It is used to treat adult patients with metastatic triple-negative breast cancer (mTNBC) and locally advanced or metastatic urothelial cancer (UC) who have received at least 2 therapies in the past. Trodelvy’s sales have increased steadily since its launch, with sales reaching US$680 million in 2022 and US$482 million in the first half of this year. However, Trodelvy’s growth rate did not meet analysts’ expectations, mainly due to efficacy and safety issues. Trodelvy’s overall efficacy is average, and its safety is a bit worrying. It also has a strong competitor, Enhertu, in the approved breast cancer field. For example, in the ASCENT clinical trial, 9% of patients experienced rash and 5% of patients experienced eye toxicity.
Despite this, enthusiasm for the development of Trop-2 ADCs is high. In addition to Trodelvy, the fastest-growing drugs currently include Daiichi Sankyo/AstraZeneca’s Dato-DXd and Kelun-Biotech’s SKB264 (MK-2870), both of which are in clinical phase 3. Different from the approved indications of Trodelvy, Dato-DXd plans to use advanced non-small cell lung cancer (NSCLC) as the first indication. In addition to single-target Trop-2 ADCs, some companies are also deploying dual-target ADCs. For example, Biocytogen’s Trop-2/PTK7 dual-antibody ADC BCG033, Trop-2/EGFR dual-antibody ADC DM001, and Trop-2/HER2 dual-antibody ADC YH012, etc. However, these are currently in preclinical research, and it will take time to verify how far they will go in the future.
Trop-2-mediated Cellular Pathways and Their Relationship with Tumors
Trophoblast cell surface antigen-2 (Trop-2) is a surface glycoprotein member of the epithelial cell adhesion molecule (EpCAM) family. It is a transmembrane glycoprotein expressed in normal tissues and many epithelial tumors, including breast, cervical, colorectal, esophageal, gastric, and lung cancers. In NSCLC, high Trop-2 expression was observed in 64% of adenocarcinomas and 75% of squamous cell carcinomas (SqCCs). In addition to its function of regulating normal fetal development, Trop-2 is also an intracellular calcium signal transducer, a key component of cell adhesion in human tissues, and plays an important role in stabilizing epithelial tight junctions. Trop-2 mediates several intracellular signaling pathways including PTEN/PIK3CA/Akt, MAPK/ERK, JAK/STAT, ErbB, TGFβ, and WNT/β-catenin (Fig. 1). In addition, Trop-2 is highly expressed in tumors and is associated with poor tumor prognosis. These characteristics all indicate that Trop-2 will become a good target for tumor treatment.
Trop-2 ADC Approved for Marketing – Trodelvy
Trodelvy (sacituzumab govitecan) is a novel Trop-2-targeting ADC originally developed by Immunomedics. In April 2020, it received accelerated approval from the FDA for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least 2 prior therapies. In September of the same year, Gilead acquired Immunomedics for US$21 billion and also acquired Trodelvy. In April 2021, the FDA granted routine approval for the mTNBC indication. In the same year, Trodelvy received accelerated approval from the FDA for a second indication in patients with locally advanced or metastatic urothelial cancer after treatment with platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.
Trodelvy consists of a humanized monoclonal IgG (designated hRS7) that binds Trop-2. IgG is lightly reduced to expose eight sulfhydryl binding sites, which are subsequently coupled to the cytotoxic topoisomerase I inhibitor SN-38 via a CL2A linker. As shown in Fig. 2, the CL2A linker has a short PEG (polyethylene glycol) residue to aid solubility and is coupled to SN-38 at position 20 of the lactone ring, thereby stabilizing the ring from opening to less active carboxylate form. The bond between CL2A and SN-38 is pH-sensitive and is more readily released in low-pH environments (e.g., found in lysosomes and even in the microenvironment of tumors). Binding of SN-38 to IgG protects position 10 of SN-38 from glucuronidation. SN-38, while bound to the antibody, remains in its most potent form before being released. Trodelvy is a very important product of Gilead. It is currently undergoing multiple clinical trials and is used alone or in combination to treat metastatic triple-negative breast cancer (first-line or adjuvant treatment), metastatic breast cancer, non-small cell lung cancer, metastatic Urothelial carcinoma, metastatic castration-resistant prostate cancer, and other solid tumors.
Other Trop-2 ADC Drugs in Development
- Datopotamab Deruxtecan
Datopotamab Deruxtecan (Dato-DXd, DS-1062) is a humanized Trop-2 ADC jointly developed by Daiichi Sankyo and AstraZeneca. It is linked to a topoisomerase 1 inhibitor payload (an exatacan derivative) via a tetrapeptide-based cleavable linker. The linker releases DXd upon proteolysis by lysosomal proteases such as cathepsin. Compared to Trodelvy’s 8 DAR, Dato-DXd’s DAR is 4, which is expected to improve security (Fig. 3). In preclinical studies, Dato-DXd significantly reduced the growth of cell lines with high Trop-2 levels but was not effective in inhibiting the growth of cells with low Trop-2 levels. Different from Trodelvy’s approved indications, AstraZeneca/Daiichi Sankyo plan to use advanced non-small cell lung cancer as the first indication for Dato-DXd, turning Dato-DXd into a potential alternative to chemotherapy for the treatment of NSCLC.
- SKB-264
SKB264 (MK-2870) is the fastest-growing ADC targeting Trop-2 developed by Kelun-Biotech. Like Trodelvy and Dato-DXd, SKB264’s cytotoxin also uses a topoisomerase I inhibitor. However, the cytotoxin of Trodelvy is SN-38, the cytotoxin of Dato-DXd is an exatacan derivative, and the cytotoxin of SKB264 is Belotecan (KL610023), and the antibodies all use recombinant anti-Trop-2 humanized monoclonal antibodies. The linker of SKB264 is a sulfonylpyrimidine-CL2A-carbonate linker.
- DB-1305
DB-1305 is a Trop2 ADC developed by Duality Biologics based on its proprietary Duality Immunotoxin Antibody Conjugate (DITAC) platform. It has demonstrated strong anti-tumor activity in preclinical tumor models, entered clinical phase I/II research (NCT05438329) in June 2022, and demonstrated strong clinical efficacy in NSCLC and other solid tumors. DB-1305 is a targeted ADC formed by coupling a Trop-2 antibody to the novel topoisomerase I inhibitor P1021 via an enzymatically cleaved tetrapeptide linker.
Trop-2 protein is highly expressed in a variety of tumors, such as pancreatic cancer, breast cancer, colon cancer, ovarian cancer, and non-small cell lung cancer. Its high expression is also closely related to shortened survival and poor prognosis of tumor patients, and it is a popular target in the ADC field after HER-2. Currently, there is only one Trop-2 ADC in the world, Trodelvy, approved for marketing to treat TNBC and advanced UC. Sales have risen steadily since its launch, reaching $482 million in the first half of this year. However, as the only Trop-2 ADC on the market, its sales growth rate did not meet expectations, mainly due to efficacy and safety issues. Despite this, many pharmaceutical companies have joined in the layout of Trop-2 ADCs.
References
- Claudia, P. et al. TROP-2 directed antibody-drug conjugates (ADCs): The revolution of smart drug delivery in advanced non-small cell lung cancer (NSCLC). Cancer Treatment Reviews. 2023, 118: 102572.
- David, M. et al. Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan. MAbs. 2019, 11(6): 987-995.