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TROP-2 directed antibody-drug conjugates (ADCs) for cancer treatment

Release time:2024/3/13 15:55:22

Trop2 has gained significant attention in antibody-drug conjugate (ADC) research as a potential therapeutic target due to…

Trophoblast cell surface antigen 2 (Trop2), also known as tumor-associated calcium signal transducer 2 (TACSTD2) and epithelial glycoprotein 1 (EGP-1), is a cell surface protein that is highly expressed in many solid tumors. It plays a crucial role in various cellular functions and has been implicated in tumor progression and metastasis. Trop2 has gained significant attention in antibody-drug conjugate (ADC) research as a potential therapeutic target due to its widespread expression in tumor tissues and limited expression in normal tissues.

According to incomplete statistics, there are a total of 11 ADCs targeting Trop2 in clinical trials, with 2 in Phase III, 7 in Phase II, and 2 in Phase I.

Introduction of Trop-2

Trop2 is a 36-kDa single-pass transmembrane protein that encodes a 323 amino acid, comprised of a large extracellular domain, a single transmembrane domain, and a short intracellular tail.

Figure 1. The structure of TROP2 [1]

TROP2 is primarily overexpressed in various human epithelial cancers, including breast, lung, gastric, colorectal, pancreatic, and prostate cancers, while its expression in normal tissues is low. Moreover, the level of TROP2 expression correlates with the severity of the disease. Overexpression of TROP2 promotes tumor cell growth, proliferation, and metastasis by modulating calcium ion signaling pathways, cell cycle protein expression, and reducing fibronectin adhesion. The distinct differential expression of TROP2 protein between normal and cancer tissues has made it an emerging target for researchers developing antibody-drug conjugates (ADCs).

Approved Trop-2 ADCTrodelvy

Currently, Gilead's TROP2 ADC Trodelvy is the only approved TROP2-directed drug globally. It is approved for the treatment of metastatic triple negative breast cancer, HR+/HER2- metastatic breast cancer and metastatic urothelial cancer.  Since its launch, Trodelvy's sales have steadily increased, reaching $680 million in 2022 and $1.1 billion in 2023.

Sacituzumab govitecan consists of a humanized monoclonal IgG (designated as hRS7) that targets TROP-2. The IgG is gently reduced to expose eight sulfhydryl-binding sites, which are subsequently linked to the CL2A-SN-38 linker-drug through the maleimide moiety of the CL2 linker. The CL2A linker includes a short PEG (polyethylene glycol) residue to enhance solubility and is attached to SN-38 at the 20th position of the lactone ring, stabilizing the ring and preventing it from converting to the less active carboxylate form. The bond between CL2A and SN-38 is pH-sensitive, making it more susceptible to release in a low pH environment (e.g., lysosomes or the tumor microenvironment). The 10th position of SN-38 is shielded from glucuronidation while bound to the IgG, ensuring that SN-38 remains in its most potent form until released.

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.

Figure 2. Structure of Trodelvy [3]

Trodelvy is a product highly valued by Gilead and is currently undergoing multiple clinical trials for the treatment of metastatic triple-negative breast cancer (first-line or adjuvant therapy), metastatic breast cancer, non-small cell lung cancer, metastatic urothelial carcinoma, metastatic castration-resistant prostate cancer, and other solid tumors (Figure 3).


Figure 3. Clinical trials of Trodelvy  [4]

Trop-2 ADCs in Clinical Trials III

Currently, Daiichi Sankyo/AstraZeneca's Dato-DXd and Kelun-Biotech's SKB264 are undergoing Phase III clinical trials. The FDA accepted the marketing application for Dato-DXd on February 19, 2024, with a PDUFA date set for December 20, 2024. The NMPA accepted the marketing application for SKB264 on December 9, 2023.

Datopotamab Deruxtecan (Dato-DXd, DS-1062a)

Datopotamab Deruxtecan (Dato-DXd, DS-1062) is a humanized Trop-2 ADC jointly developed by Daiichi Sankyo and AstraZeneca. It conjugates a topoisomerase 1 inhibitor payload (derived from exatacan) to the antibody through a cleavable tetrapeptide-based linker. This linker releases DXd after protein hydrolysis by lysosomal proteases such as cathepsin. Compared to Trodelvy with 8 Drug-to-Antibody Ratio (DAR), Dato-DXd has a DAR of 4, potentially enhancing safety. In preclinical studies, Dato-DXd significantly reduced the growth of Trop-2 high cell lines but showed limited efficacy in inhibiting cells with low Trop-2 levels.

Figure 4. Trodelvy vs. Dato-DXd [2]

AstraZeneca and Daiichi Sankyo intend to position Dato-DXd initially for late-stage non-small cell lung cancer (NSCLC), aiming to establish it as a potential alternative for NSCLC chemotherapy. Results from the TROPION-Lung02 study presented at the 2023 ASCO conference indicate that Dato-DXd, in combination with immunotherapy or immunotherapy plus chemotherapy, achieved objective response rates (ORR) of 38% and 49%, respectively, and disease control rates (DCR) of 84% and 87%, respectively. Median progression-free survival (PFS) was 8.3 months and 7.3 months, respectively, demonstrating promising anti-tumor activity and manageable safety with Dato-DXd combination therapies.

On July 3, 2023, Dato-DXd's Phase III clinical trial, TROPION-Lung01, targeting advanced NSCLC patients, met its primary endpoint of progression-free survival (PFS). However, significant safety concerns emerged during the study, including cases of interstitial pneumonia and five grade 5 adverse events resulting in patient fatalities due to drug-related reactions (Figure 5).

Figure 5. TROPION-Lung01 Resultes [5]

Currently, Dato-DXd is undergoing multiple clinical trials exploring its potential in various disease areas, including NSCLC, breast cancer, colorectal cancer, and urothelial carcinoma (Figure 6).

Figure 6. Dato-Dxd clinical trials [6]

SKB-264 (MK-2870)

SKB264 (MK-2870), developed Kelun-Biotech, is an investigational ADC that consists of an antibody targeting TROP2 linked to a belotecan-derived payload.

Figure 7. Structure of SKB264 [7]

Under a collaboration agreement, Kelun-Biotech has granted Merck & Co the exclusive rights to develop, manufacture, and commercialize SKB264 in all territories outside of Greater China.

Merck has initiated three pivotal Phase 3 clinical trials evaluating MK-2870 in which patients are now enrolling: MK-2870-004 (NCT06074588), MK-2870-007 (NCT06170788) and MK-2870-005 (NCT06132958). Besides, Merck intends to rapidly advance the global clinical development program evaluating MK-2870 as a monotherapy and in combination with KEYTRUDA in various solid tumors.


Trop-2, with its high expression and internalization activity in cancer cells, presents a novel and promising molecular target for targeted therapy. While significant progress has been made in drug development and clinical trials targeting Trop-2, several challenges remain. Future research will delve deeper into Trop-2's potential, including combining Trop-2 ADC with other anti-tumor therapies to enhance treatment efficacy. This approach may necessitate the establishment of a new personalized tumor assessment system, incorporating molecular subtyping and tumor microenvironment characteristics. Such advancements hold great promise for advancing anti-tumor treatment strategies.

[1] Lenart S , Lenart P , Smarda J , et al. Trop2: Jack of All Trades, Master of None[J]. Cancers, 2020.

[2] Claudia Parisi, Linda Mahjoubi, Anas Gazzah, Fabrice Barlesi, TROP-2 directed antibody-drug conjugates (ADCs): The revolution of smart drug delivery in advanced non-small cell lung cancer (NSCLC), Cancer Treatment Reviews 118 (2023) 102572
[3] David M. Goldenberg and Robert M. Sharkey, Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan, MAbs. 2019 Aug/Sep;11(6):987-995.
[4] Gilead Q423 Resource Book, https://s29.q4cdn.com/585078350/files/doc_financials/2023/q4/GILD-Q423-Resource-Book-6-February-2024.pdf
[5] AstraZeneca H1-and-Q2-2023-results-presentation
[6] AstraZeneca Clinical Trials Appendix, FY 2023 Results Update
[7] Yezhe Cheng, Xiaoxi Yuan, Qiang Tian, Xiuying Huang, Yang Chen, Yuzhi Pu, Hu Long, Mingyu Xu, Yafei Ji, Jia Xie, Yuping Tan, Xi Zhao and Hongmei Song, Preclinical profiles of SKB264, a novel anti-TROP2 antibody conjugated to topoisomerase inhibitor, demonstrated promising antitumor efficacy compared to IMMU-132, Frontiers in Oncology, 2022.