Trop2-targeted therapies in solid tumors: advances and future directions

Abstract

Trophoblast cell surface antigen 2 (Trop2) is overexpressed in a range of solid tumors and participants in multiple oncogenic signaling pathways, making it an attractive therapeutic target. In the past decade, the rapid development of various Trop2-targeted therapies, notably marked by the advent of the antibody-drug conjugate (ADC), revolutionized the outcome for patients facing Trop2-positive tumors with limited treatment opinions, such as triple-negative breast cancer (TNBC). This review provides a comprehensive summary of advances in Trop2-targeted therapies, including ADCs, antibodies, multispecific agents, immunotherapy, cancer vaccines, and small molecular inhibitors, along with in-depth discussions on their designs, mechanisms of action (MOAs), and limitations. Additionally, we emphasize the clinical research progress of these emerging Trop2-targeted agents, focusing on their clinical application and therapeutic efficacy against tumors. Furthermore, we propose directions for future research, such as enhancing our understanding of Trop2's structure and biology, exploring the best combination strategies, and tailoring precision treatment based on Trop2 testing methodologies.

Keywords: Trop2; solid tumor; targeted therapies; therapeutic efficacy.

Figure 1

Summary of Trop2-targeted therapies. Six types of Trop2-targeted therapeutics have been developed. The development phases are depicted with a red bar for approval, a yellow bar for clinical studies, and a blue bar for the preclinical stage. The crystal structure of Trop2-ECD (7E5M) was obtained from Protein Data Bank (PDB). The image was created with MedPeer.cn.

Figure 2

Binding sites of Trop2-targeted antibodies and small molecular inhibitors. A composite model of full-length Trop2 dimer, projected based on the structures of individual functional modules. PDB identifier 7E5N for ECD, and PDB identifier 2MVK for ICD. RS7 recognizes Q237-Q252 of CPD. AR47A6.4.2 recognizes L179-H187 and Q252-Y260 of CPD. T16, 77220, E1, 162-46.2, MOv-16, MM0588-49D6, and YY-01 recognize D146-R178 of CPD. K5-70 recognizes V43-D65 of CRD. Pr1E11 recognizes C34-K72 of CRD. The only small molecule inhibitor, Bruceine D (BD), binds to the key sites K307 and E310 of Trop2-ICD.

Figure 3

Mechanisms of action of Trop2-CD3 bispecific T cell engagers. The Trop2-CD3 bispecific antibody binds to CD3 on T cells and Trop2 antigen on tumor cells. The activated T cells release cytotoxic cytokines, resulting in the lysis of Trop2-positive tumor cells. The image was created with MedPeer.cn.

Figure 4

Mechanisms of action of a Trop2-targeted Nano-in-Gel Vaccine (NIGel-Vax) for treating Trop2-expressing tumors. The Trop2 antigen is mixed with PEI-4BImi-Man adjuvant to form nanoparticles, then incorporated into an injectable hydrogel to construct the NIGel-Vax. After subcutaneous vaccination, the Trop2-containing nanoparticles are sustainably released and are transported to lymph nodes by dendritic cells (DCs) or through passive drainage. Subsequently, activated B cells produce antigen-specific antibodies, and activated T cells migrate to the TME, leading to direct tumor killing or tumor cell apoptosis. Furthermore, NIGel-Vax induces the generation of central memory and effector memory T cells, primed for potential tumor rechallenge. Immunogenic dead tumor cells can release Trop2 antigens and danger signaling molecules, amplifying the intensity and breadth of the subsequent immune response. The image was created with MedPeer.cn.

Figure 5

Future directions of Trop2-targeted therapies for the treatment of Trop2-positive tumors. (A) A deeper understanding of the structure and mechanisms of Trop2. A proposed composite model of full-length Trop2 dimer based on the structures of individual modules. Schematics for possible dimerization and tetramerization states of Trop2 on the cell surface. PDB identifier 7E5N for cis-dimer and cis-tetramer, PDB identifier 7E5M for trans-dimer and trans-tetramer. A general view of Trop2 interaction partners and downstream signaling pathways. NRG1, neuregulin 1; IGF-1, insulin-like growth factor 1; RACK1, receptor for activated C kinase 1; PIP2, phosphatidylinositol 4,5-bisphosphate. (B) Discovery of optimal combination strategies against Trop2-positive tumors. The figure shows representative examples of potential combination strategies with Trop2-targeted agents in preclinical or early clinical stages. PARP, poly (ADP-ribose) polymerase; PD1, programmed cell death protein 1. (C) Establishment of a standard method for Trop2 testing is necessary for the biomarker-driven clinical studies that can evaluate the efficacy of potential Trop2-targeted therapeutic agents. The image was created with MedPeer.cn.