Comparative Analysis and Future Prospects of Human Epidermal Growth Factor Receptor 2 (HER2) and Trophoblast Cell-Surface Antigen 2 (Trop-2) Targeted Antibody-Drug Conjugates in Breast Cancer Treatment.

Breast cancer remains the most prevalent malignancy among women globally, presenting significant challenges in therapeutic strategies due to tumor heterogeneity, drug resistance, and adverse side effects. Recent advances in targeted therapies, particularly antibody-drug conjugates (ADCs), have shown promise in addressing these challenges by selectively targeting tumor cells while sparing normal tissues. This study provides a comprehensive analysis of two innovative ADCs targeting HER2 and Trop-2, which are critical markers in various breast cancer subtypes. These conjugates combine potent cytotoxic drugs with specific antibodies, leveraging the antigens' differential expression to enhance therapeutic efficacy and reduce systemic toxicity. Our comparative analysis highlights the clinical applications, efficacy, and safety profiles of these ADCs, drawing on data from recent clinical trials. In addition, the paper discusses the potential of these ADCs in treating other types of cancers where HER2 and Trop-2 are expressed, as well as the toxicity risks associated with targeting these antigens in normal cells. Additionally, the paper discusses novel synthetic drugs that show potential in preclinical models, focusing on their mechanisms of action and therapeutic advantages over traditional chemotherapy. The findings underscore the transformative impact of targeted ADCs in breast cancer treatment, noting significant advancements in patient outcomes and management of side effects. However, ongoing issues such as resistance mechanisms and long-term safety remain challenges. The conclusion offers a forward-looking perspective on potential improvements and the future trajectory of ADC research. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics, with particular attention to their broader applications and associated risks.

Antibody-drug conjugates (ADCs): a novel therapy for triple-negative breast cancer (TNBC).

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Revolutionizing triple-negative metastatic breast cancer treatment: sacituzumab Govitecan's role in advancing chemotherapy.

Purpose: This review aims to discuss the role and efficacy of Sacituzumab Govitecan in the management of breast cancer. Summary: Breast cancer is the most prevalent type of cancer among women worldwide. This comprehensive review delves into the advancements brought about by Sacituzumab Govitecan in the treatment of metastatic triple-negative breast cancer (TNBC). With a focus on its mode of action, efficacious role, clinical trials, and comparative advantages over conventional chemotherapy, the review highlights the therapy's precision in targeting cancer cells through monoclonal antibodies. Sacituzumab Govitecan's ability to deliver a chemotherapeutic payload specifically to cancer cells with the Trop-2 receptor sets it apart from traditional chemotherapy, minimizing collateral damage and reducing severe side effects. The impact of Sacituzumab Govitecan on improving progression-free survival, tumor response rates, and, significantly, the quality of life for patients is discussed. This article also sheds light on ongoing trials, FDA recognition, and the therapy's potential to transform breast cancer treatment. Conclusion: In conclusion, Sacituzumab Govitecan shows potential as an innovative therapeutic option for breast cancer, particularly in metastatic breast cancer and triple-negative breast cancer, but it warrants additional research.

Identification of biomarker associated with Trop2 in breast cancer: implication for targeted therapy.

PURPOSE: Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. This study aimed to explore the mutational characteristics and significance of Trop2 in breast cancer (BC). METHODS: Patients diagnosed with BC (n = 77) were enrolled to investigate expression level and clinical characteristics of Trop2. Database of cBioPortal and Kaplan-Meier Plotter were used to evaluate the effects of Trop2 (TACSTD2) genomic ateration and mRNA expression levels on disease-free survival (DFS) and relapse-free survival (RFS), respectively. Based on next generation sequencing analysis, the Trop2 mutation characteristics of BC patients were deeply depicted. In addition, Trop2 expression, mutation and methylation signature associated with Trop2 mutations were analyzed. RESULTS: Trop2 mutation and high expression of Trop2 were predictive biomarker for shorter DFS and RFS in BC. The positive rate of Trop2 expression in these 77 BC patients was 96.1% (74/77). Based on the Trop2 expression level, the patients were classified into Trop2 negative group, medium expression group and high expression group. The mutation frequencies of MAP3K1, NOTCH2, PTEN and MAGI2 were significantly higher in Trop2 medium expression group than high expression group. Moreover, we investigated the effect of the Trop2 mutations on other genes, including co-expressed genes, differentially mutated genes, differentially expressed genes, gene methylation and phosphorylation. We found that MED8, DPH2, KDM4A, EBNA1BP2, USP1, IPO13, CGAS, PRKAA2, NCOA7, ASCC3 and ABRACL were differentially expressed, mutated and methylated between Trop2 mutation group and wild group. CONCLUSION: MAP3K1, NOTCH2, PTEN and MAGI2 mutations were significantly different between Trop2 medium expression and Trop2 high expression BC patients. The effects of Trop2 mutation on the expression, variation, methylation, and phosphorylation of other genes were comprehensively revealed. High expression level of Trop2 and Trop2 mutation were predictive biomarker for poor prognosis and targeted therapy in BC.

Selection of trophoblast cell surface antigen 2-targeted aptamer for the development of cytotoxic aptamer-drug conjugate.

Trophoblast cell surface antigen 2 expressed in several malignant cancers promotes tumor growth and metastasis via several signal transduction pathways. Trop2 is reputed as a prospective biomarker and therapeutic target. Trophoblast cell surface antigen 2-targeted agents, including antibodies, antibody conjugates and therapeutic combinations, could be utilized to fight cancers. To develop an effective drug targeting strategy, we resorted to a new trophoblast cell surface antigen 2-targeted anticancer treatment through aptamer conjugated with chemotherapeutic drug. This study identified trophoblast cell surface antigen 2-specific ssDNA aptamers using engineered trophoblast cell surface antigen 2 overexpression cells for cell-SELEX. The obtained ssDNA aptamer bound to trophoblast cell surface antigen 2 overexpressed cells with nanomolar affinity and was specific for several tumor cell types which express trophoblast cell surface antigen 2 abundantly. Significant cytotoxicity against HT29 cell by the conjugate of trophoblast cell surface antigen 2 aptamer and Emtansine was observed while resulting negligible therapeutic effect on human normal intestinal epithelial cell line HIEC in vitro, indicating that the conjugate shows potential as a promising therapeutic agent. Furthermore, the isolated aptamer demonstrated the ability for the targeted delivery, resulting excellent therapeutic effectiveness of aptamer-drug conjugate for xenograft tumor model of mice with human colorectal cancer.

Phase 1a study of ESG401, a Trop2 antibody-drug conjugate, in patients with locally advanced/metastatic solid tumors.

This phase 1a study assesses ESG401 in patients with heavily pretreated locally advanced or metastatic solid tumors, focusing on metastatic breast cancer. Forty patients are enrolled: three experience dose-limiting toxicities, establishing the maximum tolerated dose at 16 mg/kg on days 1, 8, and 15 of a 28-day cycle. The most common grade ≥3 treatment-related adverse events are neutropenia and leukopenia. Among 38 efficacy-evaluable patients, the objective response rate (ORR) is 34.2%, the disease control rate (DCR) is 65.8%, and the clinical benefit rate (CBR) is 50.0% (including stable disease for at least 6 months). The median progression-free survival is 5.1 months, and the median duration of response is 6.3 months. In patients receiving therapeutically relevant doses, the ORR, DCR, and CBR are 40.6%, 75.0%, and 56.3%, respectively. ESG401 demonstrates a favorable safety profile and promising antitumor activity in this heavily treated population. The trial is registered at ClinicalTrials.gov (NCT04892342).

Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer.

Background: Treatment of recurrent platinum-resistant high grade serous ovarian cancer (HGSOC) remains a challenge. Novel treatment options for recurrent disease are an unmet need. Case: A 69-year-old with recurrent, metastatic, platinum-resistant HGSOC overexpressing TROP2 experienced a significant response to the antibody-drug conjugate (ADC) sacituzumab govitecan after multiple failed lines of chemotherapy and targeted treatment. Following sacituzumab govitecan treatment she experienced a confirmed partial response as well as a return of CA-125 to baseline. Having now completed 8 cycles (ie, over 6 months of treatment), her disease continues to demonstrate a response to sacituzumab govitecan treatment. The ADC has been well tolerated at a dose of 10 mg/kg with no dose-limiting toxicity or need for dose reductions. Conclusion: Sacituzumab govitecan may represent a treatment option for platinum-resistant/recurrent HGSOC that have previously failed prior lines of chemotherapy. Clinical trials with sacituzumab govitecan in platinum-resistant ovarian cancer patients are currently ongoing (https://classic.clinicaltrials.gov/ct2/show/NCT06028932).

Sacituzumab govitecan for hormone receptor-positive HER2-negative advanced breast cancer.

INTRODUCTION: Initial treatment for hormone-receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) typically involves endocrine therapy (ET) combined with different targeted agents. When hormonal therapies fail, until recently, the only option available was chemotherapy (ChT), presenting a significant therapeutic challenge. However, the recent introduction of antibody-drug conjugates (ADCs) has provided new treatment alternatives in this context. Sacituzumab govitecan (SG), a novel trophoblast cell-surface antigen 2 (Trop-2)-targeting ADC, has been evaluated following disease progression to ET and ChT in HR+/HER2- ABC. AREAS COVERED: This review examines the latest clinical trials, including phase I/II and III studies and evaluates the impact of SG on HR+/HER2- ABC. The literature search focused on clinical outcomes, particularly regarding efficacy and safety, comparing them with traditional ChT. EXPERT OPINION: SG has demonstrated to be an effective treatment for patients with HR+/HER2- ABC after progression to ET and cyclin-dependent kinase 4/6 inhibitors (CDKi) in any setting, and at least two ChT-containing regimens in the advanced setting. With a manageable toxicity profile, SG represents a significant advancement in the treatment landscape for this patient population. However, further research is essential to optimize its application and establish long-term benefits.

TROP2 in colorectal carcinoma: associations with histopathology, molecular phenotype, and patient prognosis.

Antibody-drug conjugates (ADCs) directed to trophoblast cell surface antigen 2 (TROP2) have gained approval as a therapeutic option for advanced triple-negative breast cancer, and TROP2 expression has been linked to unfavourable outcomes in various malignancies. In colorectal carcinoma (CRC), there is still a lack of comprehensive studies on its expression frequency and its prognostic implications in relation to the main clinicopathological parameters. We examined the expression of TROP2 in a large cohort of 1,052 CRC cases and correlated our findings with histopathological and molecular parameters, tumour stage, and patient outcomes. TROP2 was heterogeneously expressed in 214/1,052 CRCs (20.3%), with only a fraction of strongly positive tumours. TROP2 expression significantly correlated with an invasive histological phenotype (e.g. increased tumour budding/aggressive histopathological subtypes), advanced tumour stage, microsatellite stable tumours, and p53 alterations. While TROP2 expression was prognostic in univariable analyses of the overall cohort (e.g. for disease-free survival, p < 0.001), it exhibited distinct variations among important clinicopathological subgroups (e.g. right- versus left-sided CRC, microsatellite stable versus unstable CRC, Union for International Cancer Control [UICC] stages) and lost its significance in multivariable analyses that included stage and CRC histopathology. In summary, TROP2 is quite frequently expressed in CRC and associated with an aggressive histopathological phenotype and microsatellite stable tumours. Future clinical trials investigating anti-TROP2 ADCs should acknowledge the observed intratumoural heterogeneity, given that only a subset of TROP2-expressing CRC show strong positivity. The prognostic implications of TROP2 are complex and show substantial variations across crucial clinicopathological subgroups, thus indicating that TROP2 is a suboptimal parameter to predict patient prognosis.

Sacituzumab govitecan in triple-negative breast cancer: from bench to bedside, and back.

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.

Trop2-targeted therapy in breast cancer.

Human trophoblastic cell surface antigen 2 (Trop2) is a glycoprotein, a cellular marker of trophoblastic and stem cells, and a calcium signaling transducer involved in several signaling pathways, leading to the proliferation, invasion, and metastasis of tumors. It is expressed at a low level in normal epithelial cells, but at a high level in many tumors, making it an ideal target for cancer therapy. According to previous literature, Trop2 is broadly expressed in all breast cancer subtypes, especially in triple negative breast cancer (TNBC). Several clinical trials have demonstrated the effectiveness of Trop2-targeted therapy in breast cancer. Sacituzumab govitecan (SG) is a Trop2-targeted antibody-drug conjugate (ADC) that has been approved for the treatment of metastatic TNBC and hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer. This article reviews the structure and function of Trop2, several major Trop2-targeted ADCs, other appealing novel Trop2-targeted agents and relevant clinical trials to provide a landscape of how Trop2-targeted treatments will develop in the future.

Preclinical activity of datopotamab deruxtecan, a novel TROP2 directed antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (TROP2) in ovarian carcinoma.

INTRODUCTION: Epithelial ovarian cancer (EOC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical activity of datopotamab deruxtecan (Dato-Dxd), a novel TROP2 targeting antibody drug conjugate (ADC) in ovarian cancer cell lines and xenografts with variable TROP2 expression. METHODS: In vitro cell viability with Dato-DXd was assessed using flow-cytometry based assays against a panel of EOC primary cell lines with variable TROP2 expression. Fluorescent anti-phospho-histone H2A.X antibody was used to detect dsDNA breaks by flow-cytometry. The in vivo antitumor activity of Dato-DXd was tested in TROP2 overexpressing xenografts. RESULTS: TROP2 overexpressing (3+) and moderate (2+) expressing EOC cell lines demonstrated higher sensitivity to Dato-DXd when compared to TROP2 negative tumors. Dato-DXd exposed TROP2+ EOC demonstrated increased dsDNA breaks and Annexin-V positivity (a marker of apoptosis) when compared to tumor cells exposed to the non-binding conjugate (p = 0.001 and p = 0.016, respectively). Dato-DXd induced significant antibody-dependent cellular cytotoxicity (ADCC) in the presence of peripheral-blood-lymphocytes. While negligible activity was detected against EOC cell lines with low TROP2 expression, Dato-DXd demonstrated significant bystander killing against tumor cells with low/negligible TROP2 when such cells were admixed with TROP2 3+ tumor cells in vitro. Dato-DXd showed tumor growth suppression against EOC cell line derived xenograft models that overexpress TROP2 at 3+ levels, prolonging survival when compared to controls, with minimal toxicity. CONCLUSION: Dato-DXd shows promising preclinical activity against TROP2 overexpressing ovarian cancers. Future clinical trials in ovarian cancer patients are warranted.

Unveiling the placental secrets: Exploring histopathological changes and TROP2 expression in intrahepatic cholestasis of pregnancy.

INTRODUCTION: Gestational cholestasis, also known as intrahepatic cholestasis of pregnancy (ICP) or obstetric cholestasis, is a liver disease that can manifest in late pregnancy. Trophoblast cell surface antigen (TROP2) is a type I transmembrane glycoprotein identified in placental trophoblast cells that plays a critical role in trophoblast invasion of the decidua upon implantation into the placenta. Our study aims to investigate the role of TROP2 in pregnancy cholestasis. MATERIALS AND METHODS: Study groups: Group 1 (control group) (n = 10): consists of healthy normal pregnant women without any disease, Group 2 (cholestasis group) (n = 10): consists of pregnant women diagnosed with cholestasis. After routine histological follow-up, hematoxylin and eosin staining and TROP2 immunostaining were performed and scored. RESULTS: In the cholestasis group, in contrast to the control group, thrombus structures were observed in the intervillous space. In the cholestasis group compared to the control group, villus mesenchymal connective tissue cells, capillary endothelium and trophoblasts around the villus showed significantly stronger anti-TROP2 staining (p < 0.05). DISCUSSION: Cholestasis, a condition that may manifest during pregnancy, may be associated not only with observable pathological changes in placental tissues at the light microscopic level, but also with an increase in TROP2 expression. Given the critical role of TROP2 in trophoblast invasion during placental implantation, we hypothesize that TROP2 may serve as a key marker of the cholestatic processes occurring during pregnancy.

Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors.

BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.

Trophoblast Cell Surface Antigen 2 Expression in Thymic Carcinoma: Brief Report.

Introduction: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma. Methods: TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University. Results: RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%-100%) and 25.0 (range: 0-200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival. Conclusions: TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.

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

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.

Feasibility study of ADCs targeting TROP-2, HER2, and CD46 in Ductal Adenocarcinoma and Intraductal Carcinoma of the prostate.

BACKGROUND: Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma of the Prostate (IDC-P) respond poorly to all the currently available conventional therapies. Given their accurate and efficient elimination of cancer cells, Antibody-Drug Conjugates (ADCs) have become one of the most promising anticancer treatments. However, no ADCs have so far been approved for Prostate Cancer (PCa) treatment. This study investigated TROP-2, HER2, and CD46 expression in DAC/IDC-P samples, indirectly analyzing their preliminary feasibility as therapeutic targets for future treatment of the two conditions. PATIENTS AND METHODS: We conducted a retrospective study involving 184 participants (87 DAC/IDC-P patients and 97 Prostatic Acinar Adenocarcinoma (PAC) patients with a Gleason score ≥ 8) without prior treatment between August 2017 and August 2022. Immunohistochemical staining was employed to detect the differential protein expressions of TROP-2, HER2, and CD46 in DAC/IDC-P, PAC, and normal prostate tissues. RESULTS: Compared to pure PAC tissues, TROP-2 expression was significantly higher in DAC/IDC-P and DAC/IDC-P-adjacent PAC tissues (H-score 68.8 vs. 43.8, p < 0.001, and 59.8 vs. 43.8, p = 0.022, respectively). No significant differences in HER2 expression were observed across different cancer tissues. Compared to both DAC/IDC-P-adjacent PAC and pure PAC tissues, CD46 expression was significantly higher in DAC/IDC-P tissues (42.3 vs. 28.6, p = 0.041, and 42.3 vs. 24.3, p = 0.0035, respectively). CONCLUSIONS: Herein, TROP-2 and CD46 expression was higher in DAC/IDC-P tissues than in pure PAC and normal prostate tissues. This finding implies that ADCs targeting the two proteins hold significant promise as potential future treatments for DAC/IDC-P.

On the shoulder of ADC: The development of 124I-IMMU-132, an iodine-124-labelled Trop-2-targeting molecular probe for micro-PET imaging.

BACKGROUND: Trop-2 is closely related to the development and progression of a variety of tumours and poor prognosis. This study aimed to construct an iodine-124 (124I)-labelled antibody-drug conjugate (ADC) positron emission tomography (PET) probe which could noninvasively image Trop-2 in vivo, providing an important method for the diagnosis of tumours with high Trop-2 expression in clinical practice and monitoring their treatment. METHODS: In this study, a novel Trop-2-targeting molecular probe, 124I-IMMU-132, was constructed to better reveal the expression of Trop-2. The targeting and binding abilities of the probe to Trop-2-positive tumours were investigated in Capan-1/MDA-MB-468/Mcf-7 cells and their animal models. RESULTS: The constructed 124I-IMMU-132 probe maintained both reliable radiochemical characteristics and binding affinity (Kd = 2.200 nmol/L). The uptake of the probe by Trop-2-positive Capan-1/MDA-MB-468 cells increased in a time-dependent manner. The probe bound specifically to Capan-1/MDA-MB-468 tumours in vivo. The SUVmax Tumour/muscle ratio gradually increased with time, from 4.30 ± 0.55-10.78 ± 1.80 (p < 0.01) in the Capan-1 model and from 8.84 ± 0.95-32.20 ± 2.9 (p < 0.001) in the MDA-MB-468 model. The biodistribution and pharmacokinetics of 124I-IMMU-132 in a mouse model were consistent with the imaging results, and the dosimetry estimation in humans was acceptable. CONCLUSIONS: 124I-IMMU-132 PET is a promising imaging technique for delineating Trop-2-positive tumours. It has great potential in early diagnosis and targeted selection of patients that could benefit from its application.

Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2.

The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.

Trophoblast cell surface antigen-2: a promising new biomarker and potential therapeutic target in penile squamous cell carcinoma.

OBJECTIVE: To evaluate the potential utility of antibody-drug conjugates targeting trophoblast cell surface antigen-2 (TROP-2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient-matched distant metastases (MET cohort), and to assess the potential use of TROP-2 as a predictive non-invasive biomarker in PSCC. METHODS: A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. RESULTS: TROP-2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer-free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H-score 260, interquartile range [IQR] 210-300), as well as all patients in the REC (median [IQR] H-score 200 [165-290]) and MET cohorts (median [IQR] H-score 280 [260-300]) exhibited moderate to strong membranous TROP-2 expression. Additionally, The H-score (membranous TROP-2 expression) was positively correlated with TROP-2 mRNA (ρ = 0.69, P < 0.0001, R2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R2 = 0.59), indicating its potential as a non-invasive biomarker in PSCC. CONCLUSION: In summary, our results support further studies on TROP-2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC.