Among renal cell carcinoma subtypes, only papillary renal cell carcinoma demonstrated relevant TROP-2 positivity as a rationale for antibody-drug conjugates targeting TROP-2

doi:10.21203/rs.3.rs-4914603/v1

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Among renal cell carcinoma subtypes, only papillary renal cell carcinoma demonstrated relevant TROP-2 positivity as a rationale for antibody-drug conjugates targeting TROP-2

https://doi.org/10.21203/rs.3.rs-4914603/v1

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Objective

To evaluate the expression of trophoblast cell surface antigen-2 (TROP-2), a broadly expressed antibody-drug conjugate (ADC) target, in non-clear cell renal cell carcinoma (non-ccRCC) and to conduct a proof-of-concept analysis assessing the effect of TROP-2-directed ADC Sacituzumab govitecan (SG) in RCC cell lines.

Methods

A cohort comprising a ccRCC (n=44), pRCC (n=22), chRCC (n=22), and benign tumors subcohort (n=8) including oncocytoma and angiomyolipoma, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. The cytotoxic efficacy of the TROP-2-targeted ADC Sacituzumab govitecan (SG) in vitro was analysed using Western Blot, FACS, and MTT assay.

Results

We observed increased TROP-2 mRNA expression levels in pRCC compared to ccRCC, chRCC and benign tumors (p<0.001). Immunohistochemical analysis revealed moderate to strong membranous TROP-2 expression in most of pRCC patients [n=20/22 with H-score ≥ 100, median H-score 265 (IQR 202.5-290)], while TROP-2 was absent or weak in patients with ccRCC and chRCC (p<0.0001). Additionally, we detected soluble TROP-2 in the serum of RCC patients, establishing a strong positive correlation with membranous TROP-2 expression (ρ=0.78, p=0.0001, R²=0.52), indicating its potential as a non-invasive biomarker for RCC. In vitro findings indicated that the efficacy of SG depended on the extent of TROP-2 expression. Notably, SG inhibited the growth of TROP-2 expressing Caki-1 cells, whereas TROP-2 negative 769-P cells were resistant to SG (p<0.01).

Conclusion

In conclusion, the substantial expression of TROP-2 in pRCC, combined with our preclinical in vitro results, provides preclinical evidence supporting the potential effectiveness of TROP-2-directed ADCs such as SG in patients with TROP-2 positive metastatic pRCC.

renal cell carcinoma

antibody-drug conjugates

Sacituzumab govitecan

TROP-2

Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC, which accounts for approximately 75% of all RCC [1]. Therefore, drug development in all RCC subtypes is mainly performed in advanced or metastatic ccRCC [2]. Papillary RCC (pRCC), chromophobe RCC (chRCC) and others are assembled as non-ccRCC, despite their distinct pathologic features and diverse molecular profiles, and account the remaining 25% of all RCC [3, 4]. Thus, approved therapies for ccRCC, including multi-tyrosine kinase inhibitors (e.g., Cabozantinib) and immune checkpoint inhibitors (e.g., Pembrolizumab, Nivolumab) demonstrated unfavorable clinical outcomes in this heterogenous subset of patients [2, 5, 6]. Hence, the question arises whether other innovative, systemic therapies, such as antibody-drug conjugates (ADCs), could potentially fill this therapeutic gap, considering their significant clinical efficacy in metastatic solid tumors like breast, lung, and urothelial cancers [7, 8].

ADCs consist of a monoclonal antibody chemically linked to a cytotoxic agent (payload) [7-9]. Thus, ADCs combine the targeting and pharmacokinetic properties of the antibody with the cancer-killing effect of the payload, with the aim to reduce off-target toxicities by minimizing exposure of normal tissue to the active cytotoxic component [7-9].

Previous studies have demonstrated an upregulation of trophoblast cell surface antigen-2 (TROP-2) expression in various human tumors, including breast, lung, prostate, bladder and kidney, which is associated with an increased risk of disease progression and unfavorable clinical outcomes [10]. This expression pattern has prompt research into TROP-2 as a potential diagnostic and therapeutic target for various cancers [11, 12]. Sacituzumab govitecan (SG), an ADC specifically targeting TROP-2, comprises a humanized anti-TROP-2 antibody (RS7) linked to the active metabolite of irinotecan (SN-38) through a moderately stable carbonate linkage [13]. Following clinical trials (ASCENT and TROPHY trial), SG was recently approved for treating patients with metastatic triple-negative breast cancer (TNBC) and urothelial cancer (UC) [12, 14]. Hence, our primary objective was to assess the potential therapeutic utility of the TROP-2 directed ADC SG for non-ccRCC patients, along with an evaluation of TROP-2 expression levels in the serum of individuals diagnosed with RCC. This study aimed to enhance our understanding of the diagnostic and therapeutic potential of TROP-2 in non-RCC patients.

Patient cohort

A retrospective analysis was performed on a cohort comprising 96 patients diagnosed with renal cell carcinoma (RCC), consisting of 44 clear cell RCC (ccRCC), 22 papillary RCC (pRCC), and 22 chromophob RCC (chRCC) cases, and 8 patients with benign tumors, including oncocytoma and angiomyolipoma. The specimens (n=96) were obtained from partial or radical nephrectomy procedures. The control group consisted of 17 individuals with no history of oncological disease. All patients were treated between 2018 and 2023 at the Department of Urology at the University Hospital of Cologne. Table 1 provides a summary of the clinicopathological characteristics for the entire cohort. Histopathological diagnosis adhered to the 8^th TNM classification [15] for malignant tumors and the 5^th WHO classification for urogenital tumors [16]. The study received approval from the Ethics Committee of the Medical Faculty at the University of Cologne (approval number: 23-1178) and was conducted in adherence to the Declaration of Helsinki. All patients provided written informed consent.

Isolation of tumor RNA and real-time quantitative PCR (RT-qPCR)

RNA extraction from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using a validated bead-based extraction technique (STARTIFYER Molecular Pathology GmbH, Cologne, Germany), following the established laboratory protocol [17]. TROP-2 mRNA expression levels were measured through qRT-PCR, using CALM2 as a housekeeping gene, as previously described [17]. The PCR protocol involved an initial incubation at 50°C for 5 minutes, followed by denaturation at 95°C for 20 seconds, and subsequently 40 cycles of 15 seconds at 95°C and 60 seconds at 60°C.

Enzyme-linked immunoassay (ELISA)

TROP-2 levels in serum samples from both RCC and healthy control cohorts were determined using a semi-quantitative enzyme-linked immunoassay (ELISA) following an established protocol in our laboratory [18]. A monoclonal anti-TROP-2 antibody (#ENZ-ABS380-0100, ENZO Life Sciences, Farmingdale, NY, USA) was employed as primary antibody at a dilution of 1:500 and incubated at 37°C for 1 hour. The FLUOstar Omega® (BMG Labtech, Offenburg, Germany) was used to detect the fluorescence signal.

Immunohistochemistry

The TROP-2 protein detection was conducted using immunohistochemical (IHC) staining on a BOND-MAX autostainer (Leica Biosystems, Wetzlar, Germany) following an accredited staining protocol in a routine IHC laboratory. The primary antibody used was a monoclonal anti-TROP-2 antibody (#ab214488, abcam, Cambridge, UK) with a dilution of 1:1000 and incubated at 37°C for 32 minutes. Two independent pathologists (Yuri Tolkach and M. Eckstein) assessed H-score for membranous TROP-2 staining. The samples were classified as weak (H-score 15-99), moderate (H-score 100-199), and strong (H-score 200-300), as previously described [19, 20].

Cell lines and culture conditions

Human RCC cell lines, including ACHN, A-498, 769-P, 786-O and Caki-1 provided by the American Type Culture Collection (ATCC, Manassas, Virginia) were cultured in RPMI 1640 (#P04-16500, PAN-Biotech GmbH, Aidenbach, Germany), DMEM (#P04-03550, PAN-Biotech GmbH, Aidenbach, Germany) or McCoy medium (#16600-082, Thermo Fisher Scientific, Darmstadt, Germany) with 10% heat-inactivated foetal calf serum and 0.8% streptomycin-penicillin antibiotics (10,000 units/mL penicillin and 10,000 µg/mL streptomycin; #15140-122, Thermo Fisher Scientific, Darmstadt, Germany). The cell cultures were incubated at 37°C in a humid 5% carbon dioxide environment.

Western Blot

Human RCC cell lines (ACHN, A-498, 786-O, 769-P and Caki-1), were plated in 6-well plates and allowed to reach 80% to 90% confluency. The cells were subsequently harvested and lysed with RIPA lysis buffer containing protease inhibitors. The protein concentration was determined using the BCA protein assay (#23225, Pierce BCA Protein Assay Kit, Thermo Fisher Scientific, Darmstadt, Germany), after which the samples were added with 4x SDS sample loading buffer (Tris-HCl (0,2 mol/L), DTT (0,4 mol/L), SDS (277 mmol/L), 8.0% (w/v) bromophenol blue (6 mmol/L), glycerol (4,3 mol/L)] and heated at 95°C for 5 minutes for denaturation. The denatured samples were separated using an 4% SDS gel and transferred onto a 0.45 µmnitrocellulose membrane (#GE10600002, Amersham Protran Premium Western Blotting Membrane, Merck, Darmstadt, Germany). The membrane was blocked with 5% non-fat milk in TBST (50 nM Tris, 150 nM NaCl, 0.05% Tween 20, pH 7.5) for 60 minutes and then incubated overnight at 4°C with primary antibodies against TROP-2 (#ab214488, abcam, Cambridge, UK dilution 1:2000) and GAPDH (#sc-47724, Santa Cruz Biotechnology, Dallas, Texas, USA, dilution 1:1000). HRP-linked secondary antibody anti-rabbit (#7074, Cell Signaling, Danvers, MA, USA, dilution 1:2500) was applied for 1 hour in TBST. The fluorescence signal was detected using the ChemoStar ECL Imager (INTAS, Göttingen, Germany).

Flow cytometry

The immunostaining procedure was performed following standard protocols. Anti-human TROP-2 antibody (#130-115-098, Miltenyi Biotec, Bergisch Gladbach, Germany, dilution 1:100) and TrueStain FcX^TM antibody (#101319, BioLegend, San Diego, CA, USA) were used to stain single-cell suspensions of Caki-1 and 769-P. Data were acquired with an BD FACSCanto II flow cytometer (BD Biosciences, Franklin Lakes, NJ, USA) and analyzed using FlowJo software (FlowJo v10.8 BD, https://www.flowjo.com). A total of 1x10⁶ cells was measured for each sample.

Measurement of cell viability

To evaluate cell viability following treatment with the anti-TROP-2 ADC Sacituzumab govitecan (SG) 1x10⁴ cells were plated in 48-well plates and exposed to different concentrations of SG (0-50µg/ml). After 72 hours the cells were stained using MTT cell proliferation assay kit (#ab211091, abcam, Cambridge, UK) according to the manufacturer’s protocol. The absorbance of the stained cells was measured with an ultraviolet-visible spectrometer (VICTOR Nivo system, Rodgau, Germany) at OD 590 nm, and the relative viability of the cells was calculated based on the absorbance values.

Statistical analysis

Statistical analysis was conducted using SPSS (Version 28.0.1.1, IBM, https://www.ibm.com/de-de/analytics/spss-statistics-software) and PRISM (Version 9.4.0, GraphPad, http://www.graphpad.com/). The comparison of two groups employed the non-parametric Mann-Whitney test and parametric t test, while the non-parametric Kruskal-Wallis test was used for comparing multiple groups. To assess the diagnostic potential of TROP-2 in distinguishing between RCC patients and healthy individuals, receiver operating characteristic (ROC) curves were analyzed, incorporating metrics such as area under the curve (AUC), 95% confidence interval (CI), and p-value. The association between TROP-2 expression and clinicopathological parameters was calculated using Fisher's exact and Chi-squared tests. The amount of explained variance in linear regression was described using the corrected R². Effect size, correlations and regression analyses were interpreted in accordance to Cohen [21]. All p-values were calculated using a two-sided test, and statistical significance was established at p<0.05.

Increased TROP-2 mRNA expression levels in papillary RCC

To evaluate the TROP-2 mRNA expression levels across distinct RCC subtypes and benign tumors, we examined TROP-2 mRNA levels in our cohort (n=96). We observed a significant increase in TROP-2 mRNA expression in individuals with pRCC compared to ccRCC, chRCC and benign tumors (Kruskal-Wallis test, p<0.001) (Fig. 1A). The ROC curve analyses confirmed the excellent diagnostic potential of TROP-2 in distinguishing pRCC from benign tumors, yielding an AUC of 0.94 (95% CI=0.84-1.00; p=0.0002) (Fig. S1A). Additionally, TROP-2 demonstrated substantial discriminatory power in distinguishing pRCC from ccRCC and chRCC, with AUCs of 0.80 (95% CI=0.69-0.90; p<0.0001) and 0.90 (95% CI=0.81-0.98; p<0.0001), respectively (Fig. S1B+1C).

TROP-2 is broadly expressed in papillary RCC

Immunohistochemical analysis, along with H-score assessment, revealed a heterogeneous TROP-2 expression pattern within our cohort. Representative immunohistochemical images are illustrated in Figure 1C-1E. Of note, a substantial proportion of pRCC samples (n=20/22, 90.91%) exhibited moderate to strong membranous TROP-2 expression, defined by an H-score of ≥100, as previously described [19, 20], with a median H-score of 265 (IQR 202.5-290) (Fig. 1B). In contrast, the majority of ccRCC (n=36/44, 81,81%) and chRCC specimens (n=17/22, 77,27%) displayed weak or no tumoral TROP-2 expression, with a median H-score of 5 (IQR 0-80) and 29.5 (IQR 9.25-92.5), respectively (Kruskal-Wallis test, p<0.0001) (Fig. 1B).

Furthermore, we investigated the association between TROP-2 expression and clinicopathological parameters, and determined a significant association with local tumor burden (Chi-squared test, p=0.002). Yet, there were no associations with metastasis or Fuhrmann grading (Table S1).

TROP-2 can be measured in serum from RCC patients

To investigate the potential of TROP-2 as a biomarker for RCC, we developed an enzyme-linked immunoassay (ELISA) to measure TROP-2 protein levels in serum from RCC patients (n=85), benign tumors (n=8), and tumor-free controls (n=17). TROP-2 serum protein levels were significantly elevated in ccRCC, pRCC and chRCC patient samples compared to cancer-free controls (Kruskal-Wallis test, p<0.001) (Fig. 1F). Additionally, serum protein levels of TROP-2 were significantly higher in patients with pRCC compared to benign tumors (Kruskal-Wallis test, p<0.05) (Fig. 1F). While there was a notable trend of rising TROP-2 serum protein levels in pRCC, there was no statistically significant difference in the serum protein levels of TROP-2 among the various RCC subtypes (Kruskal-Wallis test, pRCC vs. ccRCC p=0.171 and pRCC vs. chRCC p=0.254). ROC curve analyses further demonstrated robust diagnostic potential, with AUCs of 0.96 (95% CI=0.90-1.00; p<0.0001), 0.83 (95% CI=0.67-0.99; p=0.004), and 0.71 (95% CI=0.56-0.85, p=0.008) for distinguishing pRCC from non-cancer controls, and benign tumors, respectively (Fig.S1D+1E).

Spearman correlation and linear regression analyses were performed to investigate the relationship among TROP-2 mRNA, serum protein levels, and the H-score in pRCC. The results indicated robust and statistically significant positive correlations, with Spearman coefficients of 0.70 (p=0.0003, R²=0.58) and 0.78 (p=0.0001, R²=0.52) for TROP-2 mRNA and TROP-2 serum protein levels, respectively (Fig. S2).

On-target efficacy of Sacituzumab govitecan in RCC cell lines

To assess the preclinical efficacy of SG in vitro, we determined the TROP-2 expression levels in a panel of RCC cell lines (ACHN, A-498, 769-P, 786-O and Caki-1) via Western blot and flow cytometry. Among them, strong TROP-2 protein expression was only observed in Caki-1 cells (Fig.2A+2B). Next, we investigated the impact of SG on RCC cell growth in vitro by exposing both Caki-1 and 769-P cells to various concentrations of SG (0-50μg). As illustrated in Fig. 2C, SG induced a dose-dependent inhibition of cell growth in TROP-2 expressing cancer cells (Caki-1). Conversely, SG treatment demonstrated inefficacy in TROP-2 negative 769-P cells, suggesting resistance to SG (unpaired t-test, p<0.01) (Fig. 2C). Western blot analysis further confirmed a substantial decrease in TROP-2 protein expression in SG-treated TROP-2 positive Caki-1 cells compared to non-treated (Caki-1 CTRL) cells. (Fig. 2D).

Due to the complexity of genomic alterations and the modest efficacy of targeted molecular therapies in non-ccRCC, particularly in pRCC [3, 4], the identification of new targeted agents is needed. Herein we present evidence for frequent expression of the ADC target TROP-2 in pRCC. This observation, along with our preclinical in vitro findings, provide a preclinical rationale for investigating TROP-2-targeted treatment such as SG in patients with advanced or metastatic pRCC. Furthermore, our findings suggest that soluble TROP-2 holds potential as a non-invasive biomarker for RCC and may serve in selecting patients for TROP-2-directed ADCs. Furthermore, we demonstrate that TROP-2 expression serves as a crucial determinant in predicting the therapeutic efficacy of TROP-2-targeted ADC therapies in pRCC patients. This aligns with previous observations on HER2 expression, which is a determinant of Trastuzumab deruxtecan efficacy in metastatic breast cancer [22]. Based on our findings, it is granted that a thorough evaluation of TROP-2 expression as a predictive marker be conducted in anti-TROP-2 ADC-treated patients with mRCC. This is important as the response to TROP-2-directed ADCs such as SG is highly dependent on the membranous TROP-2 expression, which represents the biological prerequisite as demonstrated in metastatic triple negative breast cancer [14, 23]. Building upon these insights and supported by our promising in vitro results, which indicated a potential application of TROP-2-targeted ADC such as SG in RCC patients with TROP-2 overexpression, we systematically investigated TROP-2 expression across distinct RCC subtypes, encompassing ccRCC, pRCC and chRCC. Yet, relevant TROP-2 positivity was only detected in pRCC. In contrast, most of ccRCC and chRCC displayed weak or no membranous TROP-2 expression, aligning with previous reports [24].

Therefore, our results highlight the potential therapeutic benefit of TROP-2-directed ADCs for advanced or metastatic pRCC patients with TROP-2 positivity. However, careful patient selection is crucial before administering anti-TROP-2 ADCs, although the TROP-2 expression exceeds 90% in pRCC. To address this issue, molecular biomarkers are a promising alternative to monitor disease progression and therapeutic response. TROP-2 is cleaved and released into the extracellular environment, making it a potential liquid biomarker for RCC. Hence, we assessed whether soluble TROP-2 could be detected in the serum of patients with clinical RCC, thereby providing a non-invasive biomarker to identify and potentially monitor the disease. Similar results have been reported in prostate cancer (PCa), where TROP-2 has been identified as a potential non-invasive marker for clinically significant PCa and a prognostic indicator for overall-survival in PCa. In this context, this is the first study to investigate shed TROP-2 as a potential blood-based biomarker, in addition to its therapeutic implications, in RCC, particularly in pRCC. This is particularly important given the difficulties in obtaining metastatic biopsies. The diagnostic potential of TROP-2, supported by qRT-PCR and ELISA results and its correlation with the H-score, strengthens its role as a potential serum marker for RCC and for patient selection in guiding targeted therapies with TROP-2 ADCs such as SG. Therefore, patients with elevated TROP-2 serum levels may be considered as viable candidates for targeted therapies employing TROP-2-directed ADCs, thereby potentially enhancing treatment precision and efficacy. However, comprehensive clinical trials are imperative to evaluate the efficacy and safety of anti-TROP-2 ADCs like SG, followed by an assessment of TROP-2 as a liquid biomarker for monitoring advanced or metastasized pRCC patients.

Study limitations include retrospective data collection, which may introduce potential bias, and the use of primary tumor samples in our analysis due to the lack of metastatic biopsy cohorts. However, previous reports have shown that high TROP-2 expression is maintained during metastatic spread, highlighting our findings despite the lack of longitudinal data [25]. Trials evaluating the efficacy and safety of SG in advanced or metastatic pRCC should consider target protein staining and determination for improved patient identification.

In conclusion, our findings reveal a frequent and notable overexpression of TROP-2 in pRCC. This, together with our preclinical in vitro findings, indicates the potential of TROP-2-directed ADCs such as SG, as a viable treatment option for advanced or metastasized pRCC patients. Furthermore, TROP-2 could serve as a non-invasive biomarker for patients with pRCC and be used to select patients for TROP-2-targeted ADC therapy.

ccRCC clear cell renal cell carcinoma

RCC renal cell carcinoma

pRCC papillary renal cell carcinoma

chRCC chromophobe renal cell carcinoma

non-ccRCC non-clear cell renal cell carcinoma

ADC antibody-drug-conjugate

TROP-2 trophoblast cell surface antigen-2

SG Sacituzumab govitecan

TNBC triple-negative breast cancer

UC urothelial cancer

qRT-PCR quantitative real-time PCR

FFPE formalin-fixed paraffin-embedded

ELISA enzyme-linked immunoassay

IHC immunohistochemical

PCa prostate cancer

Disclosure of Interests

PK: Personal fees, travel costs, and speaker’s honoraria from Bayer, Janssen-Cilag, Medac

NK: Personal fees, travel costs, and speaker’s honoraria from Astellas, Novartis, Ipsen, Photocure, MSD.

ME: Personal fees, travel costs and speaker’s honoraria from MSD, AstraZeneca, Janssen-Cilag, Cepheid, Roche, Astellas, Diaceutics; research funding from AstraZeneca, Janssen-Cilag, STRATIFYER, Cepheid, Roche, Gilead; advisory roles for Diaceutics, MSD, AstraZeneca, Janssen-Cilag, GenomicHealth.

All other authors declare no conflict of interest.

Ethics statement

The study received approval from the Ethics Committee of the Medical Faculty at the University of Cologne (approval number: 23-1178) and was conducted in adherence to the Declaration of Helsinki.

Informed patient consent

All patients provided written informed consent.

Data Availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgment

C. Kessler and L. Sperber are supported by the Koeln Fortune Program/ Faculty of Medicine, University of Cologne. M. Eckstein is supported by the Else Kröner-Fresenius-Stiftung (grant number: 2020_EKEA.129) and the Bavarian Center for Cancer Research (BZKF Young Clinical Scientist Fellowship). N. Klümper is supported by the Advanced Clinician Scientist Program Bonn (ACCENT) of the Medical Faculty of the University of Bonn – Grant ID 01EO2107. R. Weiten is supported by a Ferdinand Eisenberger grant of the Deutsche Gesellschaft für Urologie (German Society of Urology), grant ID WeR1/FE-22. We acknowledge support for the Article Processing Charge from the DFG (German Research Foundation, 491454339).

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Table 1. Clinicopathological characteristics for the entire cohort.

No competing interests reported.

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Among renal cell carcinoma subtypes, only papillary renal cell carcinoma demonstrated relevant TROP-2 positivity as a rationale for antibody-drug conjugates targeting TROP-2

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