Targeting uPARAP with an Antibody-Drug Conjugate Exhibits Efficacy against Mesothelioma and Synergizes with Cisplatin

Our plain-English summary of Targeting uPARAP with an Antibody-Drug Conjugate Exhibits Efficacy against Mesothelioma and Synergizes with Cisplatin, by P. Çakılkaya, I.M. Egeland Larsen, Q. Jiang, et al (Cancer Research Communications, 2026).

The study

• Authors: P. Çakılkaya, I.M. Egeland Larsen, Q. Jiang, K. Sandal Nørregaard, H. Gårdsvoll, J. Zhang, H.J. Jürgensen, M. Hansen Blomquist, A. Martinez Perlado, O. Krigslund, E. Santoni-Rugiu, L.H. Engelholm, R. Hassan, N. Behrendt
• Journal: Cancer Research Communications
• Published: 2026;6(1):130-142
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Urokinase plasminogen activator receptor-associated protein (uPARAP) is a collagen-internalizing receptor with emerging relevance as a therapeutic target. The involvement of uPARAP in extracellular matrix turnover and stromal remodeling within the tumor microenvironment (TME) makes it an especially promising target in tumors with a high stromal component. Mesothelioma, characterized by its unique complex TME, is a highly refractory cancer type for which no effective targeted therapy exists. uPARAP has been shown to be expressed across all subtypes of mesothelioma, especially in the sarcomatoid and biphasic subtypes, suggesting that a uPARAP-targeted therapy may benefit a specific patient population. In this study, we utilized an antibody-drug conjugate (ADC) comprising an anti-uPARAP mAb conjugated to monomethyl auristatin E via a protease-sensitive linker for preclinical studies on mesothelioma treatment. Using mouse xenograft models with a human mesothelioma cell line or a patient-derived mesothelioma cell isolate, we demonstrated a strong anticancer effect following treatment with the uPARAP-targeting ADC. IHC studies revealed this to be the case, even in tumors exhibiting a heterogeneous expression of uPARAP, suggesting that uPARAP-expressing cancer-associated fibroblasts also play a role in the anticancer effect through a bystander mechanism. Furthermore, we show that combination treatment with cisplatin, commonly used in first-line mesothelioma therapy, leads to a strongly enhanced anticancer effect relative to treatment with either drug alone. Our study demonstrates the potential utility of a uPARAP-targeted ADC as a therapeutic option for mesothelioma, alone or in combination with chemotherapeutics. This perspective is particularly emphasized by a recently initiated clinical trial with a humanized anti-uPARAP ADC for the treatment of other malignancies.

Significance: This study highlights the translational promise of a uPARAP-targeted ADC for the treatment of mesothelioma, a cancer lacking effective therapies. Demonstrating potent preclinical efficacy and synergy with cisplatin, our findings support the clinical advancement of a uPARAP-directed ADC strategy, particularly considering an ongoing clinical trial evaluating this approach in other malignancies.

©2025 The Authors; Published by the American Association for Cancer Research.

In plain English

This laboratory study tested an experimental drug in mice and cultured cells; no patients were treated and asbestos exposure was not studied. The drug, an antibody-drug conjugate called 9b7-MMAE, delivers a toxin (MMAE) to cells carrying a receptor called uPARAP. Human mesothelioma cells from a cell line (H-Meso-1) or from a patient (NCI-Meso79) were grown as tumors under the skin of mice. In H-Meso-1 tumors, average tumor volume in drug-treated mice was about 40% of that in saline-treated mice at day 32, and survival was significantly longer than in all control groups. In NCI-Meso79 tumors at day 29, tumors were on average 62% smaller with the drug, 43% smaller with cisplatin (a first-line mesothelioma chemotherapy) and 78% smaller with both, compared with control mice. Median survival after first treatment was 29 days for controls, 54 days with the drug and 73 days with the combination. Mouse weights did not differ between groups. The authors concluded that uPARAP is a promising drug target for mesothelioma and that the drug may be combined with platinum-based chemotherapy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: cell-culture experiments and mouse xenograft (human tumor grown in mice) treatment experiments
• Who was studied: Female immunodeficient (NSG) mice carrying tumors grown from the biphasic human mesothelioma cell line H-Meso-1 (6 mice per treatment group) or from NCI-Meso79 cells, a biphasic mesothelioma cell isolate from a patient treated at the NCI (9 mice per treatment group). Cultured cells from six patient isolates and other mesothelioma cell lines were also tested.
• Exposure: Not an asbestos exposure study. Treatments studied were the uPARAP-targeted antibody-drug conjugate 9b7-MMAE at 6 mg/kg intravenously, cisplatin at 1 mg/kg intraperitoneally, or both, each given on days 0, 4 and 7. Controls were a non-targeted drug conjugate (aTNP-MMAE), unconjugated antibody (H-Meso-1 model only), or saline/PBS.
• Main results:
  • H-Meso-1 tumors: average tumor volume with 9b7-MMAE was approximately 40% of that in the saline group at day 32.
  • H-Meso-1 tumors: 9b7-MMAE significantly prolonged mouse survival compared with all control groups.
  • H-Meso-1 tumors: neither the unconjugated antibody nor the non-targeted drug conjugate notably affected tumor growth.
  • NCI-Meso79 tumors at day 29: average tumor volume was 43% lower with cisplatin and 62% lower with 9b7-MMAE than in the PBS group.
  • NCI-Meso79 tumors: the combination of 9b7-MMAE and cisplatin reduced average tumor volume by 78% at day 29, with continued shrinkage afterward.
  • NCI-Meso79 tumors: median survival after first treatment was 54 days with 9b7-MMAE versus 29 days in the saline (PBS) control group, and 73 days with the combination.
  • NCI-Meso79 tumors: the non-targeted drug conjugate caused some delay in tumor growth, but clearly less than the uPARAP-targeted drug.
  • Mouse weight was not affected by the drug conjugates, cisplatin or the combination in the NCI-Meso79 experiment.
  • In cultured NCI-Meso79 cells, 2.5 μg/mL cisplatin combined with 0.064 μg/mL 9b7-MMAE left 0.9% of cells viable, with a synergy score of 21.
  • Similar synergy was seen in some concentration ranges in cultured H-Meso-1 and ONE58 cells, but JL-1 cells showed little or no synergy.
  • In H-Meso-1 tumors, mouse stromal (supporting) cells were strongly positive for uPARAP, while tumor cells varied in uPARAP expression.
  • In both tumor models, uPARAP expression in remaining tumor cells appeared unchanged after drug treatment.
• The authors' conclusion: The authors concluded that their work supports uPARAP as a promising drug-conjugate target for treating mesothelioma, and that such treatment may be combined with platinum-based drugs used in standard treatment.
• Limitations the authors state:
  • Relatively high doses were needed, consistent with the modest sensitivity of mesothelioma cells to the drug in culture.
  • Further studies are needed on how sensitive mesothelioma cells are to uPARAP-targeted drugs carrying different toxins.
  • The reason the non-targeted control drug had some effect on tumor growth remains unclear.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Cisplatin, Collagen, Tumor Microenvironment, Targeted Therapy, Sarcomatoid, Biphasic Mesothelioma, Fibroblast.

Related studies

• Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET — A.G. Terwisscha van Scheltinga, A. Ogasawara, et al. (2017)
• Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect — S. Golfier, C. Kopitz, et al. (2014)
• Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate — M.G. Anderson, H.D. Falls, et al. (2020)
• Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review — J.M. Lambert, C.Q. Morris (2017)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)
• FL496, an FL118-derived small molecule, induces growth inhibition, senescence, and apoptosis of malignant pleural mesothelioma (MPM) cells, and exhibits anti-MPM tumor efficacy strikingly superior to the pemetrexed-cisplatin combination — I.A.M. Aljahdali, X. Ling, et al. (2025)

Browse more research in Cancer Research Communications, or return to medical research.