Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect

Our plain-English summary of Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect, by S. Golfier, C. Kopitz, A. Kahnert, et al (Molecular Cancer Therapeutics, 2014).

The study

• Authors: S. Golfier, C. Kopitz, A. Kahnert, I. Heisler, C.A. Schatz, B. Stelte-Ludwig, A. Mayer-Bartschmid, K. Unterschemmann, S. Bruder, L. Linden, A. Harrenga, P. Hauff, F.D. Scholle, B. Müller-Tiemann, B. Kreft, K. Ziegelbauer
• Journal: Molecular Cancer Therapeutics
• Published: 2014;13(6):1537-48
• Cited by: 214 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelin is a tumor differentiation antigen frequently overexpressed in tumors such as mesothelioma, ovarian, pancreatic, and lung adenocarcinomas while showing limited expression in nonmalignant tissues. Mesothelin is therefore an attractive target for cancer therapy using antibody-drug conjugates (ADC). This study describes the detailed characterization of anetumab ravtansine, here referred to as BAY 94-9343, a novel ADC consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker. Binding properties of the anti-mesothelin antibody were analyzed using surface plasmon resonance, immunohistochemistry, flow cytometry, and fluorescence microscopy. Effects of BAY 94-9343 on cell proliferation were first studied in vitro and subsequently in vivo using subcutaneous, orthotopic, and patient-derived xenograft tumor models. The antibody binds to human mesothelin with high affinity and selectivity, thereby inducing efficient antigen internalization. In vitro, BAY 94-9343 demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC(50) of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. In vivo, BAY 94-9343 localized specifically to mesothelin-positive tumors and inhibited tumor growth in both subcutaneous and orthotopic xenograft models. In addition, BAY 94-9343 was able to induce a bystander effect on neighboring mesothelin-negative tumor cells. Antitumor efficacy of BAY 94-9343 correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models. BAY 94-9343 is a selective and highly potent ADC, and our data support its development for the treatment of patients with mesothelin-expressing tumors.

©2014 American Association for Cancer Research.

In plain English

This was a preclinical laboratory and animal study of BAY 94-9343 (anetumab ravtansine), an experimental drug made of a human antibody against mesothelin joined to a cell-killing agent, DM4. Mesothelin is a protein found on many mesothelioma, ovarian and pancreatic cancers. The study did not examine asbestos exposure. In cultured cells, the drug killed mesothelin-expressing cancer cells at low concentrations. It did not affect mesothelin-negative cells except at very high concentrations, and it did not affect nondividing mesothelial cells. In the NCI-H226 mesothelioma model in mice, the highest dose inhibited tumor growth by 94% compared with vehicle-treated mice and produced partial regression in 5 out of 8 mice. Cisplatin alone or with pemetrexed reduced growth by 70%. In a patient-derived mesothelioma model (Meso7212), all mice had at least partial regression. The drug worked better than cisplatin and pemetrexed, but its difference from vinorelbine was not statistically significant. Tumors with only 20% mesothelin-positive cells stayed the same size or shrank in 7 of 8 mice. The authors concluded that their data support developing the drug for patients with mesothelin-expressing tumors.

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 experiments (subcutaneous, orthotopic and patient-derived tumor models)
• Who was studied: Human cancer cell lines (pancreatic MIA PaCa-2, colon HT-29, ovarian OVCAR-3, mesothelioma NCI-H226), primary human mesothelial cells, and immunodeficient mice carrying these tumors or patient-derived pancreatic (PAXF736), ovarian (OVCAR6719) and mesothelioma (Meso7212) tumors; also ovarian cancer samples (primary versus matched relapse, n = 50)
• Exposure: No asbestos exposure was studied. The exposure was the antibody-drug conjugate BAY 94-9343 given intravenously, with doses expressed as the amount of DM4 (up to 0.2 mg/kg DM4); comparisons included a nontargeted control conjugate, the unconjugated antibody, free DM4 and standard drugs (cisplatin, pemetrexed, gemcitabine, vinorelbine)
• Main results:
  • In cell culture, BAY 94-9343 was toxic to mesothelin-expressing cells with an IC50 of 0.72 nmol/L
  • Mesothelin-negative tumor cells were not affected except at concentrations approaching the micromolar range
  • The drug did not affect nondividing mesothelin-positive primary mesothelial cells
  • In mice with MIA PaCa-2/meso or HT-29/meso tumors, 0.2 mg/kg (DM4) produced complete tumor eradication lasting at least 17 weeks after the final treatment; at 0.05 mg/kg, tumors were eradicated in 5 out of 6 animals in the MIA PaCa-2/meso pancreatic model
  • In the NCI-H226 mesothelioma model, 0.2 mg/kg inhibited tumor growth by 94% compared with vehicle control on day 153 (P < 0.001) and gave a 63% response rate (partial regression in 5 out of 8 mice); cisplatin alone and with pemetrexed gave a 70% reduction
  • In the NCI-H226 model, tumor weight at day 174 was 14-fold lower with two cycles of BAY 94-9343 than with cisplatin plus pemetrexed (P < 0.05)
  • In the patient-derived mesothelioma model Meso7212, all mice had at least partial tumor regression (P < 0.001); efficacy was greater than cisplatin (P < 0.05) and pemetrexed (P < 0.001), while the difference from vinorelbine was not significant
  • In HT-29 tumors with 20% mesothelin-positive cells, treatment reduced mean tumor size by 82% compared with vehicle, and tumor size stayed the same or fell in 7 out of 8 mice (4 stable disease, 3 partial regression)
  • In mesothelin-negative tumors, tumor size increased by 30% to 300% in 7 out of 8 treated mice, though tumors were about 64% smaller than in the vehicle group; the authors described this as a small target-independent effect
  • In ovarian cancer samples, mesothelin expression stayed mostly stable or increased from primary tumor to relapse in 86% of cases
• The authors' conclusion: The authors concluded that BAY 94-9343 is a selective and highly potent antibody-drug conjugate and that their data support its development for patients with mesothelin-expressing tumors
• Limitations the authors state:
  • The authors noted that tumor models based on established cell lines have low heterogeneity, which is why they added patient-derived models
  • The authors stated that the threshold of mesothelin expression needed for efficacy still has to be determined in future studies

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelioma, Lung Adenocarcinoma, Immunohistochemistry.

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)
• Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review — J.M. Lambert, C.Q. Morris (2017)
• Mesothelin as a target for cervical cancer therapy — K. Jöhrens, L. Lazzerini, et al. (2019)
• Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial — H.L. Kindler, S. Novello, et al. (2022)
• Novel mesothelin antibody-drug conjugates: current evidence and future role in the treatment of ovarian cancer — D. Mauricio, J. Harold, et al. (2021)
• Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors — E. Hatterer, X. Chauchet, et al. (2020)

Browse more research in Molecular Cancer Therapeutics, or return to medical research.