Sandra Bruder

Abstract 1754: Identification of BAY 94-9343, a mesothelin antibody-drug conjugate (ADC): Characterization and anti-tumor activity in mesothelin-positive preclinical tumor models

Monoclonal antibodies have proven to be very effective in the treatment of various cancers, including solid tumors. For example, HERCEPTIN® and Erbitux® are successfully used to treat HER2-positive breast cancer and EGFR-positive colorectal cancer, respectively. Conjugation of cytotoxic drugs to antibodies represents a promising approach to improve cancer therapy. Antibody-drug conjugates (ADCs) are able to deliver highly potent toxophores to tumors while at the same time reducing systemic toxicity. Promising efficacy and tolerability profiles of ADCs have been observed in clinical trials including Hodgkin lymphoma (brentuximab vedotin) and breast cancer (trastuzumab-DM1), thus, development of new ADCs targeting tumor- associated antigens has potential to identifiy novel cancer therapeutics. Mesothelin, a glycoprotein expressed in mesothelial cells found in the membrane lining of the peritoneal and pleural cavities, is overexpressed in all mesotheliomas as well as many ovarian and pancreatic cancers. Due to its limited expression on normal tissues and higher expression in a number of tumor types, mesothelin represents an attractive ADC target. BAY 94-9343 consists of a fully human anti-mesothelin IgG1 antibody conjugated to the potent tubulin-binding drug DM4 with an average of 3.2 drug molecules per antibody. The resulting ADC bound to human recombinant mesothelin with high affinity (Kd = 15nM) leading to antigen-dependent internalization and potent cytotoxicity (nanomolar range in vitro IC50) in tumor cells that express mesothelin either endogenously or exogenously, but not in mesothelin-negative cells. In vivo, BAY 94-9343 demonstrated dose-dependent, mesothelin-specific anti-tumor efficacy in subcutaneous and orthotopic xenograft models at doses between 2.5 and 10 mg/kg using a Q3Dx3 schedule. Endogenously expressing mesothelin tumor models included sc and orthotopic OVCAR3 (ovarian), sc BxPC-3 (pancreatic) and sc NCI-H226 (mesothelioma). Furthermore, in mesothelin-positive patient-derived preclinical tumor models of both platinum-resistant ovarian cancer and gemcitabine-resistant pancreatic cancer, BAY 94-9343 exhibited high anti-tumor efficacy leading to partial and complete tumor regressions with a 10mg/kg Q3Dx3 dosing schedule. This ADC was well tolerated in mice at 10mg/kg (Q3Dx3) without any evidence of body weight loss, compared to either cisplatin or gemcitabine treatments. In summary, BAY 94-9343 is a mesothelin-targeted ADC with promising preclinical anti-tumor activity for mesothelin-positive tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1754. doi:10.1158/1538-7445.AM2011-1754