Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

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. Mol Cancer Ther; 13(6); 1537-48. Ó2014 AACR.

An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models

“…In these five models, significant activity was seen at 5 mg/kg and tumor regressions at 10 mg/kg following a single dose. Similar results were obtained in OVCAR3, PAXF736, and H226 models with 10 mg/kg antimesothelin-DM4 conjugate (17), except with 3 to 6 repeated doses. Importantly, the models in which aMSLN-MMAE was highly active expressed clinically relevant levels of mesothelin (2-3þ by tumor IHC).…”

“…16)-offers hope for these technologies with other tumor antigens. Indeed, several other ADCs are at various stages of clinical development, including an antimesothelin-DM4 conjugate (BAY-94-9343) with a reducible SPDB linker (17). Antimesothelin ADCs have three major potential advantages over SS1P: antimitotic activity conferring inherent specificity for rapidly dividing cancerous over nondividing mesothelial cells; less immunogenicity, permitting multiple dosing cycles; and longer serum half-life to increase therapeutic exposure.…”

Preclinical Antitumor Efficacy of BAY 1129980—a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody–Drug Conjugate for the Treatment of Non–Small Cell Lung Cancer

“…The marked in vivo efficacy of C4.4A-ADC was demonstrated in CDX and PDX models with homo-and heterogeneous C4.4A expression patterns to optimally mimic the situation in the clinic and using doses and schedules earlier shown to be efficient even in less sensitive models (37,38). C4.4A-ADC was particularly potent in two medium to high C4.4A-expressing NSCLC xenograft models, NCI-H292 and NCI-H322, resulting in equal or superior efficacy compared to SOC compounds.…”

Novel systemic therapy against malignant pleural mesothelioma

“…Phage library display panning led to the identification of Fab MF-T which binds mesothelin with 10 nM affinity (148). The conjugation of MF-T to the maytansinoid tubulin inhibitor DM4 through a hindered disulfide linker generated the antibody-drug conjugate anetumab ravtansine (BAY94-9343) (148). The uptake of the DM4 toxin causes inhibition of mitosis through targeting microtubule polymerization (149).…”