Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

  • Clin Cancer Res. 2019 Aug 1;25(15):4723-4734. doi: 10.1158/1078-0432.CCR-18-3476.
Urs B Hagemann  1 ,  Christine Ellingsen  2 ,  Joachim Schuhmacher  3 ,  Alexander Kristian  2 ,  Anne Mobergslien  2 ,  Véronique Cruciani  2 ,  Katrine Wickstroem  2 ,  Christoph A Schatz  4 ,  Christoph Kneip  4 ,  Sven Golfier  4 ,  Roger Smeets  2 ,  Steinar Uran  2 ,  Hartwig Hennekes  4 ,  Jenny Karlsson  2 ,  Roger M Bjerke  2 ,  Olav B Ryan  2 ,  Dominik Mumberg  4 ,  Karl Ziegelbauer  4 ,  Alan S Cuthbertson  2
Affiliations
  • 1. Bayer AG, Berlin, Germany. [email protected].
  • 2. Bayer AS, Oslo, Norway.
  • 3. Bayer AG, Wuppertal, Germany.
  • 4. Bayer AG, Berlin, Germany.
PMID: 31064781 DOI: 10.1158/1078-0432.CCR-18-3476
Abstract

Purpose: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted Alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the Alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a Mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue.

Experimental design: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated in vitro and in vivo in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and Pancreatic Cancer.

Results: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens in vivo. In addition, significant survival benefit was observed in a disseminated Lung Cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in Tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data.

Conclusions: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and Ovarian Cancer patients (NCT03507452).