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. Epub 2019 May 7.

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).

MeSH terms

  • Alpha Particles / therapeutic use*
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / chemistry
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival
  • Drug Evaluation, Preclinical / methods*
  • Female
  • GPI-Linked Proteins / antagonists & inhibitors*
  • GPI-Linked Proteins / immunology
  • GPI-Linked Proteins / pharmacokinetics
  • GPI-Linked Proteins / pharmacology*
  • Humans
  • Immunoconjugates / administration & dosage
  • Immunoconjugates / chemistry
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mesothelioma / drug therapy
  • Mesothelioma / metabolism
  • Mesothelioma / pathology
  • Mesothelioma, Malignant
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Radiopharmaceuticals / pharmacokinetics
  • Radiopharmaceuticals / pharmacology*
  • Thorium / administration & dosage
  • Thorium / chemistry
  • Thorium / pharmacokinetics
  • Thorium / pharmacology*
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • BAY 2287411
  • GPI-Linked Proteins
  • Immunoconjugates
  • Radiopharmaceuticals
  • Thorium-227
  • Thorium
  • mesothelin

Associated data

  • ClinicalTrials.gov/NCT03507452