Targeting PLK-1 for Treating MYC Driven Lymphomas
Abstract
The overall aim of the project is to determine the potential therapeutic value of targeting PLK-1 in the treatment of MYC-driven lymphomas. Polo-like kinase (PLK)-1 selective inhibitor, Volasertib (BI 6727), has been known as a potent anti-tumor effect in various cancer cells, including B cell lymphomas. However, Volasertib was withdrawn in Phase III clinical trials due to its adverse effects. In this study, we developed an Antibody-drug conjugates (ADC), which is anti-CD19 antibody (Inebilizumab)-Volasertib conjugate (V-ADC) to increase the specificity for B-cell lymphomas and minimize the toxic effects of Volasertib. We will test the specificity of V-ADC to B-cell lymphoma cells and the efficacy of therapeutic effects in B-cell lymphomas in vitro and in vivo. We found that V-ADC exhibits very little cytotoxic effects in various B-cell lymphoma cell lines. We hypothesized that the expression level and gene mutation of CD19 may affect the binding affinity which required for V-ADC mediated cytotoxicity. We have shown that most cell lines tested have low to modest level of CD19 expression. Overexpression of wild type CD19 in Z138 cells exhibited expected cytotoxic effect of Volasertib in a dose-dependent manner. Furthermore, we have found most cell lines harbor CD19 L174V gene mutation which may significantly affect the CD19-binding. We are in the process of studying whether CD19 gene mutation affect V-ADC effect in lymphoma cell lines. Furthermore, we will further investigate the effects of CD19 expression and gene mutation in PDX models of aggressive B-cell lymphoma in vivo. All of these studies will be completed within this period of no-cost extension.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1190385
Entities
People
- Chieko Saito
- Kai Fu
Organizations
- Health Research, Incorporated