Mechanism of Action Magnifier – 2016 Desk Reference
Bavituximab: a Novel, Investigational Immunotherapy Agent Targeting Phosphatidylserine in the Vasculature of the Tumor Microenvironment
Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that blocks PS-mediated immunosuppression by multifocal reprogramming of immune cells in the tumor microenvironment to support immune activation.1 PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but âflipsâ and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anticancer treatments. PS-targeting agents block PS-mediated immunosuppression by multifocal reprogramming of immune cells in the tumor microenvironment to support immune activation.1
Preclinical data demonstrate that bavituximab:
- Blocks PS-mediated immunosuppressive signaling
- Provides specificity for innate immune responses
- Activates T-cellâdriven adaptive immunopathways to stimulate an effective immune response to the tumor.2
After binding exposed PS in tumors, bavituximab engages Fc-Î³ receptors on tumor-promoting myeloid-derived suppressor cells (MDSCs), M2-like tumor-associated macrophages (which fail to differentiate into M1-like tumor-killing macrophages and natural killer cells), and immature dendritic cells, leading to multiple immunostimulatory changes in the tumor environment.2 These changes include:
- An increase in immunostimulatory cytokines (including tumor necrosis factor alpha [TNF-Î±] and interleukin (IL)-12)
- Macrophage polarization from an M2 state to a tumor-fighting M1 state
- Differentiation of tumor-promoting MDSCs into M1 macrophages and mature dendritic cells.2
Thus, antibody-mediated PS blockade reduces the levels of MDSCs, transforming growth factor beta (TGF-Î²) and IL-10 and increases the levels of TNF-Î± and IL-12.1 M1 macrophages contribute to tumor destruction through antibody-dependent cellular cytotoxicity, while mature dendritic cells educate T cells, inducing tumor-specific cytotoxic T-cell responses.2,3
- Yopp A, Kallinteris N, Huang X, et al. Antibody-mediated blockade of phosphatidylserine enhances the antitumor activity of targeted therapy and immune checkpoint inhibitors by affecting myeloid and lymphocyte populations in the tumor microenvironment. J Immunother Cancer. 2014;2(suppl 3):P266.
- Belzile O, Zhang Z, Huang X, et al. Antibody-mediated blockade of phosphatidylserine combined with radiation improves survival and tumor eradication in a rat model of non-small cell lung cancer. Cancer Res. 2014;74(19 suppl). Abstract 639.
- Yin Y, Barbero G, Brownlee Z, et al. Targeting phosphatidylserine to improve androgen deprivation therapy of prostate cancer. Cancer Res. 2011;71(8 suppl). Abstract 621.
The advent of next-generation sequencing (NGS) technologies has revolutionized the way we approach and utilize molecular diagnostic testing in oncology.
Overexpression of the epidermal growth factor receptor (EGFR) is correlated with poor prognosis in many human cancers.1 EGFR is a member of the ErbB family of receptor tyrosine kinases (TKs). EGFR activation occurs in response to ligand stimulation and/or genetic alterations of the EGFR gene, such as somatic mutations, amplifications, [ Read More ]