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.
Approvals for new delivery methods for Herceptin and Cinvanti, and a new indication for Lonsurf close out the month of February in the FDAâs oncology-related activity.
FOLFOX plus FOLFOX-A in the Treatment of Metastatic or Advanced Unresectable Gastric/Gastroesophageal Junction Adenocarcinoma
Findings of the phase 2 study of FOLFOX plus nab-paclitaxel indicate that the anthracycline-based triplet regimen was associated with a high response rate and expected toxicities in patients with metastatic or advanced unresectable gastric/gastroesophageal junction adenocarcinoma.