Bavituximab: Targeting Phosphatidylserine, (PS) an Upstream Immune Checkpoint to Fight Cancer

Bavituximab is a !rst-in-class monoclonal antibody that targets phosphatidylserine (PS) and has demonstrated the potential to reactivate tumor-!ghting immune responses. In October 2013, data published in the American Association for Cancer Research (AACR) peer-reviewed journal Cancer Immunology Research showed that PS-targeting antibodies mediate multiple immunostimulatory changes in the tumor environment, including a reduction of tumor-promoting im-mune cells and an increase in tumor !ghting macrophages, dendritic cells and T-cells1.

Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS), a molecule found on the inside surface of the membrane of healthy cells.

Cancer leverages this same cellular process to evade immune detection, allowing tumors to grow unimpeded by the immune system. High levels of PS are exposed on the cells in tumors and on small particles shed from tumor cells known as microvesicles.

PS is engaged by immune cells leading to the secretion of signaling chemicals that keep immune cells in a dormant state, preventing them from recognizing cancer as a foreign invader. Speci!cally, myeloid derived suppressor cells (MDSC) and M2 macrophages accumulate and maintain an immunosuppressive tumor environment, TGF-beta and IL-10 levels increase, dendtritic cells fail to mature, T-cells remain naive and M1 macrophages fail to develop.

Bavituximab is an investigational cancer treatment developed by Peregrine Pharmaceuticals that targets and binds to PS, a molecule that is abundantly exposed in the tumor environment.

Bavituximab engages docking molecules on immune cells and initiates fundamental immunostimulatory changes in the tumor environment.

Bavituximab mediates an increase in powerful signal-ing chemicals that transform immune cells from a state of tolerating cancer growth, into cells that recognize and actively !ght the tumor. Speci!cally, this includes increases in TNF-alpha and IL-12, decreased MDSCs, M2 to M1 macrophage polarization and increases in mature dendritic cells and tumor-speci!c cytotoxic T-cells.

The activated cells of the immune system then work together to !ght cancer by destroying the blood vessels that feed the tumor, as well as the tumor cells. M1 macrophages destroy cells via antibody dependent cellular cytotoxicity (ADCC), while mature dendritic cells present tumor antigens to T-cells facilitating tumor-speci!c cytotoxic T-cell responses.

As a cell naturally dies, PS "ips to the outside exposed surface of the cell.

Phosphatidylserine (PS), (dark purple)

PS !ip during cell death

Macrophage

Microvesicle

[ MDSC, M2 mac, immature DC ]

Dying host cell

Tumor cell

[ Bavituximab ]

[ Bavituximab ]

[ Tumor-speci"cCytotoxic T-cell ]

[ M1 macrophage ][ Mature dendritic cell ]

[ F Receptor ]

PS is a highly immunosuppressive molecule that when exposed on the surface of a cell is engaged by docking molecules on immune cells. PS then signals these immune cells to not attack the cell as normally seen when !ghting a foreign invader.

White blood cells are then free to remove aging cells without the prompting of an immune attack against the body.

Bavituximab Targets Phosphatidylserine (PS)

Bavituximab

Bavituximab Targets Exposed PS in the Tumor Environment

High Levels of PS are Exposed in the Tumor Environment

PS Moves to the Exterior on Dying Host Cells

Exposed PS in Tumors Induces Multiple Immunosuppressive Effects

PS Engages PS Receptors on Immune Cells Bavituximab’s Immunostimulatory Effects

Routine Disposal of Dying Host Cells Bavituximab Reactivates Anti-Tumor Immune Responses

Bavituximab Engages F Receptors on Immune Cells

Peregrine Pharmaceuticals, Inc.14282 Franklin Avenue,Tustin, CA 92780 Phone: 714-508-6000

Published studies show that the upstream immune checkpoint blockade mediated by Peregrine’s PS-targeting antibodies mobilizes the immune system to !ght cancer by activating both innate and adaptive anti-tumor immune responses.

1. Yi Yin, Xianming Huang, Kristi D. Lynn, and Philip E. Thorpe, Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation, Cancer Immunology Research:#October 2013 1:256-268

Bavituximab is being evaluated in second-line non-small cell lung cancer (NSCLC) as part of the SUNRISE pivotal Phase III clinical trial. For more information, please visit www.sunrisetrial.com