Despite recent medical advancements, cancer continues to be a devastating disease, and new treatment options are desperately needed. In the US alone, there were an estimated 1,700,000 new cancer cases diagnosed and 600,000 deaths due to cancer. The risk of cancer increases significantly with age; many cancers occur more commonly in developed countries since the life expectancy is higher than in other parts of the world.

“Cancer is the second leading cause of death in the US. Current major treatments for cancer management include surgery, cytotoxic chemotherapy, targeted therapy, radiation therapy, endocrine therapy and immunotherapy. Despite the endeavors and achievements made in treating cancers during the past decades, resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies. Drug resistance, either existing before treatment (intrinsic) or generated after therapy (acquired), is responsible for most relapses of cancer, one of the major causes of death of the disease.”¹

^1”Drug resistance and combating drug resistance in cancer" (Cancer Drug Resist 2019;2:141-160)

Rubicon’s Solution

AnxA5MOD-TNFSF (Modified Annexin Immunotherapy) will target a stable, non-shedding target on tumors and tumor vasculature, the blood vessels that nourish the tumor. Our approach uses a modified version of Annexin A5, a natural protein discovered by Dr. Chris Reutelingsperger at Maastricht University which binds tightly and specifically to phosphatidylserine (PS). PS is exposed on the outer membrane on many different tumor types and tumor-specific blood vessels, but not on healthy cells. Typically, the problem with molecules binding to phosphatidylserine is that the agent, once bound to PS, will internalized into the cell, which neutralizes its effectiveness. Dr. Reutelingsperger modified the annexin so that it will not internalize into cells, preventing this problem.

Rubicon attached TNF Super Family agents to the AnxA5MOD to deliver powerful immunotherapy drugs to the tumor microenvironment where phosphatidylserine is commonly found. Since healthy cells are not affected, side effects are minimal.  By specifically delivering TNF-SF agents to the tumor, the body’s own immune system is signaled to attack the tumor.

Rubicon’s Modified Annexin technology will trigger an immunostimulatory response against a tumor by directly binding phosphatidylserine (PS) exposed on the surface of tumor cells and the tumor vasculature.

A myriad of academic studies have demonstrated that cell surface PS can be selectively targeted in the tumor microenvironment. Anionic phospholipids, like PS, are largely absent from the surface of resting mammalian cells under normal conditions but are prevalent on the surface of living tumor cells and on tumor vasculature. This selective exposure of PS in the tumor microenvironment provides the opportunity to exploit it as a target for the delivery of cancer therapeutics.

Tumors avoid a full immunological assault by manipulating key “checkpoints” designed to prevent auto-immune disease. Blockading these “checkpoints” has included development and FDA-approval of ipilimumab, an antibody targeting CTLA-4 to inhibit downregulation of T-cell activation. It has also included development of antibodies to disrupt the PD-1/PD-L1 ligand -receptor complex. Yet, these therapies localize not only to tumors and but to the general immune system. Cell surface exposure of PS within the tumor environment provides a checkpoint localized to the tumor so targeting should be less disruptive to a patient’s overall immune system.