Modified Annexin

Rubicon’s Modified Annexin Immunotherapy Program

The Problem that Rubicon is Solving: Cancers that grow resistant to certain therapeutic regimens over time by “shedding” the marker that the therapeutic agent was targeting.

Despite recent medical advancements, cancer continues to be a devastating disease, and new treatment options are desperately needed. In the US alone in 2016, there were an estimated 1,700,000 new cancer cases diagnosed and 600,000 deaths due to cancer.1 The most common types of cancer in males are lung cancer, prostate cancer, colorectal cancer and stomach cancer. In females, the most common types are breast cancer, colorectal cancer, lung cancer and cervical cancer.2 Melanoma is another solid tumor that afflicts both sexes and is especially dangerous if not detected early. 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.

Another significant problem is cancer metastasis. During metastasis, cancer cells break away from where they first formed (primary cancer), travel through the blood or lymph system, and form new tumors (metastatic tumors) in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor; hence, the metastatic disease is viewed as an extension of the primary cancer. For example, breast cancer that spreads to the lungs is called metastatic breast cancer, not lung cancer. It is treated as stage IV breast cancer, not as lung cancer.3

  1. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016
  2. http://www.wcrf.org/int/cancer-facts-figures/worldwide-data
  3. https://www.cancer.gov/types/metastatic-cancer

Rubicon’s Solution: 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 Annexin A5, a natural protein discovered by Dr. Chris Reutelingsperger at Maastricht University which binds to phosphatidylserine (PS) with high affinity (binds tightly and specifically to phosphatidylserine). Typically, the problem with molecules binding to phosphatidylserine is that the agent, once bound to PS, can be internalized into the cell, which neutralizes its effectiveness. Dr. Reutelingsperger modified the annexin so that it will not internalize into cells, preventing this problem.

Modified Annexin Mechanism of Action

PS is exposed on the outer membrane on many different tumor types and tumor-specific blood vessels, but not on healthy cells. Rubicon’s Modified Annexin binds to PS, but does not internalize, and so is able to deliver powerful immunotherapy drugs to the tumor microenvironment where phosphatidylserine is commonly found on the surface of tumors and tumor vasculature. Since healthy cells are not affected, side effects are minimal. At present, the therapeutic compounds fused to the modified annexin under development are Tumor Necrosis Factor-alpha (TNF-alpha) and an IgG antibody fragment (the Fc fragment). TNF-alpha is a potent signaling protein normally present to fight inflammation and cell damage. By specifically delivering TNF-alpha into a tumor, the body’s own immune system is signaled to attack the tumor. The Fc antibody fragment is also a powerful signal for the immune system to attack tumor and tumor vasculature.

 

Modified Annexin Data Summary


  Breast Cancer

Two Modified Annexin fusion proteins were administered intravenously in single administration and multiple dose regimens. Data will be presented in 2017.

Rubicon was awarded a grant from the National Cancer Institute (NCI) to study Modified Annexin’s ability to target tumors and tumor vasculature and deliver therapeutic quantities of immunoconjugate drugs. In this study, Rubicon has created and produced novel immunotherapeutic fusion proteins using the Modified Annexin technology, including Annexin:TNF-alpha and Annexin:Fc. A maximum tolerated dose (MTD) study was performed at Bioanalytical Systems, Inc. (BASi®), a leading contract research organization. Animal efficacy studies were then subcontracted to the laboratory of Dr. Andries Zjilstra at Vanderbilt University. In the animal studies, balb/c mice were injected with breast cancer cells, and the resulting tumor was allowed to grow to a pre-determined size. The Modified Annexin fusion protein was administered intravenously in single administration and multiple dose regimens. Favorable data has been obtained for this breast cancer model, and similar studies are underway in other animal models of melanoma and metastatic breast cancer.


Melanoma Metastases

Two Modified Annexin fusion proteins were administered intravenously in single administration and multiple dose regimens. Data will be presented in 2017.


Breast Ovarian Prostate

In addition to the animal studies being conducted at Vanderbilt, Rubicon is working with Syngene International to develop another application of Modified Annexin’s ability to target additional tumor cell lines. The results of these studies are expected to provide other novel approaches to cancer immunotherapy.

 

View and Download Rubicon’s Modified Annexin Presentation [PDF]