Annexin Pharmaceuticals directs his candidate ANXV – a 99,5 percent identical variant of the body's own protein Annexin A5 – against two focus areas. The primary focus area is the eye disease retinal vein occlusion, RVO. The company is currently conducting two RVO studies; a clinical phase II study in the USA, and an imaging study in the Netherlands. Since the beginning of the year, the candidate has also been positioned against cancer after many independent researchers published in the field, including in Nature Communications., and pointed out that Annexin A5 may have cancer-killing effects.
Annexin A5 – multiple mechanisms of action in cancer
The background to these cancer-killing effects is that Annexin A5 binds to a fatty substance, which is present in large quantities on the surface of many cancer cells – namely phosphatidylserine (phosphatidylserine, PS). By blocking PS with Annexin A5, cancer cells find it more difficult to evade immune system attacks.
Another way that Annexin A5 can work in cancer treatment, and more independently of the immune system, is by being conjugated, i.e. chemically linked, with, for example, chemotherapy drugs. In this way, the protein can help the chemotherapy drugs to be transported directly into the cancer cells and thus increase the uptake of the chemotherapy, which can both increase the effect inside the cell and reduce known side effects by reducing uptake in healthy cells in other parts of the body.
Successfully created a conjugate
It is on the latter point that Annexin announced at the end of the month that it had made progress. In its preclinical research, the company has succeeded in conjugating ANXV with a cytotoxic agent, thereby forming a new molecule. Both the cytotoxic agent and ANXV were tested individually in cell systems outside the body, including a cancer cell from a person with triple-negative breast cancer, a form of breast cancer that is known to be difficult to treat. On their own, neither the cytotoxic agent nor ANXV had any effect on the cancer cells, but the combined molecule succeeded in killing cancer cells.
CMO/CSO tells more
BioStock contacted Annexin's CMO/CSO and co-founder Anna Frostegård, who told more about the success in the cancer initiative.
The ANXV conjugate was thus able to kill a difficult-to-treat cancer cell from a patient with triple-negative breast cancer. How important is this discovery?
– A conjugated drug usually contains an antibody, which recognizes a protein receptor expressed on the surface of a cancer cell, such as a breast cancer, and another molecule that stops cancer growth or damages DNA. Anticancer conjugates are a dynamic, very promising area that has seen over 15 FDA-approved drugs.
– In our case, we use ANXV, a protein that recognizes a lipid, a fatty substance, called phosphatidylserine (PS), usually overexposed on the surface of cancer cells. We have successfully conjugated a highly toxic molecule to ANXV. The toxic molecule cannot be administered by itself, because it is too toxic and cannot distinguish between cancer and healthy cells. As we had hoped, we have also observed that our ANXV conjugate entered these cancer cells, which is very important for success because this cytotoxic molecule is expected to kill cancer cells when cleaved from ANXV inside the cell.
– If we look specifically at triple-negative breast cancer, it is often very difficult to treat. Through our experiments, we show that a PS-exposing type of cancer cell can be effectively killed by our ANXV conjugate. I believe this is a very important first step forward in realizing the potential of ANXV conjugates in anti-cancer treatment. I say conjugates because we expect that the method we used now will work to link other molecules to ANXV, opening up a platform opportunity for ANXV.
– Importantly, we see broad potential in the ANXV conjugate program as PS externalization does not appear to be limited to one or just a few cancer types – as is often the case for the antibody-based conjugates available today. Thus, the potential for ANXV conjugates to treat cancer is much broader than the standard antibody-based conjugates.
With this in mind - how do you think about which cancer indications you might target in the future?
– Our trials in triple-negative breast cancer cells are a first example of a possible indication, but that does not necessarily mean that we will start or limit ourselves to this cancer type in the future. For example, there is published data showing that cancer cells from ovaries or in head and neck tumors often expose PS. We are optimistic about finding a way to identify patients with cancer that expose PS in order to be able to select patients for future studies.
What will be the next step in the field of oncology?
– With the data we have generated in vitro, the next step in ANXV conjugate development is to investigate its ability to kill tumors in animal models. We will also investigate its toxicity and tolerability profile in a pilot study before we can assess whether the justification to proceed to patients is strong enough. It will take time and investment to produce the conjugate for human use and to perform detailed toxicological testing. In parallel, we will explore the interest in partnerships for this program.
What does the competition look like for the development of variants of the body's own protein Annexin A5? What does this mean for your positioning in the market?
– We are aware of another company based in China that is developing a, as far as we understand, very similar Annexin A5 protein for the treatment of septicemia and they are reportedly also in patient studies. We are not aware of any companies working on Annexin A5 conjugates. We believe we have the unique knowledge, data and patents to be a global leader in this area for a long time to come.