One of Annexin Pharmaceuticals’ important achievements lately is having created a conjugate of the drug candidate ANXV. By binding the candidate to a chemotherapy agent, the goal is to eventually offer a cancer treatment with a new mechanism of action where effective treatments are currently lacking. BioStock contacted the company’s CSO/CMO and co-founder Anna Frostegård to know more about the importance and the plans going forward.
Annexin Pharmaceuticals positions their candidate ANXV – a variant of the body’s own protein Annexin A5, identical up to 99.5 per cent – towards two focus areas. The primary focus area is the eye disease retinal vein occlusion, RVO. The company is conducting two RVO studies; a clinical phase II study in the USA and an imaging study in the Netherlands. Since the turn of the year, they have also positioned the candidate towards cancer after many independent researchers have published in the field, including in Nature Communications, and indicated that Annexin A5 may have cancer-killing effects.
Annexin A5 – several mechanisms of action in cancer
The background to these cancer-killing effects is that Annexin A5 binds to a fatty substance, which is abundant on the surface of many cancer cells – namely phosphatidylserine (PS). By blocking PS with Annexin A5, cancer cells find it more difficult to evade the immune system’s attacks.
Another way that Annexin A5 can play a role in cancer treatment, and more independently of the immune system, is by being conjugated, i.e., chemically linked with, for example, chemotherapy agents. In this way, the protein can assist the chemotherapy agents in being transported directly into the cancer cells, thereby increasing the uptake of the chemotherapy agent, which can both enhance the effect inside the cell and reduce known side effects by decreasing uptake in healthy cells in other parts of the body.
Successfully created a conjugate
On this latter point, Annexin reported progress at the turn of the month. In their preclinical research, the company has managed to conjugate ANXV with a chemotherapy agent, thereby forming a new molecule. Both the chemotherapy agent and ANXV were tested separately in cell systems outside the body, including a cancer cell from a person with triple-negative breast cancer, a well-known difficult-to-treat form of breast cancer. Neither the chemotherapy agent nor ANXV had any effect on the cancer cells on their own, but the combined molecule successfully killed the cancer cells.
CMO/CSO tells us more
BioStock contacted Annexin’s CMO/CSO and co-founder Anna Frostegård, who provided further details about the progress in the cancer initiative.
The ANXV conjugate was able to kill a difficult-to-treat cancer cell from a patient with triple-negative breast cancer. How significant is this discovery?
– A conjugated drug usually contains an antibody that recognises a protein receptor expressed on the surface of cancer cells, such as in breast cancer, and another molecule that halts cancer growth or damages DNA. Anticancer conjugates are a dynamic and very promising area that has seen over 15 FDA-approved drugs.
– In our case, we use ANXV, a protein that recognises a lipid, a fatty substance, called phosphatidylserine (PS) – which is typically overexpressed on the surface of cancer cells. We have successfully conjugated a highly toxic molecule to ANXV. The toxic molecule cannot be administered on its own because it is too potent and cannot differentiate between cancer and healthy cells. As we had hoped, we have also observed that our ANXV conjugate entered these cancer cells, which is crucial for success because this cytotoxic molecule is expected to kill cancer cells when it is 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 demonstrate that a PS-exposing type of cancer cell can be effectively killed by our ANXV conjugate. I believe that this is a very important first step towards realising the potential of ANXV conjugates in anti-cancer treatment. I say “conjugates” because we expect the method we used now to work for attaching other molecules to ANXV, opening up a platform for the potential of ANXV.
– What is important is that we see a broad potential in the ANXV conjugate program, as PS externalisation does not seem to be limited to just one or a few types of cancer – which 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 usual antibody-based conjugates.
With this background in mind, how are you considering which cancer indications you may focus on in the future?
– Our attempts in triple-negative breast cancer cells are the first example of a potential indication, but it does not necessarily mean that we will start or limit ourselves to this type of cancer in the future. For example, there are published data showing that cancer cells from ovaries or head and neck tumours often expose PS. We are optimistic about finding a way to identify cancer patients who exhibit PS exposure to make a selection for upcoming studies.
What is 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 tumours in animal models. We will also examine its toxicity and tolerability profile in a preliminary study before we can assess if the justification to proceed to patients is strong enough. It will take time and investment to produce the conjugate for human use and to conduct detailed toxicological tests. In parallel, we will explore interest in partnerships for this program.
What is the competition like for the development of variants of the endogenous protein Annexin A5? What does it mean for your positioning in the market?
– We are aware of another company based in China that is developing, as far as we understand, a very similar Annexin A5 protein for the treatment of sepsis, and reportedly, they are also in patient studies. We are not aware of any companies working on Annexin A5 conjugates. We believe that we have unique knowledge, data, and patents to be a globally leading company in this area for a long time to come.The content of BioStock’s news and analyses is independent but the work of BioStock is to a certain degree financed by life science companies. The above article concerns a company from which BioStock has received financing.