25 years of 5T4…

pre-clinical stages or early phase clinical trials - the 10 year wait

We live in an age of precision biology, where great advances have been made. Yet in Europe and North America combined, approximately 2.5 million people will die of cancer this year (as happened in previous years). Worldwide there will be around 8 million cancer deaths this year (see world cancer report 2014 from the WHO). Obviously, there is room for considerable improvement in mainstream treatments. Especially for those 8 million cancer patients that will end up dead by the end of the year…

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As such, one wonders what kind of life saving therapies could possibly be available to those 8 million end stage cancer patients today.

There are quite a considerable amount of promising drugs and therapies which are either in pre-clinical stages or early phase clinical trials. However, rules and regulations will prevent these drugs from entering the market for another 5 – 10 years. 

5T4 - and a range of diverse cancer therapies

Secondary structure of  IgG antibody - Image courtesy 

of Science Photo Library

One active area of cancer research that currently looks very promising is immunology. Here, I use the word immunology in the broadest sense possible. Examples of immunology-based therapies include antibodies, antibody drug conjugates (ADCs), attenuated viral and bacterial vaccines, T cell, and dendritic cell therapy, etc…

To illustrate how incredibly diverse cancer immunotherapies can be, I will highlight the next generation therapies based on a tumour associated antigen called 5T4 (otherwise known as oncotrophoblast antigen, 5T4 onco-foetal antigen, or Trophoblast glycoprotein (TPBG)) which have been developed by several groups. 

Getting acces to 5T4 based immunotherapies for cancer

The good news is that at least one of them can be legally obtained in Europe on a compassionate use basis. The bad news is that your insurance company may not cover it as it is not yet an approved drug. In addition, your oncologist / physician will have to officially apply for special dispensation to obtain and administer this drug. In other words, these drugs are NOT on the market currently and you will only be able to get potential access to them if you enroll in a clinical trial (e.g. Europe EMA / America FDA) or if your physician / oncologists gains access through a compassionate use programme.

The 5T4 based therapies are being used to treat solid tumours. Compassionate use is indicated for people with colon cancer, renal cancer, and prostate cancer. 

Who is developing these 5T4 based therapies?

Currently, there are three pharmaceutical / biotech companies developing and commercialising 5T4 targeted therapies:

1. Oxford Biomedica, based in the UK, has a therapy in development called TroVax. This is a recombinant viral vaccine based on an attenuated strain of Modified Vaccinia virus Ankara (MVA) that delivers the 5T4 antigen.
2. Active Biotech, based in Lund, Sweden, has been developing a next generation drug called Anyara. This is an anti-5t4 antibody fragment (Fab) conjugated to a superantigen variant called mutated staphylococcal enterotoxin A (SEA/E-2). Research suggests that the proposed mechanism by which Anyara (Naptumomab estafenatox; ABR-217620) exerts its effect on cancer is through targeting T cells to tumours.
3. Pfizer, based in the USA, is currently working on its next generation Antibody Drug Conjugate (ADC) called A1mcMMAF (PF-06263507). This biologic is a novel anti-5T4 ADC, which comprises a humanised anti-5T4 A1 antibody linked to a potent tubulin inhibitor called monomethylauristatin F (MMAF). These components (the antibody and the cytotoxic “payload” are linked via a noncleavable maleimidocaproyl (mc) linker. They published a paper in 2013, in which they compare their first generation ADC with this next generation version. Their first generation ADC was an anti-5T4 antibody linked to calicheamicin. The concept is really quite simple and very elegant. ADCs combine very precise and selective targeting of cancer cells with extremely toxic compounds that will subsequently only damage the tumour cells. Thereby, generating agents that are safe and highly effective.

Who discovered 5T4?

Two scientists called N. Hole and P. L. Stern from the University of Liverpool, UK (with funding from Cancer Research UK). They discovered the 5T4 antigen in 1987 when they were searching for novel trophoblast cell surface antigens. This investigation led them to a 72kDa protein, which they called 5T4 antigen (5T4.B8 is the name/code they gave to the mouse IgG1 monoclonal antibody (subclone) with which they did their initial research in the late eighties). 5T4 antigen (the target) is a transmembrane glycoprotein that is overexpressed by a wide spectrum of cancers, but has only limited expression in normal tissue. As such it represents a rational and interesting target for cancer immunotherapy.

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