Despite its position right next door to the medical and pharmaceutical powerhouse that is the United States, the island nation of Cuba has long been unable to access the latest drugs and devices from the US for its people.
This is due to the ongoing almost total economic embargo against it that was imposed in 1962 by then US President John F. Kennedy due to Cuba’s proclamation of its Marxist and socialist status, and alignment with the then Soviet Union.
This lack of access has meant that Cuba’s doctors and scientists have had to put in their fair share of research and development to come up with their own drugs and devices.
“By 1991, we already had some Cuban products in development, and we also had other people’s products being manufactured in Cuba.
“Because of the economic embargo by the US, we didn’t have access to several medicines that were developed at that time.
“One of them was tissue plasminogen activator (which breaks down blood clots and is used to treat stroke), another was interferon (used to treat various cancers and viral infections), another is erythropoeitin for the treatment of nephrotic syndrome (and other conditions with low red blood cells levels).
“Making those drugs, which we manufactured in Cuba for the use of the Cuban people, helped us to boost the biotechnology and development of new drugs in Cuba,” says the country’s Centro de Immunologia Molecular (Centre of Molecular Immunology) business manager and researcher Dr Normando Iznaga-Escobar.
Not only does Cuba offer free universal healthcare for its citizens, but its biotechnology products and exported medical services are also top contributors to its economy.
Creating A Single Line
One of the most promising drugs to come out of the Caribbean island to date is the cancer treatment nimotuzumab.
“We’ve come out with something that is now helping people – it’s improving the survival of the patient, improving the quality of life, and also, increasing the survival rate at five years.
“Because the target is not only to improve the survival by a few months, it’s the survival rate at five years, which was very low for many cancers.
“And now, for example, in Cuba, for head and neck cancers, which include cancers of the nasopharynx, oropharynx, tongue and tonsils, the survival rate at five years is more than 60%,” says Dr Iznaga-Escobar.
According to the Union for International Cancer Control, the five-year survival rate for squamous cell carcinomas of the head and neck, which comprise about 90% of all head and neck cancers, is about 40%-50%.
Nimotuzumab, which has been around for 20 years and was patented in the US in 1999, is a monoclonal antibody that is currently being used to treat not only squamous cell carcinomas of the head and neck, but also glioma, pancreatic cancer, oesophageal cancer and nasopharyngeal cancer in various countries.
It is also being tested in clinical trials for cancers of the colon, breast, liver, stomach and the epithelium.
Antibodies are highly specialised proteins that are designed to stick to one other specific protein called an antigen, which are found on the surface of cells, in order to help other immune cells find and destroy them.
Antibodies in the body are polyclonal, meaning that they come from more than one cell line.
In contrast, monoclonal antibodies come from only one specific cell line (or clone) and are harder to create in the laboratory, compared to polyclonal antibodies.
As Dr Iznaga-Escobar explains, the target antigen has to be injected to an animal – in this case, a mouse – along with Freund’s Complete Adjuvant, a chemical emulsion that helps stimulate the production of antibodies.
Once the mouse’s spleen has produced the appropriate antibodies, it is removed and fused with a myeloma (a form of cancer cell) in the laboratory to enable the resulting hybridoma to continue reproducing the antibodies indefinitely.
Then, using a technique called CDR (complementarity-determining region) grafting via recombinant DNA technology, the specific part of the antibody that recognises the antigen is removed – a sequence of 110 amino acids – and placed within the framework of a human antibody (versus its original mouse antibody structure).
After that, the now-humanised monoclonal antibody is tested against various cancer cell lines to see which one(s) it recognises and affects.
Double Action Antibody
In the case of nimotuzunab, the antigen that is targeted is the epidermal growth factor receptor (EGFR).
“Epidermal growth factor is a general protein that is vital for the cell to survive and grow,” shares Dr Iznaga-Escobar, who is also the chief scientific officer and Global Nimotuzumab Project Leader at the Singaporean-Cuban joint venture company Innocimab.
“The function of epidermal growth factor in the cell is to send signals to the cell to stimulate DNA synthesis (resulting in cell division and differentiation).”
EGRF is like the lock on the cell membrane to which the factor is the key that opens it to initiate cell division (see Lock and key).
EGRF can be found on the epithelial cells of the body, which line all our blood vessels and organs, and forms our skin.
Certain cancers result from uncontrolled activation of EGRF, which causes rapid division of the affected cells to form a tumour.
As Dr Iznaga-Escobar explains, nimotuzunab works in two ways.
“When the monoclonal antibody binds to the EGRF, it will stop the signal transduction and that means the cell will not be able to duplicate.
“It will die or it will stop DNA synthesis,” he says.
“Because EGRF is overexpressed – maybe a million times – more than in normal tissue, we’re able to inject a certain amount of the monoclonal antibody and about 10%-15% of whatever you inject goes into the tumour.
“The rest is discarded by the body,” he adds.
Nimotuzunab can also act as a transporter, carrying either drugs or radioactive isotopes directly to the cancer cells to kill them.
Dr Iznaga-Escobar notes that both activities are equally important as cancer cells can sometimes find a way to bypass the EGRF blockage and reproduce; therefore, using two methods of stopping it gives a higher chance of success.
While nimotuzunab is not the only EGRF monoclonal antibody in the market, Dr Iznaga-Escobar notes that other similar monoclonal antibodies have more toxic side effects because they have a higher affinity for EGRF.
“That’s the problem – very high affinity is good because you target more in the tumour, but at the same time, you target the normal tissue.
“And targeting the normal tissue causes skin rash, pruritis (itchiness), paronychial inflammation (an infection where the nails meet the skin), conjunctivitis, hypomagnesaemia (low magnesium levels) – all these things that cause damage to the skin, eyes, liver, kidney.
“Naturally, we didn’t try to do it like that.
“Our antibody has the same affinity for the receptor like the natural factor, so when we inject the antibody in the amount we inject, it will not bind to the skin, the kidneys, the liver, all those things.
“Using our product, you avoid the side effects,” he explains.
And this is a significant consideration when it comes to the long-term use such anti-cancer drugs require.
While in Cuba, medications come free under their healthcare service, for the rest of us, this monoclonal antibody does not come cheap.
According to Dr Iznaga-Escobar, it costs about US$1,200 (RM5,069) per treatment.
The first round involves weekly injections for 12 weeks, followed by monthly injections for the rest of the patient’s life to control the tumour size.
Dr Iznaga-Escobar was in town recently for the 2017 Latin American Business Day held in Kuala Lumpur.