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During the annual routine checkup, the doctor said that your cholesterol is high and you have become one of the many unhealthy adults with cholesterol. According to the World Health Organization, in 2008, the global prevalence of adult total cholesterol (≥5.0 mmol/L) was 39%, of which the proportion of women was slightly higher than that of men (37% for men and 40% for women). The ratio of body fat to women is generally slightly higher than that of men.

Then you start to get rid of bad habits, try a balanced Mediterranean diet, choose foods marked with “Cholesterol-free” on the packaging; you start exercising, walk or yoga every day; friends say you are thin The spirit is also much better, but a blood test six months later, cholesterol is still high. The doctor said that you are a hypercholesterolemia patient and you should take medicine, otherwise the risk of myocardial infarction increases.

The doctor prescribed a statin to tell you that the drug is effective and has been the best drug in the world. Before this drug appeared, patients with hypercholesterolemia could not be cured. Statins can lower LDL cholesterol levels, thereby significantly reducing the risk of cardiovascular events (unstable angina, angina attacks, heart attack deaths, etc.). They also seem to reduce the risk of stroke and may even protect you from osteoporosis and Alzheimer’s disease. Although there are side effects, most of the side effects are mild and reversible, and the odds are very small. You should always be assured.

Unfortunately, you have become one of the few. In a population of hypercholesterolaemia patients, a small proportion of people who rely solely on statin drugs are not enough to lower cholesterol, and a few people cannot take statin because of side effects. The most common side effects are impaired liver function, abnormal liver enzymes, and some patients have abdominal distress, loss of appetite, or other symptoms. Another major side effect is muscle soreness, which can cause severe spasms when severe. Both of these major side effects can be confirmed by blood tests.

How to do? Can you only reserve a bed for yourself in the coronary care unit of the hospital?

In fact, your situation is not so bad. There is already a whole new class of monoclonal antibody drugs. It is also effective for certain cholesterol problems, especially those patients who still cannot achieve the desired level after statin treatment. That is us. PCSK9 antibody drug to be talked about today.

Functional mutations in PCSK9: “God’s genetic modification”

When the “genetically modified” was brought up, some people supported it and others opposed it. The controversy was very great. But “God’s genetically modified” – natural genetic mutations have always existed in all species, is one of the necessary conditions for species to survive in order to adapt to environmental changes, and those functional (mutations in biological function) genetic mutations for basic medicine Research has an irreplaceable role.

In 2003, a new major cellular regulatory pathway controlling the number and function of low-density lipoprotein cholesterol receptors was discovered. According to a report from the Montreal Clinical Research Institute in Canada, they have discovered a new gene encoding Proprotein Convertase on chromosome 1. This new proprotein convertase is called Proprotein Convertase Subtilisin/Kexin type 9, referred to as PCSK9.

Having found the gene, we can do genetic testing to see if there is any variation in this gene in hypercholesterolemic patients. Results In France, the team members really found an important piece of information: A functionally-acquired mutation in this gene was found in the family members of a family in France with familial hypercholesterolemia (FH).

The Contrast of Two Families: Gene Function “Switch”

In other words, in this French family, there is a common (that is, we often say “genetic”) gene mutations, this mutation makes them particularly strong PCSK9 function, leading to hypercholesterolemia. This is an important piece of information that reveals that the function of PCSK9 is likely to be related to the biological regulation of cholesterol.

If the enhancement of PCSK9 function really causes hypercholesterolemia, then we change our mind. Is it possible that the weakening of PCSK9 function may reduce cholesterol? Researchers in this area began to look for functional loss mutations of the PCSK9 gene in the population.

Sure enough, the results of the Dallas Heart Study soon after this showed that there were functional deletion mutations of the PCSK9 gene in members of some African-American families. This common gene mutation caused the loss of PCSK9 function in these individuals. The cholesterol levels of these family members were very low and their cardiovascular disease incidence was also low. This is a reversed correlation: the opposite functional mutation brings the opposite apparent characteristics.

These “contrary” comparisons provide direct genetic evidence that the gains and losses of PCSK9 have a significant role in the regulation of cholesterol. Therefore, PCSK9 has become an attractive drug target and has attracted the pharmaceutical industry. strong interest.

After a large amount of resources were invested, we quickly got a proof of concept in the animal model. In PCSK9 knockout mice, deposition of cholesterol in the aorta was significantly reduced; in contrast, mice with high PCSK9 gene expression exhibited excessive atherosclerosis. However, if the low density lipoprotein cholesterol (LDL-C) receptor is absent, changes in PCSK9 function have no significant difference in cholesterol deposition and plaque size, suggesting that PCSK9 enhances atherosclerosis mainly through LDL-C The role of receptors.

At the same time, the development of PCSK9 inhibitors has also been vigorously launched in all directions. In competition with antisense oligonucleotide gene silencing, short-interfering RNA, monoclonal antibodies, and auto-catalysed inhibition of the small molecule inhibitor PCSK9, the PCSK9 monoclonal antibody drug is one of the first to enter the market.

Monoclonal Antibody Drugs

To say clearly what a “monoclonal antibody drug” is, we must first talk about what is “monoclonal antibody.”

We know that antibodies are the product of immune responses in humans and mammals. In order to completely eliminate potentially harmful “invaders (antigens)”, the human body will produce up to 10 million different antibody molecules for the same antigen. We call this undivided mixture of antibodies a “multiple The “clonal antibody”.

It is not difficult to imagine that separating and purifying 10 million different antibody molecules by conventional methods is not practical. In the mid-1970s, scientists invented the hybridoma technique. Through cell engineering, hybridoma cells can produce a single antibody molecule, and a monoclonal antibody (abbreviated as mAb) emerged. This is a major breakthrough in the era of molecular biology and biotechnology engineering. It was soon widely used in the basic research of molecular biology and in various fields of biotechnology engineering. (Niels K. Jerne), Georges JF Köhler, and César Milstein received the 1984 Nobel Prize in Physiology or Medicine.

This technique makes it possible to use monoclonal antibodies as therapeutic drugs, because in theory, hybridoma technology can produce any one of a wide range of monoclonal antibodies with a defined specificity and class. In 1986, the first monoclonal antibody drug was launched for acute rejection of kidney transplants. However, the early antibody technology is not very mature. The immune response caused by non-human antibodies is a hidden danger. The cost of producing and purifying antibodies is also quite high.

In recent years, with the rapid development of gene sequencing and the transformation of basic medical scientific research into clinical medicine, especially the breakthrough of cancer immunotherapy, monoclonal antibodies have become the fastest growing biological drugs in clinical research (Biologics, The drugs produced by engineering technology, rather than chemically synthesized drugs, have an exponential upward trend in annual sales of the global antibody drug market. The new antibody technology allowed us to develop from the first generation of mouse-derived antibodies to the second generation of genetically modified chimeric antibodies, the third generation of humanized antibodies, and the latest fourth-generation fully human antibodies. Their properties in most aspects, like naturally occurring human immune proteins, generally do not cause the host immune system to respond. These novel monoclonal antibodies also have a similar half-life to native human immune proteins and can be extended to weekly or monthly intervals, some even longer. They also have a good synergy with the body’s own immune system.

Early monoclonal antibody drugs were used to treat rheumatism and tumors, but many other therapeutic areas are making progress. Currently, FDA-approved monoclonal antibody drugs have been used to treat a variety of diseases, including infectious diseases and cardiovascular diseases.

A new generation of lipid-lowering drugs Alirocumab

On July 24, 2015, the US FDA and the European Commission later approved the Alcocumab (Praluent®), a PCSK9 monoclonal antibody drug developed by Sanofi and Regenerators, for adult heterozygous familial high cholesterol. Heterozygous familial hypercholesterolemia, as well as patients with clinical atherosclerotic cardiovascular disease, still require additional reductions in LDL cholesterol levels after dietary control and maximally tolerated statin therapy.


Alirocumab is a new class of lipid-lowering drugs that are administered bi-weekly as subcutaneous injections and can be very effective in lowering LDL cholesterol, especially for families with high risk of inherited hyperlipidemia or cardiovascular disease Patients unable to rely on statins to lower LDL cholesterol provide new treatments. The data from ongoing clinical trials and postmarketing follow-up studies will provide more information on how these drugs can be used to treat dyslipidemia and prevent cardiovascular disease.

An initial study published by the American College of Cardiology at the American College of Cardiology called “ODYSSEY Outcomes” showed that the maximum tolerated dose of statin is combined with alirocumab compared to the maximum tolerated dose of statins alone In patients with high cardiovascular risk, the major adverse cardiovascular events were significantly reduced. In a post hoc analysis, the significant reduction in low-density lipoprotein cholesterol was also associated with a decline in the composite end point of a range of cardiovascular events, including coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or Needs hospitalization for unstable angina.


The ODYSSEY Outcomes long-term study evaluated a total of 18,924 patients. It is worth mentioning that this study also enrolled 614 Chinese patients. In the words of Professor Huo Yong, the first major researcher in Peking University, said: This study can not only reflect the role of drugs in the overall cardiovascular outcome, but also reflect the reduction in different end points. Shows the validity and safety data of Chinese subjects.

Become a history of high cholesterol

Another one-year physical examination.

The doctor locked his brow and turned to see your blood test report page by page. You sit uneasily on the opposite side of the doctor, keep rubbing your hands gently, swallowing the problem that has come to your mouth, and watching the changes in the doctor’s expression with a little nervousness.

The doctor finally read the report. The brow was stretched but he did not speak at all. He closes the folder and pushes it aside. Then he puts on a stethoscope and starts listening to your heart and lungs…

You finally couldn’t help it: “Doctor, my cholesterol?…”

The doctor gave a silent gesture and continued to listen intently. You had no choice but to continue to endure. Your heart said, “No heart disease will get you out.”

“Cholesterol,” the doctor took the stethoscope. “There is no problem at all. It seems that this drug is for you. It will continue to be used this year.”

You spit a long breath: “Help me measure blood pressure, I seem to think that blood pressure is a bit high.”


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