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Once upon a time, bacterial infections claimed the lives of thousands of people. With the discovery and widespread clinical use of penicillin in the first half of the 20th century, antibiotics have greatly reduced the mortality caused by bacterial infections and made a great contribution to the health of all human beings. This is beyond doubt. However, people are over-reliant on antibiotics, and unreasonable use and abuse are widespread, leading to the continuous breeding of drug-resistant bacteria and becoming a “superbug” that continues to threaten human health.

 

Where do the resistant bacteria come from?

Natural selection, survival of the fittest. Everything in the world follows this law of survival. Humans are like this, and bacteria are the same. In order to survive, humans invented the antibiotic-resistant bacteria threat of various mechanisms of action and won one victory. For bacteria, the pressure of choice in the face of antibiotics is also becoming stronger. The so-called selective pressure, also known as evolutionary pressure, refers to the pressure exerted by the outside world on a biological evolutionary process, thereby changing the direction of the process, or Darwin’s natural selection, that is, the choice of nature and the choice of organisms. Stress makes it possible for people who adapt to the natural environment to survive and multiply. In general, in the long-term use of antibiotics, the majority of sensitive strains are constantly being eliminated, while the drug-resistant strains that originally belonged to the minority survived and gained more space to multiply, instead of sensitive strains. The rate of resistance of bacteria to antibiotics is increasing.

Bacteria compete with the survival of human beings, just like “the height of a magic is one foot, the height of a road is one foot”, and the turn takes the upper hand. In order to be able to fight multiple bacteria at the same time, humans are keen to develop broad-spectrum antibiotics. Therefore, the surviving bacteria are as good as the King Kong, and can resist multiple antibiotics, gradually forming multi-drug resistant bacteria, extensive resistant bacteria and pan-resistant bacteria. What is worrying is that the efficiency of new drug research and development is low, and the stamina is weak. The traditional antibiotics for treating bacterial infections are under tremendous pressure, and human health faces severe challenges. This caused a panic in the “post-antibiotic era”, as human antibiotics were invented and widely used before, and humans had no cure for bacterial infections.

In the past few years, researchers have proposed the concept of “ESCAPE” pathogen, highlighting the most threatening bacteria to humans, including:

  • Enterococcus faecium
  • Staphylococcus aureus
  • Clostridium difficile
  • Acinetobacter baumannii
  • Pseudomonas aeruginosa
  • Enterobacteriaceae

In-hospital infections caused by the above-mentioned drug-resistant bacteria are very common in severe and immunocompromised patients, and they are life-threatening. It is urgent to develop new drugs to curb them, otherwise we will face a drug-free environment and allow bacteria to erode. In this context, people are working on the rational use of antibiotics on the one hand, and developing new antibiotics to resist resistant bacteria on the other. Although some achievements have been made, the situation is still grim, especially in the field of new drug research and development. Due to the pressure of biological evolution, antibiotics and drug-resistant bacteria are a race for you to catch up with. Humans can’t guarantee that they will always be in the lead in this competition. Once they are overtaken by resistant bacteria, death will come at any time. .So is there a way to get rid of this endless race?

 

Taking history as a guide, looking for a way out

From the perspective of pathogenesis, bacterial pathogens produce virulence factors that prevent the host from clearing pathogens, thereby invading deep tissues and destroying host cells. In addition to the direct inhibition or killing of bacteria by antibiotics, scientists also thought of developing antibody therapy with pathogen specificity to prevent and treat bacterial infections. Antibodies are natural proteins produced by the adaptive immune system. Passive immunization of the human body not only neutralizes the virulence factors, but also strengthens the host’s ability to respond to the pathogen’s immune response, so that it will not develop.

Passive immunization with antibodies to prevent or treat bacterial infections is not a new theory. Humans have successfully practiced such theories in serum therapy long before the discovery of antibiotics. Since the end of the 19th century, serum therapy has been used to treat various infectious diseases, including diphtheria, pneumonia, meningitis, erysipelas, anthrax, etc., demonstrating that antibody therapy is a powerful weapon against infectious diseases. The possibility of drug resistance of this treatment is very low, because it does not directly kill or inhibit the growth of bacterial pathogens, but neutralizes the virulence factors produced by bacterial pathogens. In this way, not only the disease-causing process is prevented, but also the selection pressure is avoided, and the drug-resistant bacteria will not rapidly overgrow.

However, the use of heterologous serum in the human body produces immunological complications, and, coupled with the high cost, serum therapy is later replaced by a more affordable broad-spectrum antibiotic. Over time, some problems can be solved with modern technology. Serum antibodies are a mixture of polyclonal antibodies with different specificities, and today the antibody purification process is significantly improved. Together with the all-human technology, immune complications can be greatly reduced. In addition, most monoclonal antibodies bind only to invading pathogen targets compared to antibiotic-bound broad bacterial targets. This specificity has once been abandoned by a wide range of pharmaceutical companies that prefer broad-spectrum drugs, but it now appears to be an advantage because Broad-spectrum antibiotics destroy all of the original micro-ecology, leading to ecological imbalances and diseases such as C. difficile colitis.

The development and application of monoclonal antibody therapy in the field of bacterial infection is far less than in the field of tumor and autoimmune diseases. There are many reasons for this, including the fact that there are already a large number of antibacterial drugs on the market, leaving a small market for monoclonal antibody therapy, and the cost of monoclonal antibody itself is high, and there are antigenic variations in microorganisms. However, with the increasing antibiotic resistance problem, there is no treatment for new pathogens, and the combination of monoclonal antibody therapy is becoming more and more common. In addition, the development of monoclonal antibodies is becoming more advanced, and the prospect of monoclonal antibody prevention and treatment of bacterial infections It is worth looking forward to.

 

The future is bright, the road is tortuous

At present, the main disadvantage of monoclonal antibody therapy is its high cost and cumbersome use. However, with the high expression of cell lines and continuous process technology, the cost of monoclonal antibodies is continuously decreasing and gradually reaching an acceptable level. For critically ill patients, even if antibiotics are used, infusion methods are generally used. There was no difference between administration and monoclonal antibody. Therefore, these two disadvantages are not insurmountable. In contrast to its advantages, there is reason to believe that monoclonal antibody is well worth investing in the arsenal of preventing and treating bacterial infections.

First, the monoclonal antibody is specific and only targets specific pathogens. Once the pathogen is identified by the pre-diagnosis, the corresponding monoclonal antibody can be directly used, and the beneficial bacteria are not affected, and the safety is higher;

Second, the monoclonal antibody does not directly kill the bacteria, but neutralizes the virulence factors, so unlike antibiotics, the monoclonal antibody does not cross-resist with other bacteria;

Third, the half-life of the monoclonal antibody is longer than that of the antibiotic, and can be maintained for several weeks or even months after a single administration;

Fourth, the mechanism of action of the monoclonal antibody indicates that it does not interact with antibiotics and does not impose restrictions;

Fifth, the combination of monoclonal antibody and antibiotics can reduce the use of antibiotics and reduce the risk of drug resistance, whether it is treatment or prevention;

Sixth, monoclonal antibodies can enhance host bacterial clearance, inhibit bacterial colonization, and reduce inflammation sequelae;

Although monoclonal antibody therapy has become more and more obvious in the increasingly severe problem of drug resistance, it has to be said that difficulties and challenges are still quite numerous.

The first obstacle is the lack of effective animal models to accurately simulate human infections. Because the efficacy of monoclonal antibody depends mainly on its ability to cooperate with the host immune system, rather than the ability to inhibit bacterial growth in vitro, as in antibiotics, monoclonal antibodies must be studied in animal models in the preclinical phase. . However, currently used infection models include: very high inoculation of pathogens, standard strains in laboratory passage, specific inbreeding mice, and unnatural infection pathways.

Second, the pathogenic mechanism of bacteria in different animals is different. Some strains that cause serious complex infections in the human body are rapidly cleared in mice and rats, causing pharmacodynamic illusions. This is why drugs that have been very successful in preclinical studies have gone to phase 2 clinical trials. In contrast, candidate monoclonal antibodies that have no effect in animal experiments do not necessarily fail in the human body.

Another obstacle to the development of monoclonal antibodies is the heterogeneity of clinical pathogen antigens. Studies have shown that clinical strains have extensive micro-evolution and heterogeneity, and the generality of the conclusions obtained from the research using laboratory standard strains has been questioned. The protein epitopes of E. coli and Klebsiella pneumoniae are highly conserved, but this conservation is due to the fact that the epitope is hidden by the highly variable polysaccharide layer. This variability makes it necessary to combine the antibodies or to quickly and accurately diagnose them before administration. This is why broad-spectrum antibiotics are widely used in the treatment of various bacterial infections, and antibody therapy cannot become the mainstream in the first place.

The antibody structure itself also presents some challenges. Unlike small molecule drugs that bind to a single target, the mAb is a macromolecule with two or more binding sites. Different from the isotype and subclass antibody backbone, by limiting the binding site configuration, it not only affects downstream functions, but also affects binding affinity. More research work is needed to determine which isotypes and subclasses can improve binding and effector functions.

Finally, since infection progresses more rapidly than cancer and immune system diseases, it is also a very challenging question to accurately determine when to administer a monoclonal antibody to treat infection. Monoclonal antibody is a treatment that uses the immune system, and it will not be effective in patients with impaired immune system.

Although there are many challenges in finding the right target and optimizing the monoclonal antibody in the development of the monoclonal antibody, in general, the monoclonal antibody has good safety, and as the technology continues to advance, the cost will also decrease, and its pharmacokinetics The characteristics help the monoclonal antibody develop into an effective treatment.

 

Success is late, but will not be absent

In December 2012, it welcomed the world’s first monoclonal antibody for bacterial infection. The US FDA approved GSK’s Raxibacumab for the treatment of inhaled anthrax with antibiotics. Inhalation anthrax is very rare, but exposure to inhaled anthrax may result from exposure to infected animals, contaminated animal products, or an environment in which anthrax spores are intentionally released. When a person inhales an anthrax spore, anthrax will replicate in the human body and produce toxins, which can lead to serious and irreversible tissue damage or even death. Both drugs neutralize this toxin. Anthrax is a potential threat of biochemical terrorism because anthrax spores are difficult to destroy and can be transmitted through the air. In March 2016, the US FDA approved Elusys’ Obiltoxaximab, which is also used to treat inhaled anthrax.

Although these two drugs are aimed at the rare anthrax fever, and more for the United States to cope with possible terrorist attacks, there is no direct benefit to the global fight against drug-resistant bacteria. However, one can see that monoclonal antibody drugs can be used to prevent and treat bacterial infections. Sure enough, without waiting for a long time, the first monoclonal antibody was finally ushered in the arsenal of anti-resistant bacteria, and there has been a new choice.

In October 2016, the US FDA approved the listing of Bezlotoxumab (trade name Zinplava) from Merck Sharp Dohme. Bezlotoxumab is a fully human-derived monoclonal antibody that binds to C. difficile toxin B and is used to reduce the recurrence of C. difficile infection in patients 18 years of age and older who are receiving antibiotics for C. difficile infection or a high risk of C. difficile recurrence.

What is Clostridium difficile infection (CDI) and C. difficile Toxin B? C. difficile toxin B destroys the intestinal wall and causes inflammation, which causes symptoms of C. difficile enteritis, including abdominal pain and diarrhea.

Once C. difficile recurrence occurs, the risk of subsequent recurrence will gradually increase and it will continue to receive antibiotic treatment. As the number and dosage of antibiotics increase, the probability of developing resistant bacteria will naturally increase dramatically.

The incidence of C. difficile infection (CDI) is on the rise. Looking at the US data for 2011:

  • 453,000 patients
  • 29,000 deaths
  • 83,000 first recurrence
  • 53,000 repeated recurrences

Antibiotic therapy has long been approved for the prevention of CDI recurrence, while antibiotic therapy can treat CDI, but it cannot be used to prevent recurrence, but it also aggravates the destruction of the intestinal flora.

Originally developed by MassBio Laboratories of the University of Massachusetts Medical School in conjunction with Medarex (acquired by Squibb), Bezlotoxumab was transferred to Merck in 2009 and approved by the US FDA in 2016, filling the gap in the prevention of CDI recurrence. Two large phase 3 clinical trials, MODIFY I and MODIFY II, indicate that a single administration of the anti-toxin drug Bezlotoxumab in combination with standard antibiotics for C. difficile antibiotics can significantly reduce the recurrence of C. difficile infections compared to standard therapy alone. It can be maintained for 12 weeks, even in high-risk populations with recurrent C. difficile. Combination therapy can reduce the recurrence rate of CDI by about 40%.

 

After the approval of the first monoclonal antibody against drug-resistant bacteria, we have more expectations for monoclonal antibodies against other resistant bacteria. The following is a review of the monoclonal antibody used in the prevention and treatment of drug-resistant bacteria in the middle and late stages of clinical research. Although it is far less than the currently popular tumor immunity and autoimmune system, it has changed the antibacterial strategy and enriched it. From the point of view of the antibacterial product line, the significance is far-reaching.

In the battlefield against resistant bacteria, we can develop weapons other than antibiotics. Monoclonal drugs, with their unique mechanism of action, do not create new drug resistance problems, can also be combined with antibiotics, reduce the use of antibiotics, and better prevent drug-resistant infections. From the perspective of many antibiotic companies, not only with the original product line, but also into the development and production of monoclonal antibody, and expand to other therapeutic areas.

Of course, antibody antibacterials are still an emerging field. The US FDA has approved a small number of listed drugs, and the products under research are not particularly large.

A single spark can start a prairie fire. Although there are still very few companies and institutions engaged in the development of anti-infective monoclonal antibodies, the demand for new anti-infective drugs is very urgent. As clinical applications gain more practical benefits and practical experience, as well as continuous improvement in the production of single antibody production detection technology, the cost will be further reduced, and the monoclonal antibody will have a greater role in the field of anti-infection.

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