The power of monoclonal antibody is the "full coverage" of the epidemic process

Image source @ Visual China

Text | State the fundamentals, the author | Chen Gen

The epidemic has entered its third year, and as the new crown drug research and development pipeline is ready to develop, a large number of new drugs and new uses of old drugs are also about to be released.

Among them, the development of monoclonal antibodies is one of the focuses of the fight against the new crown virus. In fact, at the beginning of the outbreak of the new crown epidemic, many research teams began to look for "special drugs" for treating the new crown in the plasma of the recovered people - neutralizing antibodies. Today, a number of monoclonal neutralizing antibodies have entered the clinical development stage at home and abroad, and a number of neutralizing antibodies have been authorized for emergency use by regulatory agencies.

Although in the past two years, the knowledge of how to use these macromolecules clinically in the field of anti-infective monoclonal antibodies has almost exceeded the sum of the previous two decades, but this is inseparable from the previous two decades of medical research on the field of monoclonal antibodies - in the history of human anti-disease, the emergence of monoclonal antibodies has brought revolutionary therapies to treat cancer, autoimmune diseases and inflammation and other disease types.

01 Advent of monoclonal antibodies

In 1890, at the age of 36, Emil Adolf von Behring published a landmark study in a German journal: plasma from animals that produce immunity to diphtheria can be used to treat diphtheria infections. Emile Adolf von Bellin later published a groundbreaking article linking therapeutic antivenoms to neutralizing antibodies.

It was because of this work that Emile Adolf von Behring received the first Nobel Prize in Physiology or Medicine awarded in 1901. It was also the first major success of modern immune interventions — foreshadowing the presence of neutralizing antibodies against pathogenic microbes in the plasma of convalescents.

Since then, convalescent plasma therapy has been tried to treat influenza viruses, respiratory syncytial virus (RSV), Ebola virus, and other coronavirus infections.

The reason is that while polyclonal antibodies collected from immune animals are the main source of antiserum, there is also a risk of serum disease, especially after repeated exposure, as recipients may develop an immune response to antibodies of non-human origin, and the use of convalescent plasma from human patients can reduce these risks. By careful screening (e.g., assessing the presence of the source of infection and determining antibody titers and neutralization capacity), convalescent plasma therapy can achieve effective treatment with minimal safety risks.

Today, of course, passive immunity has long since shifted from a source of non-human or human blood products to specific monoclonal antibodies or polyclonal antibodies – in the 85 years since the publication of Emil Adolf von Belling's paper, scientists have discovered B cells that produce antibodies, and have also figured out the structure of antibodies at atomic-level resolution, making the scientific community's understanding of antibodies clearer and clearer. It wasn't until 1975 that Georges K Hler and César Milstein invented the technology to produce monoclonal antibodies that made antibodies truly a drug. Nine years later, they also won the Nobel Prize in Physiology or Medicine.

Specifically, monoclonal antibodies, as a class of antibodies made by only one type of immune cell, overcome the limitations inherent in convalescent plasma therapy, such as the risk of blood-borne diseases, the time to develop detectable high-affinity antibodies, the risk of low antibody titers, and variable epitopes. Therefore, monoclonal antibodies can avoid or reduce the risk of convalescent plasma therapy, etc.

Further, monoclonal antibodies can be administered more precisely to ensure proper neutralization of the antibody. In addition, high titers of neutralizing antibodies are inherent in neutralizing monoclonal antibodies. Today, the process of mass production of recombinant monoclonal antibodies has become scalable to meet demand and have a competitive cost with other treatments.

As a targeted therapeutic drug, monoclonal antibodies have the characteristics of strong specificity, significant efficacy and low toxicity, which can effectively prevent the virus from entering the cell proliferation, which can be used as a short-term prevention of high-risk groups and the treatment of post-virus diseases, so it is also a hot spot in the global new crown epidemic prevention and control research.

02 "Full coverage" of the epidemic process

In fact, whether it was SARS-CoV in 2003 or sars-CoV-2 in the present, the main antigenic epitope of the virus is the S protein, which promotes the binding and fusion of target cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface, while the ACE2 receptor is distributed in the respiratory system, gastrointestinal tract and endothelial cells. Thus, antibodies against the S protein are thought to neutralize the virus's ability to bind and fuse with the target host cell.

Currently, convalescent plasma from humanized mouse techniques or convalescent patients has been used to obtain neutralizing monoclonal antibodies against S protein RBD. To date, state-of-the-art research efforts for the therapeutic use of neutral monoclonal antibodies have focused on a small number of products under clinical development, some of which have been approved for emergency use based on Phase I/II and Phase II data.

For example, Eli Lilly's bamlanivimab/etesevimab reduced the risk of hospitalization and death for patients with mild and moderate illness at high risk by 87%, and the regenerative casirivimab/imdevimab also reduced the risk of hospitalization and death for this group by 70%, compared with sotrovimab's 79%. Although another Eli Lilly neutralizing antibody, bebtelovimab, has not yet published phase III clinical study data, it has also been authorized for emergency use by the U.S. FDA.

The first anti-coronavirus drug approved by the State Drug Administration of China (NMPA) is also a neutralizing antibody, amphavir monoclonal antibody/romimab. From the final analysis of the phase III study, patients in the ambavidumab/romimab treatment group had an 80% lower risk of hospitalization and death (P-value> compared with the placebo group

It is based on the above data that ambavir monoclonal antibody/romizumab is also included as an antiviral program in the newly released "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Trial Ninth Edition)".

It should be pointed out that compared with monoclonal antibody drugs, the immunity generated in the body of the recovered population and the vaccinated person with natural infection, in addition to a variety of neutralizing antibodies, there are memory B cells, T cell immunity and so on. After all, the mechanism by which monoclonal antibodies inhibit the virus is very simple, and when used as a drug, the number of antibodies produced by injecting the human body is known, so once the mutation strain cannot be neutralized in the experiment, it means that the antibody drug is ineffective.

Especially after the emergence of the new crown mutant strain Omilton, because Omilon has more than 30 mutations in the spike protein, of which 15 mutations are on the RBD, so so many mutations are naturally likely to affect the neutralization of antibody recognition sites, which in turn threatens the effectiveness of vaccines and monoclonal antibody drugs.

On December 9, 2021, Peking University's Xie Xiaoliang research group uploaded the results of a study through the preprint paper website to test the effects of Omicron's RBD mutation on nine monoclonal antibody drugs authorized by regulatory authorities for emergency use. Judging from the results of the medium and experiments, for Omicron, the combined monoclonal antibodies of Eli Lilly, Regenerator and AstraZeneca all showed different degrees of failure, and only Vir-7831 and DXP-604 could inhibit the Omicron mutant strain. In addition, the paper showed that the antibody BRII-196 in the approved combination therapy of Temsex was inactivated by Omicron, but did not show the results of another antibody, BRII-198.

Another important role of neutralizing antibodies is to prevent COVID-19 infection. Clinical research data prove that long-term neutralizing antibodies are an important long-term passive immune tool. For example, results from a Phase 3 clinical trial of post-exposure prophylaxis in the family of family members of COVID-19 patients with a neutralizing antibody combination showed that a single dose of subcutaneous injection reduced the risk of symptomatic COVID-19 infection by 81%.

Data from the Phase 3 clinical study of long-acting neutralizing antibody combination titxagevimab/cilgavimab showed a median follow-up of 83 days, which reduced the risk of developing symptoms of COVID-19 infection by 77% compared with placebo. Both of these precautions have been authorized by the FDA for emergency use of post-exposure prophylaxis and PRD, respectively. In addition, the bamlanivimab/etesevimab combination is also authorized by the FDA for emergency use for post-exposure prevention.

03 Power of monoclonal antibodies

Although in the past two years, the field of anti-infective monoclonal antibodies seems to have made a breakthrough development, behind the breakthrough development of monoclonal antibodies is the deep cultivation of the scientific community for many years.

Especially in the field of cancer, in fact, monoclonal antibodies — antibodies that specifically target a single target — are the first cancer immunotherapies that have been widely used in the clinic. By modifying an antibody to recognize two molecular targets (antigens), it can enhance its therapeutic efficacy. These bispecific antibodies can bind to both tumor cells and immune cells called T cells, allowing T cells to kill tumor cells.

Specifically, the mammalian immune system produces a large number of antibodies; if modified, it can allow the antibodies to recognize specific therapeutic targets. Typically, antibodies can only recognize a single antigen, which can be a pathogenic component or an abnormal protein or carbohydrate molecule. Monoclonal antibodies against a target on cancer cells recruit immune cells such as neutrophil cells, natural killer cells, and macrophages to kill or engulf cancer cells.

Engineered antibodies can also block or stimulate the function of proteins that bind to them. For example, some regulatory receptors inhibit T cell function, and engineered antibodies can block these receptors, and this clinical treatment strategy that enhances T cell function is called "checkpoint blocking" therapy.

These inhibitory receptors control "T cell failure"—a state in which T cells are not functioning and can avoid autoimmune responses; there is also "T cell failure" in the tumor microenvironment, allowing tumor cells to escape T cell-mediated anti-tumor effects. However, checkpoint blockade therapy can awaken failing anti-tumor T cells, providing great clinical benefits, but also contributing to autoimmune toxicity.

Due to the high affinity and specificity of monoclonal antibodies, monoclonal antibodies have become the main force of emerging oncology therapy. From the approval of CD3 murine-derived monoclonal antibodies in 1986, about 100 antibody drugs have been approved for marketing to date. In the past few years, PD-1/PD-L1, CD38, CD19, etc. have been the hot targets of anti-tumor drugs approved. It is precisely the emergence of targeted therapy or immunotherapy antibody drugs for PD-1/PD-L1, CD38, CD19 targets, that have allowed people to change the treatment paradigm of cancer.

In the field of antivirals, in addition to the new crown virus, monoclonal antibodies also play an important role. According to statistics, as of March 2021, at least 21 neutralizing antibodies in nine infectious disease areas, including respiratory syncytial virus infection and Ebola virus infection, have entered the late clinical stage or been approved for marketing.

Among them, the first approved antiviral neutralizing antibody dates back to 1998, when the US FDA approved the monoanthan antibody palivizumab for the prevention of respiratory syncytial virus infection in children.

Even the first approved treatment for Ebola was neutralizing antibodies. In October 2020, the U.S. FDA approved the monoclonal antibody combination Inmazeb (atoltivimab, maftimab, and odesivimab-ebgn) for the treatment of adults and children infected with Ebola virus. Just two months later, the FDA approved a second drug to treat Ebola infection, the neutralizing antibody Ebanga (Ansuvimab-zykl), the only two anti-Ebola drugs approved.

It is undeniable that in the history of human anti-disease, the emergence of monoclonal antibodies has brought revolutionary therapies to the treatment of cancer, autoimmune diseases and inflammation and other disease types, and the new crown epidemic has made monoclonal antibodies further the latest frontier in the treatment of infectious diseases. Just like the mRNA vaccine, as an important therapeutic tool, monoclonal antibodies will also contribute to the fight against disease. (This article was first published on the Titanium Media APP)