The outbreak of Corona Virus Disease has become a new global pandemic and an important public health event of global concern. According to the latest real-time statistics of WHO, as of 23:13 on the 22nd December, Beijing time, there were a total of 76,250,431 confirmed cases of COVID-19 worldwide, and a total of 1,699,230 deaths. With the arrival of winter, many countries may enter a new round of outbreaks. On December 14, local time, Secretary of State for Health and Social Care, Matt Hancock said that a new variant of the new Corona Virus is accelerating its spread in parts of England. The transmissibility of the virus after mutation may be 70% higher than that of the existing virus strain. Global epidemic prevention and control still faces challenges.
COVID-19 is a single-stranded RNA coronavirus, homologous to SARS-CoV and MERS-CoV, but it is more infectious. The International Committee on Taxonomy of Viruses named the coronavirus as "SARS-CoV-2", and the pneumonia caused by the coronavirus was named "COVID-19". COVID-19 is an acronym that stands for coronavirus disease of 2019. Current studies have shown that the SARS-CoV-2 spike protein (S protein) binds angiotensin-converting enzyme 2 protein (ACE2) with 10-20 times higher affinity than the S protein of the previous coronavirus SARS-CoV, which may be higher, and this may be the reason for its high infectiousness. The virus S protein has also become one of the key proteins for the development of vaccines, therapeutic antibodies and diagnostics.
In terms of development strategies, facing the sudden outbreak of an epidemic virus, strategies for new use of old drugs are often used in the short term to verify the clinical efficacy of drugs that are already in the clinic stage or on the market. The medium- and long-term strategy is to develop therapeutic neutralizing antibodies and preventive vaccines. Alphamab Oncology is currently working on the development of next-generation multispecific neutralizing antibodies based on the new mechanisms.
In terms of biological mechanism, therapeutic treatment methods are divided into two categories. One is to directly target the coronavirus. It means to target a series of targets involving virus-cell receptor interaction, gene replication, transcription, translation, and assembly involved in the entire process of virus infection of host cells. The other is to develop drugs for the human immune response caused by the virus. In the early stage of virus infection, the activation of interferon or innate immune receptors can appropriately improve/activate the body's own immunity to fight the virus. For severely advanced/over-immune patients, due to patients are attacked by their own immune system, immunosuppressive drugs can be considered to adjust.
The antiviral drug Lopinavir/Ritonavir developed for HIV can effectively inhibit protease replication in the virus, thereby interfering with the assembly of the virus, reducing its infectivity, and ultimately preventing viral infection. Low-dose Ritonavir can inhibit the catabolism of lopinavir by the liver and achieve the effect of improving the bioavailability of lopinavir. Therefore, the combination therapy of two protease inhibitors can effectively improve the antiviral therapeutic effect. The protease activity of HIV and COVID-19 is similar, but the target protein structure is different.
RNA polymerase inhibitor
Remdesivir (GS-5734) is an antiviral nucleotide analog drug developed by Gilead Sciences that has been evaluated in humans against acute Ebola virus disease Remdesivir acts on RdRP to achieve antiviral effects by inhibiting viral RNA replication. Previous studies have confirmed that Remdesivir has a certain effect on SARS and MERS. According to the similarity between the structure of the catalytic site of the COVID-19 and the structure of the catalytic site of SARS and MERS, a large-scale clinical trial of this drug for the treatment of COVID-19 was launched in the later period. Different clinical results in various countries are controversial. The recent WHO clinical trials have denied its efficacy, but the FDA has approved Remdesivir for the treatment of COVID-19.
Another RdRP inhibitor Favipiravir (Favipiravir) is a public listed broad-spectrum antiviral drug that has a good therapeutic effect on severe and drug-resistant influenza patients. It can also effectively prevent virus replication in host cells.
Antiviral drugs targeting the host
Small molecule drugs that regulate the interaction between the coronavirus and the host by targeting the host and effectively inhibit the virus from invading human cells may also have therapeutic potential, including the antimalarial drug chloroquine, which has been used clinically for more than 70 years in treatment of immune diseases, Abidol developed for the treatment of influenza viruses, etc. Such drugs are aimed at the target of virus infection of human cells and cell fusion, and their safety has been guaranteed for many years in the market. Based on the urgent needs of current clinical treatment, such drugs have been included in the "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 8)" issued by The National Health Commission of the People's Republic of China on August 19 this year. Chloroquine phosphate and alpha-interferon can be tried, but not Recommend the use of hydroxychloroquine or combined use of azithromycin.
According to the eighth edition of the diagnosis and treatment plan, three clinical regime are recommended for immunomodulatory treatment. For patients with rapid disease progression, severe and critically sick patients, convalescent plasma can be used. Normal and severe patients with faster disease progression are recommended for emergency neutralization Antibodies: For patients with extensive lung disease and severe patients with elevated IL-6 levels detected in the laboratory, the anti-IL-6 receptor antibody tocilizumab can be used to combat the immune factor storm in severe patients. However, this year the IL-6 receptor antibodies of many companies failed in the third phase clinical trial of severe and critical re-coronary disease. Although one of the clinical trials failed to improve the disease and the 4-week mortality rate, it seemed to shorten the hospital stay.
OncoImmune's immunomodulatory drug CD24Fc fusion protein has achieved positive results in phase three clinical trial, which can improve the recovery speed of severe or critical cases of coronavirus disease, and the probability of disease progression to death or respiratory failure is significantly reduced. It is the world's first major breakthrough in the third-phase treatment of severe COVID-19. Alphamab Oncology actively cooperated with OncoImmune to participate in the development of the CD24-Fc project.
Glucocorticoids have anti-inflammatory, antiviral, and anti-shock effects, and are widely used in clinics to treat serious infectious diseases, autoimmune diseases, respiratory diseases, skin diseases and so on. According to the eighth edition of the diagnosis and treatment plan, for patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive activation of the body's inflammatory response, in a short period of time (generally recommended 3 to 5 days, no more than 10 days), the recommended dose is equivalent to Methylprednisolone 0.5～1mg/kg/day, glucocorticoids are used, but larger doses will suppress the immune system and delay virus clearance.
WHO cooperates with the non-profit foundation MAGIC to synthesize the data of 8 randomized trials of systemic hormones for COVID-19. Through meta-analysis, it is believed that the use of hormones may reduce the 28-day mortality rate of patients with critically COVID-19. Therefore, for patients with severe and severe Corona Virus Disease, WHO recommends systemic corticosteroids (strong recommendation, based on moderately certain evidence), including dexamethasone or other corticosteroids, such as hydrocortisone or prednisone. It is not recommended for non-serious patients.
About virus neutralizing antibodies
Neutralizing antibody is a soluble protein secreted by human adaptive immune response cells. After the virus invades the human body, the human immune system produces antibodies, especially neutralizing antibodies, which bind to virus particles in the blood to block the virus from infecting cells and remove them. Using modern biopharmaceutical technology and antibody engineering technology, neutralizing antibodies with antiviral activity can be developed as drugs for treating viral infections.
Preliminary research believes that human neutralizing antibodies targeting the ACE2 receptor binding domain (RBD) of COVID-19 S protein have good therapeutic prospects. Another clinical study in the New England Journal of Medicine (NEJM) published the results of a neutralizing antibody treatment for non-hospital patients. The clinical results show that neutralizing antibody therapy has a certain effect on mild to moderate patients, and significantly reduces the number of patients. However, the control effect of the virus is not obvious enough, and it cannot effectively alleviate the condition and reduce the mortality rate in clinical trials of severely hospitalized patients. In addition, the use of super high doses and the corresponding production costs also impede the widespread application in the future.
With more than 10 years of experience in antibody drug development and has fully integrated proprietary biologics platforms in bi-specifics and protein engineering, Alphamab Oncology collaborated with Professor Zhong Huang from Institut Pasteur of Shanghai, Chinese Academy of Sciences to screen three high-affinity neutralizing antibodies that bind to different key proteins of the COVID-19, and they specifically bind to the protein epitopes of COVID-19’s RBD, S1-NTD and S2. In the in vitro and in vivo efficacy tests, the three antibodies have good neutralizing activity against pseudoviruses and viruses. The combination of the three antibodies has a synergistic effect. At present, the three antibodies have been humanized, and multispecific neutralizing antibodies of the three are under development. The strategy of multispecific antibodies targeting different proteins of the virus is adopted to reduce the dosage, improve the efficacy and prevent the escape of virus mutation. It is expected to provide a new and effective therapeutic drug option for the treatment of the COVID-19.
1. Science. 2020 Mar 13;367(6483):1260-1263. doi: 10.1126/science. abb2507
2. WHO website
3. N Engl J Med.2020 Oct 28.doi: 10.1056/NEJMoa2029849
4. " Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 8)"
About Alphamab Oncology
Alphamab Oncology is a biopharmaceutical company focusing on innovative biologics medicine for oncology. On December 12, 2019, the Company was listed in the mainboard of Hong Kong Stock Exchange with stock code 9966.
Alphamab has fully integrated proprietary biologics platforms in bi-specifics and protein engineering. Its highly differentiated in-house pipeline includes eight tumor monoclonal antibodies and bispecific antibodies and a Covid-19 multifunctional antibody. Four products have advanced into phase I-III clinical trials or pre-marketing stage in China, the United States, Japan and Australia. The BLA for KN035 (Envafolimab) has been accepted by the National Medical Products Administration (NMPA) on December 17, 2020.
The Company also has state-of-the-art manufacturing capabilities designed and built to meet NMPA and EU/FDA’s cGMP standards and a complete quality system which has passed the on-site inspection of an European Union qualified person. Alphamab Oncology is committed to building a global leading, multi-dimensional drug development and commercialization platform, focusing on multifunctional biological innovative drugs, and to benefit patients in China and around the world.
Visit http://www.alphamabonc.com for more information.
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