Monoclonal antibodies (MAbs) are one of the emerging therapeutic agents efficacious for treating infectious diseases such as COVID-19. They are one of the fastest-growing pharmaceuticals and are considered to be highly specific in their action. MAbs are lab-grown antibodies that specifically target the pathogen, causing its destruction immediately.
Until now, the disease has infected millions of people and killed a significant number of them. The virus belongs to the large family of beta-coronavirus and is named as Severe Acute Respiratory Syndrome Coronavirus two (SARS-CoV-2). Other important members of this class of virus are the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and SARS-CoV-1 . The virus is being mutated at regular intervals, and some of the variants have been found to be more virulent and resistant to certain vaccines. Major parts of the world are still suffering from the spread of the infection and are causing an unrepairable severe economic slowdown due to repeated lockdowns .
In over 80% of patients, the disease is characterized by mild symptoms, such as cough, fever, and difficult breathing. However, in aged people, immunocompromised and co-morbid patients, the infection can cause severe pneumonia, pulmonary edema, acute respiratory syndrome, sepsis, multiorgan failure and death . Symptomatic diagnosis of COVID-19 is difficult and is considered inaccurate due to the resemblance to a common seasonal viral infection. Suspected individuals should be diagnosed with real-time polymerase chain reaction (RT-PCR) by collecting samples from nasal and/or throat swabs to confirm the infection .
SARS-CoV-2 is a beta-coronavirus containing RNA as the nuclear component. The genetic sequencing indicated that the virus has 80% similarity with SARS-CoV-1 and 96% with bat coronavirus. The outer surface of the virus contains three major components: spike (S) glycoproteins, envelope (E) and film (M) protein. The S protein binds to angiotensin-converting enzyme-2 (ACE2) located on the surface of host cells and initiates the process of infection . The S protein was identified to contain two functional subunits that assist in the interaction with the host cell. The S 1 subunits contain four core domains named S 1A , S 1B , S1C, and S1D, which are responsible for attaching the virus to the host. The S 2 subunit then assists in fusion of the virus with the cellular membrane of host cells .
Monoclonal antibodies (MAbs) are one of the emerging therapeutic agents efficacious for treating infectious diseases such as COVID-19. They are one of the fastest-growing pharmaceuticals and are considered to be highly specific in their action . MAbs are lab-grown antibodies that specifically target the pathogen, causing its destruction immediately. Normally, MAbs are produced by B cells in patients after several days of infection. They can be isolated from recovered individuals, can be generated in the laboratory by immunizing animals and can also be constructed by molecular engineering in the laboratory . Modern technology helps in the identification of specific antibodies after their production, isolation, characterization, and growth in laboratory conditions. MAbs are gaining popularity among both physicians and patients because these agents easily meet the three important requirements for being a drug: safety, efficacy and quality . The MAbs currently tested against COVID-19 can either neutralize the virus action or decrease the inflammatory process due to infection. Some of them, such as bamlanivimab, sarilumab and siltuximab, have received emergency use authorization. Side effects, unpredictable bioavailability and the emergence of resistant strains are the important limitations of MAbs tested against COVID-19 . The present patent review focuses on MAbs as a therapeutic option for treating COVID-19 and the innovation, patenting information and important characteristics of MAbs.
The patent review on MAbs was conducted using internet search engines, such as PubMed, Google Scholar, Science Direct and WIPO (The World Intellectual Property Organization) websites by using key words such as ‘Monoclonal’, ‘Antibodies’, ‘COVID-19’, ‘Patent Information’, ‘Clinical Trials’, ‘Mechanism’ and ‘Adverse Reactions’ . ItThe review included clinical trials conducted from the beginning of 2020, coinciding with reports of the identification of the SARS-CoV-2 genome, until the end of July 2021. The search resulted in more than 1500 total articles. However, only 88 articles were selected for the present study based on the inclusion criteria. The authors independently reviewed the titles, abstracts, and text of the articles. The information, such as English language, study center, number of subjects, study design, study protocol, dose, duration, route of administration, ethical approval, statistical methods, and biochemical estimations, were considered critical parameters for evaluating the content and were considered the inclusion criteria . Only those articles containing the required information were selected for the analysis. The patent information retrieved from the WIPO is categorized separately in a table given in discussion section.
Multifunctional immunoglobulins/antibodies are considered multifunctional since they show numerous cellular and humoral reactions to antigens. They are produced by the immune system and are usually polyclonal, i.e., produced by different B lymphocytes. In terms of antigen binding capacity, these antibodies behave slightly differently from one another . Technological innovations have made it possible to identify one single B cell that can be stimulated to produce one specific type of antibody called a monoclonal antibody. Therefore, MAbs are homogenous preparations of antibodies obtained from single B cells and have an identical protein sequence. These antibodies possess a common antigen recognition site, affinity, biological interaction, and similar physiological effects .
This technique is commonly used in cancer chemotherapy. The antibodies formed in the patients and having the capacity to infiltrate the tumor are identified. They are isolated from the regional lymph node and the tissues can be harvested to produce specific antibodies . Peripheral blood, bone marrow and lymphoid tissues can also be used for the extraction of antibodies. MAbs isolated from this technique were found to be useful in the treatment of HIV. Bamlanivimab is a new MAb that has been tested against SARS-CoV-2 infection and is synthesized by isolating from recovered patients .
In this way, these agents were specifically targeted to treat the disease. Anti-CFRP receptor antibodies (Erenumab), anti-fibroblast growth factor 23 (FGF 23) antibodies (Burosumab), and anti-Willebrand factor antibodies (Caplacizumab) are some of the important MAbs that have revolutionized the approach to treating disease [28,44,45]. Research is also in progress to isolate human antibodies from patients who have recovered from Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV). Attempts have been made to grow these antibodies in the lab . Concurrent use of MAbs with other therapeutic agents, such as chemotherapy, radiotherapy, hormonal replacement, and other biological agents is also being tested, and the results suggest that such a combination has the potential to be an effective treatment . The conjugation of antibodies with other therapeutic agents with the help of advanced technology is reported to provide novelty in the management of diseases. Some of the conjugates being tested include immuno-cytokines, antibody-drug conjugates, antibody-radionuclide conjugates, bispecific antibodies, immunoliposomes and chimeric antigen receptor T cell therapy [28,47].
Antigenization is a newer approach for delivering a vaccine molecule with the help of MAbs. The specific sequence/fragment of the antigen can be incorporated into one of the several binding domains of MAbs . The MAbs, being specific in their target, deliver the vaccine molecule inside the cell. The vaccine molecule will then activate the cells to produce immunogenic antigens, leading to the production of antibodies. However, this technology is still in the preclinical stage, where bovine herpes virus B cell epitopes have been successfully grafted onto a bovine immunoglobulin molecule .
A patent literature review revealed more than 100 different MAbs for SARS-CoV-2 registered by pharmaceutical companies. The technique to produce these MAbs has been patented. We selected 88 such patents based on their content and these were reviewed and analyzed for patent status, technological innovations, research conducted, mechanism of action, side effects, contraindications/precautions, and any special description about the agents. According to the patent analysis, approximately 30% of published patents are registered by US-based companies, with the remainder registered by Chinese (10%) and UK (9%) companies . Patent information about the articles retrieved from search engines, such as Google Scholar, Pubmed and Science Direct are represented in Table 13 , while those retrieved from WIPO are mentioned in Table 24 . WIPO is an intergovernmental organization that basically protects the intellectual property rights of the signatory bodies and functions as per the international treaties . The data collected from this website is separately indicated in Table 24 .
Method of preparation and use of human monoclonal antibodies for neutralizing the action of SARS-CoV.|
Institute for Research in Biomedicine|
Information about monoclonal antibodies used for diagnosis and treatment of SARS-coronavirus-associated disease and evaluating the efficacy of vaccine or anti-SARS agent.|
Dana-Farber Cancer Institute|
Technique of production and use of a monoclonal antibody against severe acute respiratory syndrome coronavirus.|
RBD of S protein|
Chinese Academy of Sciences|
Human monoclonal antibodies to treat the infection in patients caused by SARS-associated coronavirus.|
Ultra Biotech Ltd.; University of California|
Production and therapeutic application of neutralizing monoclonal antibodies against severe acute respiratory syndrome-associated coronavirus.|
New York Blood Center, Inc.|
Production of monoclonal antibodies against the peptides derived from SARS virus E2, N-terminal-alpha helix or C-terminal-alpha helix of virus.|
Synthesis of a monoclonal antibody targeted against N proteins of SARS coronavirus and testing its clinical use in the treatment of SARS infections.|
Chinese Academy of Sciences|
Production and clinical evaluation of monoclonal antibodies that neutralize the pathogenesis of severe acute respiratory syndrome-associated Coronavirus.|
New York Blood Center, Inc.|
Production of anti-SARS-coronavirus monoclonal antibodies for diagnosis and treatment and for testing its use in vaccine preparation.|
New human monoclonal antibodies against spike (S) proteins of SARS and testing their diagnostic and therapeutic application.|
University of Massachusetts|
Library-driven production of human monoclonal antibodies against SARS virus caused infection.|
S, N, and M Proteins|
Igcon Therapeutics Co., Ltd.; Genetastix|
Production and testing the use of a new class of monoclonal antibodies against human interleukin.|
Note: RBD—Receptor binding domains, Il—Interleukins, S, N, M proteins—Spike, Nucleocapsid, Membrane proteins.
WO 2021158521 A1 20210812|
Neutralizing monoclonal antibody variants targeting SARS CoV-2 for use in diagnosis, prophylaxis, and treatment of SARS CoV-2 infection.|
Spike protein and/or its receptor binding domain|
Davide C, Katja F, Martina B, et al.|
CN 113004395 A 20210622|
Production of monoclonal antibody against SARS-CoV-2 and application thereof in immunoassay of SARS CoV-2.|
Li Z, Xingsu G, Binyang Z, et al.|
CN 112940110 A 20210611|
Production of anti-SARS-CoV-2 N protein monoclonal antibodies for diagnosis and treatment of COVID-19.|
Yaoqing C, Bing H, Shuning L, et al.|
CN 112794899 A 20210514|
Human anti-SARS-CoV-2 neutralizing monoclonal antibodies for diagnosis, prevention, and treatment of COVID-19.|
Viral receptor binding domain (RBD)|
Lei C, Tengsen G, Min D, et al.|
CN 112724248 A 20210430|
Humanized anti-SARS-CoV-2 spike protein nanobodies for diagnosis, prevention, and treatment of COVID-19.|
Receptor binding domain|
Xilin W, Zhiwei W.|
CN 112661841 A 20210416|
Anti-SARS-CoV-2 S2 protein human monoclonal antibody 17-2 for combination therapy with S1-RBD/S1-NTD epitope-neutralizing antibody and for prevention and treatment of COVID-19.|
Epitope S1-RBD and S1-NTD|
Lei Y, Yingfen W, Wenjing G, et al.|
CN 112625136 A 20210409|
Bi-specific antibody having neutralizing activity against two epitopes of SARS-CoV-2 spike protein for diagnosis, prevention, and treatment of COVID-19.|
Two epitopes of SARS-CoV-2 spike protein|
Guojun L, Chanjuan L, Junbin S, et al.|
CN 112574300 A 20210330|
Human anti-SARS-CoV-2 S protein monoclonal antibody for diagnosis, prevention, and treatment of SAR-COV-2 infection.|
Xiaochun W, and Junxin L.|
CN 112521496 A 20210319|
Anti-SARS-CoV-2 spike protein RBD domain monoclonal antibodies for diagnosis and treatment of COVID-19.|
Spike protein RBD domain|
Ke D, Zhaowei G, Xi W, et al.|
CN 112409488 A 20210226|
Preparation of monoclonal anti-human ACE2 antibody for ACE2 detection, prevention, or treatment of various coronavirus-related disease.|
Chunhe W, Yuning C, Yili C, et al.|
CN 112225806 A 20210115|
Preparation of human antibodies specific to SARS-CoV-2 spike RBD protein for diagnosis and therapy of SARS-CoV-2 infection, SARS, COVID-19 or related disease.|
Spike RBD protein|
CN 112210004 A 20210112|
Preparation of monoclonal anti-SARS-CoV-2 spike protein antibodies for diagnosis and treatment of COVID-19.|
Yang W, Xuefeng N, Chunlin W, et al.|
CN 112175073 A 20210105|
Preparation of broad spectrum neutralizing anti-SARS-CoV-2 spike protein antibodies for diagnosis, prevention, and treatment of COVID-19.|
Jinghe H, Fan W, Mei L, et al.|
CN 112175071 A 20210105|
Preparation of novel anti-SARS-CoV-2 spike protein monoclonal antibodies for treatment of COVID-19.|
Jingui Y, Lei Z, Lianjun M, et al.|
CN 112159469 A 20210101|
anti-SARS-CoV-2 S1-RBD antibodies derived from in vitro monoclonal B cells and high throughput screening for treatment and/or prevention of COVID-19.|
Jinghe H, Fan W, Mei L, et al.|
Note: SARS CoV-2—severe acute respiratory syndrome coronavirus-2; RBD—Receptor binding domain; S, N, proteins—Spike, Nucleocapsid, proteins; ACE2—Angiotensin converting enzyme-2.