OR WAIT 15 SECS
Therapies for early and late treatment and passive immunization of COVID-19 are needed and can be developed using antibodies from recovered patients.
Antibody therapies-such as those derived directly from plasma-or versions based on native antibodies but produced using recombinant technology-aim to provide individuals with a passive immunity to fight a particular disease. These therapies can be used in four ways: to prevent people at high risk, such as healthcare workers and at-risk patients, from ever becoming infected (pre-exposure prophylaxis); to prevent those infected from developing severe symptoms (early treatment); to treat people who are already experiencing severe symptoms (late treatment); and for post-exposure prophylaxis.
“Whereas vaccines can take many weeks to produce protective antibodies, plasma-derived antibody therapies, like convalescent plasma (CP) or concentrated antibody preparations manufactured from CP (i.e., hyperimmune globulins), provide immediate passive humoral antibody protection. This feature allows plasma-derived antibody therapies to be used prophylactically in cases of exposure, which is vitally important to first responders and healthcare workers on the frontlines, or to treat infected persons who are at a high risk of a poor outcome,” explains David Bell, chief innovation officer for Grifols. “In addition, plasma-derived therapies are especially important to immunocompromised patients who cannot mount a strong immune response to a vaccine.”
Convalescent plasma, or plasma from recovered patients containing antibodies, can be used as an emergency measure when other treatments are not available. Antibodies isolated from pooled donated plasma have been produced by patient immune systems as a defense to a foreign antigen and therefore possess specificity against that antigen. On the other hand, production of potent antibodies identified in recovered patient blood samples using recombinant technology enables manufacturing scalability and continued supply.
The present COVID-19 pandemic, as well as the Ebola epidemics in East and West Africa, highlight the desperate need for readily-accessible, safe antiviral therapies that can be produced in a short period of time amidst rapid viral spread, according to Bell. “During an outbreak of a novel coronavirus or other agent, CP is the only antibody source available for near-immediate use,” he explains.
Although not referred to as CP at the time, this approach-with antibodies from animals-was used by Emil von Behring to cure sick patients with diphtheria, work for which he won the first Nobel Prize in Physiology and Medicine in 1901 (1). CP was later used to dramatically reduce the fatality rate during the influenza pandemic (Spanish flu) of 1918 and during the Korean War to treat United Nations troops in the field that were sick with Korean hemorrhagic fever, also known as hantavirus. More recently, CP has been used to treat severe acute respiratory syndrome (SARS), the 2009 influenza A (H1N1), avian influenza A (H5N1), several hemorrhagic fevers such as Ebola, and other viral infections (2).
Compared to other methods to produce antibodies (i.e., recombinant monoclonals), CP also has the advantage of possessing a breadth of antibodies to a viral antigen that vary with respect to their epitopes. “This polyclonal nature of CP antibodies allows them, without further manipulation or purification, to exhibit high overall affinity and sensitivity to an antigen,” notes Bell.
In addition, CP harbors antibodies to a plethora of microbial antagonists to which the CP donor has mounted a prior humoral immune response that can protect against concurrent infections, Bell adds. This property is especially important to CP recipients whose immune systems may be compromised.
A silver lining of the COVID-19 pandemic, Bell points out, is that many folks have mounted successful humoral responses to the disease, whether severe or asymptomatic, and developed antibodies against SARS-CoV-2, the virus that causes COVID-19. Presently, there are multiple clinical trials underway across the globe to evaluate the potential of CP to prevent or mitigate the severity of illness in recipient COVID-19 patients, and results are beginning to be published. In a timely report from investigators in China, CP therapy was found to be well-tolerated and to potentially improve the clinical outcomes in severe cases by neutralizing viremia (3).
In the United States, FDA is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through emergency Investigational New Drug Applications, working in collaboration with the National Institutes of Health and the Centers for Disease Control and Prevention to develop master protocols for the collections and use of COVID-19 CP, and encouraging people who have recovered from COVID-19 infections to donate plasma (4,5). The first CP treatment approved by FDA took place at Houston Methodist Hospital in late March (6). Grifols is currently conducting a clinical trial in Spain with convalescent human plasma inactivated with methylene blue.
Ultimately, any efficacy that CP exhibits in initial clinical trials will provide an impetus to use CP to manufacture highly-purified preparations of antibodies with high neutralizing activity and longer-term potential therapy (7), according to Bell. “So-called hyperimmune globulin (H-IG) preparations, manufactured from convalescent or immunized donors’ plasma, comprise a widely tested, safe, and proven prophylactic and therapeutic intervention for certain infectious diseases [e.g., measles, diphtheria, polio, hepatitis A and B, tetanus, rabies, and disease brought on by respiratory syncytial virus (8)],” Bell states.
CP donated from many individuals is transported to manufacturing facilities where it is pooled together. During the manufacturing process, the virus-specific antibodies from multiple donors are concentrated. The plasma then undergoes virus inactivation and removal processes and is finally purified into the H-IG therapy with a consistent amount of neutralizing antibodies in each dose.
“This approach ensures the quality and safety of the final product, as well as provides a more realistic shelf-life for global use. H-IG therapy means a higher concentration of antibodies can be administered with lower volumes. The high concentration of antibodies, which has a known neutralization titer, will have an established benefit-risk profile in multiple populations of patients,” says Chris Morabito, head of R&D, plasma-derived therapies at Takeda.
A key benefit of a plasma-derived immune globulin therapy is that the production of the H-IG is based on already-approved manufacturing systems, according to Morabito. Plasma-derived intravenous immunoglobulin (IVIG) therapy also has an established safety profile based on years of clinical evidence. “In addition,” Morabito notes, “a plasma-derived polyclonal immune globulin therapy can bind multiple antigens on the virus, including the ones that have been shown to be effective in clearing the infection from the recovered donor, whereas a monoclonal approach covers one single antigen.”
And while a direct plasma approach may be quicker to develop than an H-IG therapy, before the former method can be put into wide use, scientists must work out safety issues, such as making sure the plasma taken from recovered patients is free of other viruses and toxins. The antibody levels also vary significantly from individual to individual, so the potential effectiveness of the convalescent plasma is dependent on the specific donor. Furthermore, larger volume dosing is likely to be required as the virus-specific antibodies in the CP would not be concentrated through a manufacturing process.
Plasma-derived hyperimmune globulin therapies have shown preliminary signs of effectiveness in the treatment of severe acute respiratory infections of viral etiology and may present a potential treatment option for individuals with COVID-19, as well to potentially prevent infection in those at high risk of developing COVID-19 from exposure to SARS-CoV-2, such as healthcare workers, according to Morabito notes.
Takeda is leveraging its experience in the development of plasma-based antibody therapies in the fight against COVID-19. The company successfully produced an H-IG to address the 2009 H1N1 influenza pandemic and manufactured two full-scale lots using its novel Gammagard Liquid (GGL) IG process from approximately 15,000 L of CP, resulting in approximately 50 Kg of hyperimmune globulin product. “GGL has a proven track record of safety and efficacy for 16 years and is available in 39 countries (marketed as Kiovig outside of US and Canada),” Morabito comments.
Recently, Takeda announced that in order to accelerate development of an H-IG treatment, it is partnering with other plasma therapy developers (CSL Behring, Biotest, Bio Products Laboratory, Octapharma, and LFB) in the United Kingdom, Switzerland, Germany, and France to develop a single, nonbranded product. “We believe that by collaborating on plasma collection, clinical trials, and manufacturing, the CoVIg-19 Plasma Alliance can accelerate bringing a potential therapy to market and increase the potential supply,” states Morabito.
CoVIg-19, a polyclonal H-IG, is an investigational treatment prepared from the pooled plasma of individuals who have fully recovered from COVID-19 and whose blood contains high titers of antibodies that can fight SARS-CoV-2, the virus that causes COVID-19.â¯ This plasma-derived therapy has the potential to treat COVID-19 patients and to possibly prevent infection in frontline healthcare workers.
“The CoVIg-19 Plasma Alliance is collaborating closely with regulatory agencies, governments, and healthcare partners to advance this program. If successful, it is anticipated that this potential therapy could be available within nine to 18 months from the time work was initiated in January 2020,” Morabito says.
Grifols is another company leveraging experience in the development of H-IG therapies for the fight against SARS-CoV-2. Specifically, Grifols has developed a platform to produce hyperimmune globulin from disease-state CP in an isolated, dedicated manufacturing facility, which has been used to successfully produce a purified, concentrated intravenous immune globulin preparation enriched with antibodies to Ebola virus.
The company is currently collaborating with FDA, the US Biomedical Advanced Research Development Authority (BARDA), and other federal health agencies for collection of CP using its network of FDA-approved plasma donor centers. Grifols is manufacturing hyperimmune globulins in its purpose-built Clayton, NC facility and conducting preclinical and clinical trials. The company also is participating in discussions for the potential development of a clinical trial in IVIG, according to Bell.
Emergent BioSolutions, which has extensive experience with the development and licensure of six FDA-approved hyperimmune products, also initiated the development of two hyperimmune treatments for COVID-19. COVID-Human Immune Globulin (COVID-HIG), manufactured from human plasma with antibodies to SARS-CoV-2, is being developed as a potential treatment for COVID-19 in severe hospitalized patients and high-risk patients; COVID-EIG, manufactured from plasma of immunized horses with antibodies to SARS-CoV-2, is a potential treatment for hospitalized patients with severe symptoms. The company’s goal is begin a clinical trial as early as the summer of 2020.
Emergent is collaborating with the US government to expedite the development of COVID-HIG, receiving funding from BARDA and participating in a study with the National Institute of Allergy and Infectious Diseases (NAID), part of the National Institutes of Health (NIH), to assess potential treatments for COVID-19.
“We are expanding our partnership with the US government working closely with BARDA, NIH/NIAID, FDA, and other key agencies to stay aligned on our development goals and near-term response plan,” said Laura Saward, senior vice-president and therapeutics business unit head at Emergent BioSolutions. “COVID-HIG will leverage the platform that was established in partnership with BARDA through their investment in our treatments for anthrax and smallpox vaccine complications, and it provides a sustainable capability for responding to emerging infectious diseases such as COVID-19.”
The technology Emergent is employing for the COVID-19 therapies has been used by the company to develop other FDA-approved plasma-based treatments for different diseases. “As we develop these new drugs, we will be able to leverage many of the same elements around the safety and [pharmacokinetic] PK profiles, as well as the validated manufacturing controls and assays,” says Saward.
Recombinant antibody therapies based on antibodies generated in recovered patients can be either polyclonal or monoclonal. Due to their recombinant nature, a single donor can be used to generate millions of doses, according to David Johnson, CEO and co-founder of GigaGen, a biotechnology company developing a recombinant polyclonal antibody therapy.
“Administering therapeutic antibodies that target and neutralize the virus can provide protection much faster than vaccines and is a safer, more effective, less variable, and scalable treatment approach than convalescent serum,” adds Carl Hansen, cofounder and CEO of AbCellera, a biotechnology company developing a monoclonal antibody therapy.
In addition, the specific antibodies against COVID-19 are not selected for in serum- or plasma-derived therapies. “In the collected serum, there are antibodies against all types of diseases, and those diseases might have been ones that the patients were exposed to months ago and not necessarily coronavirus,” Johnson observes. He goes on to add that there is also greater batch-to-batch consistency with recombinant therapies.
One challenge for some recombinant therapies is the need to select clones with a cost-effective production yield. It is also necessary for all recombinant therapies to develop robust upstream and downstream processes yielding products that fulfill the required specifications for human use from the point of view of purity, identity, and potency, according to Bell.
GigaGen is developing the recombinant polyclonal therapy rCIG (recombinant anti-coronavirus 19 hyperimmune gammaglobulin), which according to Johnson, combines the advantages of a polyclonal approach and a recombinant approach.
“Polyclonal antibody therapies have the advantage of ‘polyclonality’; they contain many different antibodies. Unlike monoclonal antibody (mAb) therapies, which focus on a single antibody and thus only target the virus at one specific location, polyclonal antibody therapies have a broader scope,” Johnson states. He adds that because they provide patients with a diverse and comprehensive library of antibodies, the chances of efficacy are increased.
“That comprehensive set of antibodies coats the virus at various locations, making it difficult for the virus to attach to the human cell, and ultimately stopping disease progression,” Johnson explains. The company has shown that recombinant polyclonals can have much higher potency than other therapeutic options, which may result in better clinical outcomes.
“The primary indication of our polyclonal antibody therapy is for people actively suffering from COVID-19. We want to help infected patients survive the worst part of the disease,” Johnson comments. In many cases, he adds, if a patient gets through the worst, they will retain immunity through their own immune system, so they wouldn’t need more of GigaGen’s drug. If the patient is generally immune incompetent, however, they would need follow-on doses as a prophylactic against re-infection.
GigaGen is using its proprietary Surge single-cell technology to capture and recreate complete libraries of antibodies from COVID-19 convalescent patients. Blood is collected from COVID-19 convalescent patients and their B-cell repertoires (antibody producing cells) are used to replicate their natural diversity of antibodies at high concentrations. Specifically, antibody-coding DNA is captured from millions of B cells and used to engineer a library of antibodies into cell lines that produce the drug.
“Our plan is to use antibodies from the best 5–10 donors/responders. Not all patients respond the same way. Our technology enables us to select the best donors and replicate their antibody repertoires in the laboratory to generate a drug that can treat millions of patients,” Johnson asserts.
The biggest challenge for GigaGen going forward at this point is securing sufficient funding to scale production. The tens of thousands of clones making different antibodies will need to be produced at larger scale. Toxicology studies in monkeys also need to be performed before GigaGen can move into clinical trials. “We expect to do tech transfer to a manufacturing facility sometime this summer  for GMP [good manufacturing practice] production, with plans to start first clinical doses at the beginning of 2021, dependent on our conversations with FDA,” says Johnson. He notes that it would be helpful to receive clearer information from FDA regarding current policies related to expedited review and expedited paths to the clinic.
AbCellera has elected to develop a mAb-based therapy for COVID-19. The problem, says Hansen, is that the human body makes billions of unique antibodies, each unique type secreted by a single antibody-producing immune B cell. The challenge is to find the few cells among billions that make the very best antibodies for fighting SARS-CoV-2. “We’ve adapted our platform for exactly this scenario. Through our participation in the Defense Advanced Research Projects Agency’s P3 [Pandemic Prevention Platform] program, we’ve successfully tested our platform against MERS coronavirus and pandemic flu,” he remarks.
AbCellera’s drug discovery platform combines high-throughput microfluidics, big data, artificial intelligence, machine learning, and genomics to search and analyze the immune system to find the best antibodies against a disease or virus. “We can screen millions of immune cells (B-cells) in days-not weeks or months-to quickly find the best antibodies for fighting diseases,” Hansen states.
A microfluidic device approximately the size of a credit card possesses arrays of more than 200,000 nanoliter-volume reaction chambers where individual B-cells are isolated, each secreting a unique antibody. The antibodies in each chamber are tested to determine their ability to bind the spike protein on SARS-CoV-2 and identified using machine vision. Celium, AbCellera’s proprietary antibody visualization software, is applied to narrow the thousands of antibodies that can bind the target down to the best antibody candidates.
“Because we don’t need to create cell lines or clones and we can search the natural immune system so thoroughly, we can quickly and cost-effectively find thousands of diverse antibody drug candidates. The speed, depth, and integration of our technology has redefined how antibody drugs are discovered,” Hansen asserts. Indeed, the company was able to go from a recovered patient sample to a group of 24 lead drug candidates in just three weeks, a process Hansen indicates could normally take a decade.
Being able to deeply and rapidly search the diversity of the natural immune system also affords AbCellera the best chance of finding the most potent, neutralizing antibody candidates. For very potent antibodies, the amount of antibody needed for dose is reduced, which is one of the most effective ways to alleviate some of the manufacturing challenges, according to Hansen. “Antibodies from natural immune systems also require less engineering to become a drug, which reduces safety risk and time to clinical trials,” he adds.
To manufacture at the speed and scale needed for the COVID-19 pandemic, AbCellera has partnered with Eli Lilly, which has global capabilities for rapid development, manufacturing, and distribution of therapeutic antibodies. Lilly has already started GMP manufacturing of an antibody drug candidate that has demonstrated potent neutralization of SARS-CoV-2 and expects to begin clinical trials in July 2020.
Vir Biotechnology is also producing potent neutralizing human mAbs against SARS-CoV-2. The company’s leading candidates VIR-7831 and VIR-7832 have demonstrated high affinity for the SARS-CoV-2 spike protein and are highly potent in neutralizing SARS-CoV-2 in live virus-cellular assays. They were isolated from SARS-CoV-1 recovered patients using its proprietary platform technology, which identifies rare antibodies from survivors that have the potential to treat and prevent rapidly evolving and/or previously untreatable pathogens via direct pathogen neutralization and immune system stimulation
Vir has signed agreements with both GlaxoSmithKline (GSK) (9) and Generation Bio (10) to accelerate development of solutions for coronaviruses, including SARS-CoV-2. The collaboration with GSK will use Vir’s proprietary mAb platform technology to accelerate existing and identify new anti-viral antibodies that could be used as therapeutic or preventative options against COVID-19 and GSK’s expertise in functional genomics, as well as both companies’ clustered regularly interspaced short palindromic repeats (CRISPR) screening and artificial intelligence capabilities (9). The collaboration with Generation Bio is intended to extend the impact and reach of Vir’s mAbs against SARS-CoV-2 using Generation Bio’s proprietary ceDNA non-viral gene therapy platform and scalable manufacturing process (10).
Vir has also signed a $363-million agreement with Samsung Biologics for the large-scale manufacturing of its two COVID-19 mAb candidates (11). Production is expected to begin as early as October 2020. This deal follows agreements Vir signed in February with WuXi Biologics and mid-March with Biogen to scale up cell-line development, process development, and clinical manufacturing for its mAbs. Vir is hoping to move VIR-7831 and VIR-7832 into Phase II clinical testing within the next three to five months.
Rather than start only with antibodies isolated from plasma obtained from recovered COVID-19 patients, Regeneron is using a two-pronged approach that also includes generation of hundreds of neutralizing antibodies against SARS-CoV-2 obtained from humanized mouse models exposed to the virus (12).
The company previously used its proprietary VelociSuite technologies, including VelocImmune mice that have been genetically-modified to have a human immune system, to rapidly develop a promising mAb triplet therapy for Ebola, moving into clinical trials just four months after the August 2018 outbreak. REGN-EB3 is currently under review by FDA (13). Regeneron is developing a two-mAb candidate therapy (REGN3048-3051) against MERS-CoV using the same technology.
Isolation of the hundreds of virus-neutralizing, fully human antibodies from the mice took just one month (12). Regeneron has also isolated antibodies from humans who have recovered from COVID-19 to maximize the pool of potentially potent antibodies. Both sets of antibodies have been screened, and Regeneron has selected a small number to move into cell line production.
Each of the mAbs ultimately selected for a combination treatment will elicit a robust response but target slightly different parts of the virus to provide protection against multiple viral variants. Regeneron is using its VelociMab technology to prepare manufacturing-ready cell lines as lead antibodies are selected, so that clinical-scale production can begin immediately (12). In mid-April, the company moved the most potent antibodies into pre-clinical and clinical-scale cell production lines (13).
The cocktail could potentially be used as a prophylactic for at-risk people or as a treatment for people who are already infected, according to Regeneron (12). “Our three decades of investment in our VelociSuite antibody technologies, which accelerate and improve the traditional drug discovery process, have hopefully prepared us for this critical time and to meet this important challenge,” said George D. Yancopoulos, co-founder, president, and chief scientific officer of Regeneron, in a press release (12).
Regeneron is on track to begin human clinical trials in June 2020 and plans to scale production to have hundreds of thousands of lower prophylactic doses or tens of thousands of treatment doses per month by the end of August 2020 (14). Regeneron is also working with BARDA and other organizations to further increase manufacturing capacity (12).
For development of antibody-based therapies for COVID-19 disease, the main challenge that must be overcome is the current limited knowledge and understanding about the virus infectivity process itself and the disease caused by it, according to Bell. “There are still many uncertainties that complicate identifying and validating the right therapeutic target that could also be dependent on the timing of the infection process, so, there could be a target for the initial steps of the infection process and a therapeutic target for posterior phases where the main objective is to treat the clinical symptoms,” he says.
Understanding the biology of the disease, Bell believes, will lead to identifying what proteins or processes are the optimal to be targeted with a therapy. Then, the challenge will be to develop a targeted mAb product that has the needed potency and selectivity in order to have an adequate efficacy and safety profile.
As importantly, Johnson stresses that multiple health systems need prophylactics (i.e., active vaccines, passive vaccines) and therapeutics. “Vaccines are very cheap and often help 90% or so of the population. Passive vaccines help people with immune deficiencies, for example people who don’t respond to the active vaccine, or people at high risk (nurses in emergency rooms). Therapeutics help people who get sick despite the availability of both active and passive vaccines. It is important that a variety of treatment options be developed so that we have multiple avenues to target this virus,” he explains.
Bell adds that there is even precedent for concomitant administration of hyperimmune globulin (H-IG) and vaccine in order to ensure protection while vaccine-generated antibodies increase in titer. Others have proposed the combined use of convalescent plasma and H-IG in a complementary fashion to treat patients infected with SARS-CoV-2, the virus that causes COVID-19, both presently and in subsequent infectious waves (15). In the absence of a vaccine, though, as is the case with the current COVID-19 pandemic, Bell stresses that plasma-derived antibody therapies can bridge the early stages of an outbreak until the time one is available.
1. D. Roos, “Before Vaccines, Doctors ‘Borrowed’ Antibodies from Recovered Patients to Save Lives,” History.com, March 31, 2020.
2. A. Casadevall and L.Pirofski, J. of Clin. Invest. Online, 10.1172/JCI138003 (March 13, 2020).
3. K. Duan, et al. Proc Natl Acad Sci 117 (17) 9490-9496 (April 28, 2020).
4. FDA, “Coronavirus (COVID-19) Update: FDA Coordinates National Effort to Develop Blood-Related Therapies for COVID-19,” Press Release, April 3, 2020.
5. FDA, “Coronavirus (COVID-19) Update: FDA Encourages Recovered Patients to Donate Plasma for Development of Blood-Related Therapies,” Press Release, April 16, 2020.
6. Houston Methodist Hospital, “FDA Approves First Plasma Therapy for Houston Methodist COVID-19 Patient,” Press Release, March 30, 2020.
7. S. Jolles, W.A. Sewell, S.A. Misbah, Clin Exp Immunol 142:1–11 (2005).
8. J.L. HsU, N. Safdar, Infect Dis Clin North Am 25:773–88 (2011).
9. Vir Biotechnology, “GSK and Vir Biotechnology Enter Collaboration to Find Coronavirus Solutions,” Press Release, April 6, 2020.
10. Generation Bio, “Generation Bio and Vir Biotechnology to Collaborate on Research to Leverage Scalable Non-Viral Gene Therapy Platform for Durable Production of Monoclonal Antibodies Against Coronavirus That Causes COVID-19,” Press Release, March 30, 2020.
11. Vir Biotechnology, “Samsung Biologics and Vir Biotechnology Enter into Agreement for Large Scale Manufacture of SARS-COV-2 Antibodies for Potential COVID-19 Treatment,” Press Release, April 9, 2020.
12. Regeneron, “Regeneron Announces Important Advances in Novel COVID-19 Antibody Program,” Press Release, March 17, 2020.
13. Regeneron, “FDA Accepts for Priority Review Biologics License Application for REGN-EB3 to Treat Ebola,” Press Release, April 16, 2020.
14. Regeneron, “Regeneron’s Covid-19 Response Efforts: Developing A New Antibody Medicine,” www.regeneron.com, accessed May 1, 2020.
15. J.D. Roback and J. Guarner, JAMA 323(16):1561-1562 (2020).
Vol. 33, No. 6
Pages: 16–21, 35
When referring to this article, please cite it as C. Challener, “Plasma-Based Antibody Therapies Battle Against COVID-19," BioPharm International 33 (6) 2020.