All About Antibodies

1. What Are Antibodies?

2. What Are Antibody-based Therapeutics and How to They Work?

3. How Are Antibodies Different from Vaccines?

4. What Are the Risks of Antibody-based Therapeutics?

5. What Are the Methods of Production – and Can These Be Scaled?


What Are Antibodies?

Antibodies are one of your body’s natural defense systems against foreign attackers. Specifically, an antibody is a Y-shaped protein produced by B cells, which are part of the immune system. When your body detects foreign intruders (like bacteria or viruses), your immune system makes antibodies that recognizes them. These specific antibodies attach to the foreign intruders and target them for destruction.

Illustration of an antibody binding to the surface of a virus, blocking entry into a person's cells.

Antibodies that bind to the surface of a virus and block entry into a person’s cells can actually prevent infection or disease: this is called neutralization. Typically vaccines are designed to produce the antibodies that recognize and “tag” viruses as foreign invaders by binding to unique parts of a virus. To treat or prevent disease, scientists can also use antibodies from the blood of people who have recovered from the infection (i.e., “convalescent plasma”) or use antibodies selected, copied or even synthesized in a lab (monoclonal and polyclonal antibodies) that will attach to and neutralize the foreign intruders as a prevention option or treatment. Credit: COVID-19 Prevention Network.

Further Reading:


What Are Antibody-based Therapeutics and How Do They Work?

Antibody-based therapeutics are treatments which are developed based on the natural antibodies produced by someone that has been infected and recovered from a virus. There are several different types, with different histories and technologies involved. But all are based on the simple principle of harnessing the immune system of someone that has successfully beaten a virus to protect those that do not have immunity yet.

Convalescent Plasma

A century ago, doctors filtered plasma from the blood of recovered patients during the infamous Spanish Flu Epidemic (recommended reading: The Great Influenza). So-called convalescent plasma, rich with antibodies, helped people sick with flu fight their illness. Now researchers are trying out this strategy on COVID-19. Hundreds of thousands of people have donated blood plasma, and tens of thousands of patients in the U.S. have received plasma through the National COVID-19 Convalescent Plasma Project a program launched by Johns Hopkins, the Mayo Clinic and the federal government.

You can think of Convalescent Plasma like raw sugar. It is the direct extraction of the antibodies from the blood of someone that has recovered from the virus – like extracting or squeezing the sugar from sugar cane. It is then given to another person in the same manner as a blood transfusion. Generally speaking, this is pretty manual and one-to-one process – i.e. it’s hard to scale.

Immunoglobulin (IGG) and Hyper Immune Globulin

In 1960, antibodies were found to be carried on immunoglobulin G (IgG) molecule. This resulted in the production of concentrated IgG antibodies as a byproduct of blood donations. For several decades, this product, hyper-immune gamma globulin (IGG) – also sometimes called Gamma Globulin – prevented disease for which there were no vaccines.  In the 1950s, just before the Salk vaccine came on the market, William McD Hammon at the University of Pittsburgh used to IGG to prevent polio in trials involving hundreds of thousands of children in a blinded efficacy trial that successfully blunted attack rates of paralysis during epidemics of poliomyelitis.  IGG has been licensed in the United States to prevent hepatitis A and B in travelers, and more broadly used for persons exposed to rabies, chickenpox, measles, tetanus, respiratory syncytial virus or cytomegalovirus.

IGG is a more processed product, where additional steps of selection of the best antibodies, with refinement and concentration into serum that packs a lot more immune protection per unit volume. This can then usually be given to another person as a shot or infusion under the skin. Generally speaking, more scalable techniques of manufacturing and production can be applied.

As technologies for identifying and selecting the antibodies with the strongest responses to the targeted virus have been developed, an even more powerful and refined version of this has been created, termed Hyper Immune Globulin. Since this takes much more ‘raw sugar’ – antibodies from many donors – it is generally more expensive to produce. Hyper Immune Globulins are used primarily for immunotherapies for cancer, as well as extreme immunodeficiency conditions such as people that have no or a very underdeveloped immune system caused by either disease or genetics.

Currently, the CoVIg-19 Plasma Alliance – an unprecedented global alliance of the world’s leading plasma companies, spanning plasma collection, development, production, and distribution – is dedicated to both the collection of plasma, and using the plasma they collect to develop IGG therapies on a large scale. Many of these therapies are now in Phase 3 trials and could be approved and available for use by the end of 2020.

Monoclonal and Polyclonal Antibodies

Convalescent plasma from people who recover from COVID-19 contains a mix of billions of different kinds of antibodies. Some of the molecules can attack the coronavirus, but the vast majority are directed at other pathogens. When the pandemic began, scientists began sifting through this slurry of antibodies and picked out a few dozen types that provide a potent defense against COVID-19 in cells and animals according to preclinical studies.

These potent molecules, known as monoclonal antibodies, have a long track record in medicine. Monoclonal antibodies were first investigated in the 1970s, and since then the F.D.A. has approved them for 79 diseases, ranging from cancer to AIDS. Over the summer, companies and universities began giving monoclonal antibodies for COVID-19 to patients in a number of clinical trials.

Unfortunately, many viruses – including the Coronavirus – tend to mutate frequently. So over time, a particular monoclonal antibody may become less effective – or only work against one strain of the virus. The term “polyclonal” refers to the laboratory selection, synthesis and reproduction of multiple different antibodies, addressing different strains and mutations of the virus that have been identified. Generally speaking, these have a better chance of being more broadly effective during a large, long term epidemic such as COVID-19.

An important aspect of of monoclonal and polyclonal antibodies is their mode of production. Over the last few decades, Biotech and Pharma companies have developed advanced technologies for selecting – or even synthesizing – biological molecules and then reproducing them in “Bioreactors”. This means that once the best monoclonal and polyclonal antibody “cocktails” are tested and proven, they can be manufactured at scale. If Convalescent Plasma is the ‘raw sugar’, and Immunoglobulins the ‘refined sugar’, then these are in effect the Saccharines and Aspartames – although perhaps more like Stevia in their organic basis!

While the current manufacturing processes are not as inexpensive or scalable as vaccines, we do have significant capacity and the ability to expand it.

Further reading:

Super Antibodies

Recently, some companies have been working on so called ‘Super Antibodies’. This is more or less the holy grail: an antibody that protects against not just the virus, but also related pathogens that may threaten humans. An example of a group working on that right now is Prometheus, a network of private and government labs who are racing to develop a super antibody for COVID-19. Unlike the monoclonal and polyclonal antibodies, whose immune protection fades over 2 or 3 months, Prometheus’s antibody aims to be effective for up to six months. In mice and laboratory tests, Prometheus’s antibody also has been shown to protect against not just the coronavirus, but also the SARS virus and similar bat viruses — suggesting that the treatment may protect against any coronaviruses emerging in the future.

This is important not only because of the mutation of virus already in the human population, but because of how modern civilization has exponentially increased the rate of transmissions from “wild reservoirs” of viruses into humans – and then out across the world in global pandemics. A study published last year, for example, recorded about 400 strains of bat-origin coronaviruses in China, some of which had already spilled over into people. And of course, the current COVID-19 pandemic had exactly this origin.


How Are Antibody-based Drugs Different from Vaccines?

With vaccines, the principle mechanism for immunity is to give a person either a weakened (“attenuated) virus, or just the parts of the virus that provoke an immune response, while eliminating its ability to cause disease. Our bodies will then respond to the vaccine by making antibodies against the virus, producing what is called Adaptive Immunity. In effective vaccines, this produces a long term ‘memory’ of the virus in our immune system, generating immunity for years or even a lifetime.

With antibody-based drugs, that step and process of generating an immune response is skipped. Instead, antibodies – or the specific parts of antibodies that combat or “neutralize” a virus – are administered directly. This is done using intravenous infusions, commonly known as “getting an IV,” as well as with shots into the skin or infusions under the skin. Effectively, you have received the antibodies that someone else generated based on their immune response, and we already know works to neutralize the virus.

But whereas the antibodies produced naturally by your body in response to a vaccine can last for a long time, these laboratory-made antibodies usually only last for a few months, thus requiring people to get multiple infusions or injections on a regular schedule. That’s why for most people, antibody-based drugs are seen as a “bridging solution” until safe and effective vaccines are widely available.

On the other hand, some viruses – and COVID-19 in particular – are particularly deadly for people whose immune systems are weakened, which includes the elderly and those with pre-existing conditions. Vaccines tend not to be as effective in protecting these people from severe disease or death – a problem we see with the Flu virus every winter. For these people, antibody-based drugs can be a vital, long term tool for both treatment and preventing infection during times of outbreaks and when they are facing increased exposure risk (e.g. travels, holidays with lots of social interaction).


What Are the Risks of Antibody-based Therapeutics?

Antibody-based therapeutics are generally easier to produce and inherently safer than vaccines. There are several reasons for this.

  1. These drugs do not use weakened viruses, or parts of viruses – which creates risks that need to be tested at scale and over time to be fully understood and avoided.
  2. Instead, they are bolstering the immune system directly with antibodies that have already been successful in fighting the virus in other people.
  3. They are based on the same principles as convalescent plasma and immunoglobulin that have been used successfully and safely for prevention and treatment for over 100 years.

But like any drug or therapy, they do have risks of course. The most important ones for an antibody-based drug for a disease like COVID-19 are the following.

  1. Allergic Reactions. This can range from the ‘garden variety’ reaction that people have to shots of all kinds, including redness and swelling, itching, dizziness, nausea, mild fevers, and so on.
  2. Severe Allergic Reactions. For a very small subset of people, there are two types of much more serious reactions that can occur:   (a) possible idiosyncratic immune system response; (b) exaggerated allergic reaction that is driven by unusual blood or protein profiles. Fortunately, the former is exceedingly rare (not seen as yet in any trials for COVID antibody drugs) and the latter can be easily screened with blood tests to avoid this hazard.

As with vaccines, there is always a small risk of something going wrong in the manufacturing process itself. However, modern techniques and the rigorous protocols and safety testing processes that are followed make this an infinitesimal possibility. The most important factor here is not to rush, or take shortcuts to pushing products to market.


5. What Are the Methods of Production – and Can These Be Scaled?

The methods of production vary according to the type of treatment.

Convalescent Plasma

Generally speaking, the methods to extract and prepare convalescent plasma – although involving lots of technology – are pretty labor intensive and hard to scale. It starts with extracting plasma from donors, much like a blood donation, except that the donated blood is processed to remove blood cells, leaving behind liquid (plasma) and antibodies – in this case specific to COVID-19. That plasma – after a variety of tests to ensure there are no diseases in the donors blood, and protein typing to ensure compatability, is then given to a patient hat has been exposed to COVID-19. So in the best case, one plasma donor could ‘treat’ one patient.

But the amount of antibodies in the plasma from a donor and whether they are effective depends on a lot of factors. Therefore, generally plasma based treatments come from donations from many donors and involve steps for testing and preparation that are not easy to automate. On the other hand, given the large number of cases, there is a lot of potential supply. The National COVID-19 Convalescent Plasma Project is a very well organized effort to systematically collect, prepare and distribute Convalescent Plasma as a therapeutic treatment.

Immunoglobulin (IGG) and Hyper Immune Globulin (HIG)

IGG is a more processed product, where additional steps of pooling blood serum and selecting the best antibodies (those specific and most effective to neutralizing COVID-19 in this case), with refinement and concentration into purified gamma globulin that packs a lot more immune protection per unit volume. The term “hyperimmune” simply describes a process of selecting and pooling sera with high antibody titers and then preparing them as purified gamma globulin. This can then usually be given to another person as a shot or infusion under the skin. Generally speaking, more scalable techniques of manufacturing and production can be applied than for Convalescent Plasma. However, much more supply is needed for a given dose of IGG and HIG, and more steps are involved to produce it.

Monoclonal and Polyclonal Antibodies

An important aspect of of monoclonal and polyclonal antibodies is their mode of production. Over the last few decades, Biotech and Pharma companies have developed advanced technologies for selecting – or even synthesizing – biological molecules and then reproducing them in “Bioreactors.” This means that once the best monoclonal and polyclonal antibody “cocktails” are tested and proven, they can be manufactured at scale. If Convalescent Plasma is the ‘raw sugar’, and Immunoglobulins the ‘refined sugar’, then these are in effect the Saccharines and Aspartames – although perhaps more like Stevia in their organic basis!

Unfortunately, our manufacturing capacity is limited, and there has been no national effort thus far (as of October 26, 2020) to change that. In the short term, we can produce with existing capacity – which is substantial, with plans for millions of doses per month by Q1 2021. But given the current rates of infection, this will limit use to only high risk population groups. But with focus and action now, the Federal government can play a critical role in 3 areas to change capacity for both the mid and long term.

1. capital investment – or covering the risks of these – to ramp production;
2. coordination of supplies and production with existing facilities – as Operation Warp Speed is doing now for vaccines; and
3. expand manufacturing on a relatively short timeframe using replicate single-use modular platforms or by identifying and bringing online mothballed facilities

Further reading
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