Discovery and development of antibody therapies for COVID-19

Neutralizing antibodies (nAbs) against SARS-CoV-2 represent a promising option for treating COVID-19. Screening a large and diverse antibody phage library has allowed for the rapid discovery of anti-SARS-CoV-2 nAbs.

In this on-demand webinar, presented by Dr. Zhiqiang Ku, Postdoctoral Fellow at the Brown Foundation Institute of Molecular Medicine, find out how high-throughput epitope binning and mapping using label-free biolayer interferometry (BLI) detection and advanced flow cytometry systems has enabled the development of an antibody cocktail that can reduce the risk of drug resistance.

Read on for highlights from the live Q&A session or register to watch the webinar at a time that suits you.

Q: Is there a single monoclonal antibody (mAb) that can prevent escape mutation, or does it have to be a cocktail?

ZK: Unfortunately, there is no single mAb that can prevent escape mutation, meaning it has to be a cocktail. Some labs and companies are working on antibodies targeting very conserved epitopes. However, they can still be escaped by a virus. I think it has to be a cocktail in order to prevent the virus getting mutations.

Q: Is it possible to use antibody cocktails containing more than two components, and would it be more effective?

ZK: I think it's definitely possible to use more than two antibodies, but you need to keep in mind that if you use more than one, it means a higher cost for the drug.

I can give you the example of Ebola antibodies. That antibody is a cocktail of three monoclonal antibodies. In terms of efficacy, the more antibodies you have in the cocktail, the more effective it will be in preventing viral escape, but it's always a balance of efficacy against the cost.

Q: Which antibody is better for nasal delivery, IgA or IgM?

ZK: In our preliminary data, we tested IgA and IgM for prophylactic treatment in mouse infection models. We’ve found that both IgA and IgM work very well against a SARS-CoV-2 infection. However, we didn't compare those evaluations.

So far, we found IgM works the best, and for in vitro neutralization. IgM is hundreds of times more potent than IgG against the wild-type virus and against some of the variants of concern that have recently emerged. That’s why we are focusing on IgM.

Q: How effective can the nasal spray be, as it’s been proved that SARS-CoV-2 may enter through our eyes?

ZK: We actually compared the IgG efficacy in a mouse infection model to intraperitoneal (IP) injection and the intranasal spray. The intranasal spray is much more potent than the IP delivery of antibodies. I think it's because SARS-CoV-2 infects people mainly through the respiratory tract. If you directly spray the antibodies into the nasal cavity or into the airway tissues, that means the antibody can directly neutralize the virus. However, if you deliver antibodies through IP or intravenous (IV) injection, you know that IgG has limited access to mucosa compartments, so I think nasal spray is more effective than IV/IP injection.

Q: How does the format of bispecific antibodies (bsAb) affect the potency?

ZK: We are working on two different formats. As you may know, there are a lot of bispecific formats. According to our data, there are two formats we tested, tetravalent and bivalent. I think the antibody valence is very important for the potency.

We think tetravalent is more potent than bivalent antibodies because this kind of format targets different epitopes and can engage more spike proteins. That is why multivalent bispecific antibodies are more potent than bivalent bispecific antibodies.

Q: Does any antibody work better when converting from IgG1 isotype into IgM isotype?

ZK: We tested six antibodies, converting IgG1 into IgM. In general, all those antibodies for the IgM work better than IgG1. However, in terms of enhancing neutralization and preventing virus escape, you need to select a proper epitope. That means epitope is very important for IgM antibodies. Our conclusion is that both the antibody ability and the epitope are important for IgM antibodies.

Q: Is it possible that the body produces its antibodies against bispecific antibodies (bsAb), especially for CrossMAb?

ZK: That really depends on the format of your bispecific antibodies. If you engineer bispecific antibodies, where you may expose new epitopes to the body, I think it's possible. But for the CrossMAb, I think is case by case.

With CrossMAb, there are already antibodies under clinical trials and approved for human use. I think it's a technical problem that you can overcome by antibody engineering. To answer your question, I think it's possible that the body may produce autoantibodies. That's even true for the monovalent antibodies such as the IgG.

Q: Are you going to be using the monoclonal antibody (mAb) as prophylactic or as a treatment? Is it going to be used in a severe disease?

ZK: We are planning to use it as both prophylactic and therapeutic options. We want to use a nasal spray, so this would be simpler for prophylactic than IV infusion of IgG.

In terms of treating patients, we are focusing on patients of mild disease. We're not going to target severe disease because the severe disease antibody therapy will be of a very limited efficacy. We only target mild to moderate patients.

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