24 November 2020

With the COVID-19 pandemic still raging and a vaccine still many months away, where are we with antibodies to treat COVID-19? This approach has got a certain amount of publicity since President Trump recently received Regeneron’s experimental monoclonal antibody.

There is a good review article in Nature Biotechnology but for all of you who are busy, here are the highlights.

The normal way to try and prevent certain infectious diseases is to give a vaccine to which the body produces antibodies. Once formed these antibodies either prevent you developing the disease or make the disease milder should you contract it.

So, what are therapeutic antibodies? 
I would describe them as “cutting out the middleman “. So instead of the body making antibodies to the infectious agent such as COVID-19, you give antibodies that already bind to the virus. 

Where do you get the antibodies from?
They can be obtained from patients who have recovered from COVID-19 infection or made in Chinese hamster ovaries cells (CHO) like the majority of therapeutic antibodies.

Is there an historical precedent for this treatment? 
There certainly is, several agents have been efficacious in reducing infection rates in respiratory syncytial virus, Ebola, rabies and hepatitis C.

How many therapeutic antibodies are being developed? 
There are over 150 potential therapeutic antibodies in preclinical and clinical development.

What is the antigen target?
The majority of agents in the clinic are targeting the Spike protein of the virus.

What is the structure and format of these antibodies?
The majority are standard IgG1, but other formats such as fab fragments, single FV chain Fragments and nanobodies could be considered. These alternative formats that have lower molecular weights may improve tissue penetration, but this is at the cost of shorter half-lives.

Should the antibodies have effector function?
I think the jury is out on this but probably the safest approach is to initially study antibodies that do not have effector function.

Will they affect the efficacy of antibody therapy be Affected by viral mutation?
One approach is to give a cocktail of antibodies that bind to noncompeting epitopes, but this is controversial.

The alternative approach is to give a single Antibody and Swap to an alternative antibody if neutralisation escape is observed, a similar way that antibiotics are used. This of course assumes multiple antibody therapies would be available.

What clinical data are available for anti-COVID antibodies?
The lead candidates are being developed by Regeneron, Lilly/AbCellera, Vir Biotech/GlaxoSmithKline. 

Published data from the Lilly/AbCellera antibody (Bamlanivimab) show that this was not effective in hospitalised patients. However the U.S. Food and Drug Administration (FDA) authorized the EUA for this antibody for the treatment of mild to moderate COVID-19 in adults and pediatric patients 12 years and older with a positive COVID-19 test, who are at high risk for progressing to severe COVID-19 and/or hospitalization. 

Will this therapy work?
It is back to the old adage “right patient, right treatment, right dose”

In seriously ill patients with high viral load there may be limits to what this treatment can achieve.  It is reasonable to assume the dose will be dependent upon viral load.

In the case of mild disease, prophylaxis for healthcare workers, and those who are immunocompromised, this treatment could be useful.

However, in the case of prophylaxis the need for a long half-life of the therapeutic antibody is of critical importance to reduce both the frequency and cost of treatment.

How should these antibodies be administered? 
Antibodies are normally administered as intravenous infusions or subcutaneous injections but in the case of respiratory infection local application to the nose and lungs should be considered when used for treatment (rather than prophylaxis).  Local administration is more likely to induce antidrug antibody formation, but hopefully repeated administration will not be common.

Any downsides? 
The main downside has to be the cost of production.  The other is emergence of viral escape mutants that no longer express the correct binding epitope.