Spike and block: The search for a SARS-CoV-2 antibody treatment
Since COVID-19 has spread rapidly across the world, the urgency to develop an effective treatment for it has been a principal focus of many researchers. To date, over 3.5 million people have been positively diagnosed with COVID-19, killing more than 250,000 individuals. There has been a massive collaborative effort among research groups in academia and pharmaceutical industries to accelerate development of effective, efficacious, and non-toxic treatments.
In order to develop a suitable therapy, we must first understand the components that make up this virus and the properties that allow it to infect human cells. SARS-CoV-2 contains four structural proteins that include the necessary instructions for viral replication and entry into host. One of those structural proteins, the spike protein, coats the surface of the virus and is responsible for binding to human receptors that act as doorways into the cell. The virus attaches to the host cell, fuses with the membrane, and the contents are disseminated inside. Upon successful infection, the virus hijacks the host cell machinery to produce and propagate tens of thousands of copies that can infect other cells.
While the race for a SARS-CoV-2 vaccine is still underway, several groups have identified potential antibodies that could treat or prevent infection of SARS-CoV-2. The way an antibody works is by attaching itself to a specific molecule found on the surface of a virus to shut down its cellular function. Some antibodies are designed to also alert the immune system to destroy the particle they’ve latched on to. In the context of preventing replication and invasion of this coronavirus, scientists rationalized that if attachment and fusion can be prevented, so can entry. Two recently published articles have identified antibodies that target the spike protein of SARS-CoV-2 that can block infection.
In one study, scientists from the University of Texas at Austin, the National Institutes of Health, and Ghent University teamed up together to identify one of the first antibodies to neutralize SARS-CoV-2. In a previous study from 2016, researchers at Ghent University were interested in finding an antibody that could stop two earlier coronaviruses, SARS-CoV-1 and MERS-CoV, from displaying spike proteins. In a parallel process to immunizing humans against a virus, they injected a llama with stabilized spike proteins from the coronaviruses, collected blood samples after six weeks, and isolated antibodies to see which bound to the spike proteins. One antibody showed promising results by preventing SARS-CoV-1 from infecting cells in a dish. Based on this previous finding, they hypothesized that this antibody could potentially be effective against its viral cousin, SARS-CoV-2. Though both viruses share a high degree of genomic sequence identity, the team had to engineer a refined version of the llama antibody by linking two copies together. They demonstrated that the new, re-engineered antibody bound tightly to the spike protein and neutralized them from SARS-CoV-2 in cell cultures.
A separate study from Utrecht University identified one of the first fully human antibodies that blocks SARS-CoV-2 infection in cultured cells. Building on previous work from the 2002-2003 SARS mini-pandemic, scientists were able to test an inventory of antibodies generated during that time to see if they could find one that neutralizes infection of SARS-CoV-2 in cultured cells. The antibodies were originally developed in mice, but have since been modified to increase their similarity to antibody variants produced naturally in humans, a process called humanization of antibodies. From their collection of SARS-CoV antibodies, they found one that binds to a conserved region on the spike protein found on both SARS-CoV and SARS-CoV-2, explaining its ability to cross-neutralize both coronavirus variants.
The discovery of different antibodies that target different regions of the spike protein offers several advantages. While the first group discovered one that targets the core domain that mediates entry of the virus into the host, the second group identified another that binds to the receptor-binding domain important for the recognition of human receptor, ACE2. These antibodies – either alone or in combination – offers the potential to develop treatments for COVID-19 and can additionally be useful for detection test and serological assay development against SARS-CoV-2.
While the development of a vaccine is imperative in providing long-term and sustained immunity to SARS-CoV-2, it takes a long time to license a vaccine and distribute it to the public. It is a time-consuming, evidence-based process that requires multiple safety checks and clinical testing that can take 12-18 months on an accelerated timeline. They generally have to be given a month or two before infection to provide useful protection. Antibody treatment on the other hand can provide protection immediately and be given to those already sick to decrease burden of disease. While the llama antibody still needs to undergo preclinical studies in nonhuman primates, the fully humanized antibody allows for faster therapeutic development and reduces the potential for immune-related side effects. There is promise in these antibodies, but further work still needs to be done to establish efficacy and safety before disseminated to COVID-19 patients.
By Anthony Venida.
Study 1: https://www.sciencedirect.com/science/article/pii/S0092867420304943
The spike protein helps the virus infect human cells; therefore, it is a major target of antibody-based strategies to neutralize the virus.