First-generation therapeutics have been largely ineffective against the SARS-CoV-2 virus, resulting in significant challenges and opportunities for the second-generation therapeutics that are being designed now.
First-generation therapeutics have been largely ineffective against the SARS-CoV-2 virus, resulting in significant challenges and opportunities for the second-generation therapeutics that are being designed now.
“As first generation therapeutics for COVID-19 struggle, we must learn why they struggle and how to address their limitations,” Daniel Chen, M.D., Ph.D., CMO for IGM Bioscience, said at the recent Bioinsider virtual meeting discussing the therapeutic pipeline for COVID-19.
The opportunities for second generation therapies, as Chen sees them, include:
• Enhancing CD8 T cell memory T cell responses.
• Increasing the longevity of the protective humoral immune response.
• Enhancing the specificity of antiviral medications, and thus the potency of SARS-CoV-2 oral inhibitors.
• Specifically targeting the hyperinflammatory biology.
• Stimulating the cellular immune response early in the infection.
• Inhibiting inflammation late in the disease.
• Increasing neutralization in the primary infection compartments.
• Increasing inhibition of viral variants.
Because the initial SARS-CoV-2 infection presents primarily as a respiratory virus, “protection needs to focus on the mucosal space. We need to inhibit the virus’ early activation, and recognize that it can cause viremia, thrombosis, and other conditions, and is a visceral disease affecting cells in the heart, kidneys, brain, and beyond. It’s a broad-ranging virus.
“We’ve seen growing evidence of the importance of the CD8 T cell response in combatting the SARS-CoV-2 virus, the lack of potency and specificity of SMI therapeutics (like remdisivir), learned that immune modulators aren’t directed against hyperinflammation, and that neutralizing antibodies offer poor protection in mucosal compartments,” Chen said.
“We’ve learned that the spike protein may not generate the best immune response,” Chen continued. “We now know there are variants in the spike protein, so interventions need to address not just one sequence, but the broad range that will present” to generate a sustained CD8 T cell response.
For the next generation of antibody-based anti-COVID-19 therapeutics, Chen recommended identifying the right epitopes and targets, and then selecting the right antibody or combination of antibodies.
Today, he said, “Most efforts around neutralizing antibodies are focused on IgG platforms.”
Chen, whose company focuses on IgM antibodies, said the humoral response elicited by IgG is not as effective for respiratory tract infections and that other antibodies may be more effective.
For example, he suggested designing bi-or multi-specific antibodies or antibody fusions, as well as investigating the efficacy of IgM, IgA, DARPins and nanobodies, and considering CAR-T and TRAP approaches. PEGylation also may be promising.
“With the SARS-CoV-2 virus, infections usually first occur in the mucosal spaces,” Chen pointed out. The lung, eyes, upper respiratory tract and intestines, for example, each have a mucosal compartment. The need to deliver therapeutics to those compartments has caused physicians to push massively high doses of medications. The alternative, he said, is to deliver the antibody directly into those spaces.
As an example, Chen cited research by Michael Schoof and colleagues at the University of California – San Francisco. Schoof’s team used a high affinity trimeric antibody mNb6-tri to bind to multiple epitopes on the spike protein and block ACE2 interaction.
“The virus was bound in an inactive stage,” Chen said, so it couldn’t infect other cells. “This antibody won’t provide systemic protection, but could be given early after exposure or, later, in combination with systemic approaches.”
In terms of delivery, he noted that while intravenous administration may first come to mind, nebulizers, intranasal atomizers, and dry powder inhalers also are effective delivery systems for pulmonary diseases.
The possibility that the SARS-CoV-2 virus will mutate poses another challenge. One solution is to add multiple antibodies to a therapeutic, but that soon becomes unwieldy. A more elegant solution, Chen suggested, relies upon physical mechanics.
Choosing molecules with high avidity (the premise behind Velcro™), he said, may enable the antibodies to bind with stronger and stronger characteristics to variations of the original target.
“As you get larger and larger molecules, that leads to steric hindrance. The larger the molecule you use to cover the virion, the better able you may be to account for escaped viruses by glomming up the molecule,” he said.
Basically, even if the virus mutates, this strategy can effectively envelop it and prevent it from binding to human cells.
“When large, multivalent antibodies with high specificity, affinity and avidity bind to the target, they just don’t come off,” he said.
“Vaccines are the foundation of our fight against COVID-19, but of themselves won’t solve the problem,” Chen concluded. Therapeutics are needed. To make them effective, “we urgently need a better understanding of the complexity of COVID-19 virus and host biology interactions.”
