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Insider Highlights from Bioinsider’s Friday Roundtable, “How COVID-19 has Changed the Immunogenicity Risk of Immune Modulatory Biologics”

Insider Highlights from Bioinsider’s Friday Roundtable, “How COVID-19 has Changed the Immunogenicity Risk of Immune Modulatory Biologics”

Scientists are making rapid and significant strides to develop anti-COVID-19 therapeutics. However, it is vital to understand the nature of the immune response in COVID-19 infected people and, whether, the infection has an influence on the ability of the immune system to cause a differential immune response is an important consideration that needs to be evaluated during therapeutic clinical trial evaluations.

Bioinsider hosted its virtual Friday Roundtable, How COVID-19 has Changed the Immunogenicity Risk of Immune Modulatory Biologics, to discuss the impact of COVID-19-mediated immune modulation and the impact on response to investigational biotherapeutics. This discussion was moderated by Drs. Vibha Jawa, Director and Lead, Predictive and Clinical Immunogenicity, PPDM, Merck & Co Inc, and Narendra Chirmule, CEO, SymphonyTech Biologics; CSO, AcuImmune.

Critical questions posed in the discussion:

  1. Does COVID-19-mediated hyper activation of the immune system result in dysregulation of immune responses?
    • We now understand that COVID-19 evades a critical early type-1 IFN response early allowing it to spread and cause a tremendous hyperinflammatory syndrome.
      • Studies have shown that COVID-19 viral proteins bind to Toll-like receptors 3 and 8, and downstream proteins of the innate phase. This results in the inhibition of interferon (IFNα and β) production and subsequent IFN receptor-mediated signaling.
      • IL-1 and IL-6 are hallmarks of this massive systemic inflammatory response.
    • Patients treated with IFN-α, cleared the virus more quickly compared to untreated patients.
    • CD4 T-helper cells (Th1) produce cytokines the produce proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses.
      • COVID-19-induced Th1-type cytokines have been shown to damage normal tissues.
    • NK cells, macrophages, and ϒδ T-cells have also shown to be activated by COVID-19. Panel members believe that T-cell networks are being highly impacted.
    • COVID-19-induced inflammatory response is thought to increase the activation of pre-existing autoimmune diseases such as Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, which is why these patients are even higher risk of mortality.
    • The microbiome is also involved, but it is unknown to what degree it is impacted by COVID-19.

Investigative initiatives

    • An FDA task force has been created for collecting IFN response information from patients being treated with various biotherapeutics in current clinical trials in order to modify or prevent the disease from becoming severe.
    • Pharmaceutical companies are now ramping-up IFN-based clinical trials, where a Th1-type IFN is given prior to therapeutic administration.
    • The National Institutes for Health is conducting a detailed analysis of cytokine responses in patients infected with COVID-19.
  1. How does a hyperinflammatory immune response affect biotherapeutics?
    • It is really a black box. Scientists don’t understand the effect of the hyperinflammatory state on immunogenicity on biotherapeutics.
    • Experts who have experience treating patients with familial hemophagocytic lymphohistiocytosis and macrophage activating syndrome, which have a similar a similar hyperinflammatory disorder similar to that observed in patients infected with COVID-19, are unsure if whether there would be an enhancement or diminished response to protein therapeutics in this context.
    • There is also strong evidence of diminished response to protein therapeutics in preclinical models of hyperinflammation, this may suggest that patients with a hyperinflammatory response may have limited benefit.

Investigative initiatives

    • None exist. A detailed risk assessment is imperative. For example, patients should be profiled for the potential to have anti-drug (i.e. antibody/biologic) antibodies and these patients should not be treated.
  1. What is the influence of COVID-19 on B-cell responses?
    • It is known that some patients induce robust neutralizing antibodies targeting the Spike protein, while other patients have poor antibody production.
    • Contrasting observations further complicate the therapeutic relevance of neutralizing antibodies. For example, a high level of neutralizing antibodies occurs in patients with severe viral disease. However, the absence of neutralizing antibodies has also occurred in infected patients who do not develop severe disease. Taken together, these observations suggest a strong antibody response may not be therapeutically relevant for COVID-19.
    • The proportion of antibody isotype (IgG1, IgA1, 2, …, IgM) is thought to be important. Patients with delirious cell counts contained preferential levels of certain antibody isotypes. Thus, the isotype ratios are important and need to be considered.
    • Currently, evidence points to that neutralizing antibodies do not induce an increased mutation rate for COVID-19.
  1. What about use of immune checkpoint inhibitor antibodies to treat COVID-19?
    • The data is conflicting but ultimately not encouraging.
    • PD-1 has been shown to overexpressed and decreased on the cell surface of immune cells in patients infected with COVID-19.
    • A recent study showed that patients with lung cancer who were also COVID-19+ had severe infection severity (>50% hospitalizations, ~25% deaths). PD-1 blockade was not associated with an increased risk of severity of COVID-19.
    • However, a combination of concurrent IFN therapy was discussed and potentially effective.

Conclusion and open questions

The conclusions from this discussion were several, however, the most pressing is that more research is rapidly needed to understand immunogenicity of COVID-19 in its natural pathogenesis in order to identify potential responders and nonresponders to biotherapeutic therapies.

Due to high demand, Bioinsider will provide a follow-up Friday Roundtable to discuss and find potential solutions to these open questions. If you missed the first one, make sure to sign up for the follow-up Friday Roundtable on this topic here.

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