Casirivimab and Imdevimab, a combination therapy developed by Regeneron (often called REGEN-COV), emerged as an early pharmaceutical intervention against the SARS-CoV-2 virus. This dual-antibody treatment provided the body with immediate, pre-made immune defenses. Its purpose was to treat individuals with mild-to-moderate COVID-19 and prevent the progression to severe disease. This therapy was a significant step in managing the pandemic before widespread vaccination was available.
Monoclonal Antibodies Explained
Monoclonal antibodies (MABs) are laboratory-engineered proteins designed to function like the natural antibodies produced by the human immune system. These therapeutic molecules recognize and bind to a specific target, such as a protein on the surface of a virus. Once administered, these antibodies provide immediate passive immunity, as the body does not need to learn how to fight the pathogen.
The biotechnological process involves isolating an effective natural antibody and then mass-producing it in a controlled environment. The resulting MABs are highly specialized, ensuring they target only the intended viral structures. This approach differs from a vaccine, which trains the body’s immune system to generate its own lasting antibodies.
Specific Mechanism of Action
Casirivimab and Imdevimab work together to neutralize the SARS-CoV-2 virus by targeting its spike (S) protein. The spike protein is the structure the virus uses to attach to and enter human cells via the ACE2 receptor. Both Casirivimab and Imdevimab are human immunoglobulin G-1 (IgG1) antibodies directed against this protein, preventing attachment and cellular entry.
The combination, or “cocktail,” approach is a deliberate strategy to ensure robust protection. Casirivimab binds to one specific site on the receptor-binding domain (RBD) of the spike protein, while Imdevimab binds to a different, non-overlapping site. Because the two antibodies bind non-competitively to distinct locations, the virus is blocked from multiple angles simultaneously. This dual-targeting mechanism reduces the likelihood of viral escape, where a single mutation allows the virus to evade neutralization.
Authorized Patient Criteria and Administration
The initial Emergency Use Authorization (EUA) strictly defined the eligible population. It was authorized for non-hospitalized individuals with mild-to-moderate COVID-19 who tested positive for SARS-CoV-2. Patients also had to be at high risk for progressing to severe disease, hospitalization, or death. This high-risk designation included individuals aged 65 and older, or those with underlying conditions like obesity, chronic kidney disease, or diabetes.
The treatment was explicitly not authorized for patients already hospitalized or requiring oxygen therapy, as evidence suggested this could lead to worse clinical outcomes. The initial authorized dose was a single combination of \(1,200\) mg of Casirivimab and \(1,200\) mg of Imdevimab. This was initially given as an intravenous (IV) infusion, but subcutaneous (SQ) injection later became an authorized alternative when IV administration was not feasible, emphasizing the need for early treatment.
Effectiveness Against Evolving Variants
The efficacy of Casirivimab and Imdevimab depended highly on the stability of the targeted spike protein structures. As SARS-CoV-2 evolved, its genetic code accumulated mutations, particularly in the spike protein. For a period, the cocktail demonstrated strong neutralizing activity against early variants and retained potency against the Delta variant, representing its peak utility.
The landscape shifted dramatically with the emergence of the Omicron variant and its subsequent subvariants. The numerous mutations in the Omicron spike protein occurred at the specific binding sites targeted by the antibodies. These genetic changes structurally altered the RBD, preventing the antibodies from attaching effectively. Laboratory studies demonstrated that the cocktail had significantly reduced neutralization potency against Omicron.
This loss of neutralizing activity meant the therapy could no longer effectively block the virus for the most common circulating strain. Because the treatment failed to meet the statutory criteria of likely effectiveness, the EUA for Casirivimab and Imdevimab was put on hold in the United States and other regions with high Omicron prevalence. This experience underscored the challenge of developing antibody therapies against rapidly evolving RNA viruses.
Current Regulatory Status
As a consequence of the drug’s inability to neutralize the widely circulating Omicron variant, the regulatory status of Casirivimab and Imdevimab changed. Following the initial suspension of its use, the Emergency Use Authorization (EUA) in the United States was formally revoked by the Food and Drug Administration (FDA). This revocation was prompted by a request from the manufacturer, Regeneron, as the drug was no longer authorized for use due to the continued high frequency of non-susceptible SARS-CoV-2 variants.
The withdrawal of the EUA signaled the end of the treatment’s role in the US pandemic response. The decision was also supported by the fact that the shelf life for nearly all manufactured lots had expired. Their regulatory fate was sealed by viral evolution, shifting the focus to newer antiviral pills and monoclonal antibodies designed to retain broader activity against diverse variants.