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Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus
Sumathi Sivapalasingam1, George A Saviolakis2, Kirsten Kulcsar3
1Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.
Background:
REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells.
Methods:
Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation.
Results:
Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic.
Conclusions:
REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.
Insights
Two human monoclonal antibodies, REGN3048 and REGN3051, show promise for preventing and treating Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Combination therapy was safe and effective in preclinical and early human trials.
Area of Science:
- Immunology
- Virology
- Pharmacology
Background:
- Middle East respiratory syndrome coronavirus (MERS-CoV) uses the dipeptidyl peptidase-4 (DPP4) receptor for cell entry.
- REGN3048 and REGN3051 are human monoclonal antibodies targeting the MERS-CoV spike glycoprotein.
Purpose of the Study:
- To evaluate the efficacy and safety of combined REGN3048 and REGN3051 for MERS-CoV infection.
- To assess the pharmacokinetic and immunogenic properties of the antibodies in humans.
Main Methods:
- Preclinical studies involved MERS-CoV infected humanized DPP4 mice treated with antibodies.
- Phase 1 clinical trial administered escalating doses of combined antibodies or placebo to healthy adults.
- Safety, viral titers, lung pathology, pharmacokinetics, and immunogenicity were assessed.
Main Results:
- Combination therapy significantly reduced viral load, lung inflammation, and pathology in mice compared to monotherapy or controls.
- The combined antibodies were well-tolerated in humans with no serious adverse events or dose-limiting toxicities.
- Antibodies exhibited expected human IgG1 pharmacokinetics and were not immunogenic.
Conclusions:
- Combined REGN3048 and REGN3051 demonstrated significant efficacy in preclinical models.
- The antibody combination is safe and well-tolerated in humans.
- Further development for MERS-CoV treatment or prophylaxis is warranted.
