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Cross-reactivity

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  3. Research Domains
  5. Biomedical And Clinical Sciences
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  11. Genetic Barrier To Resistance: A Critical Parameter For Efficacy Of Neutralizing Monoclonal Antibodies Against Sars-cov-2 In A Nonhuman Primate Model

Genetic barrier to resistance: a critical parameter for efficacy of neutralizing monoclonal antibodies against SARS-CoV-2 in a nonhuman primate model

Christiane Stahl-Hennig1, Antonia Sophia Peter2, Arne Cordsmeier2

  • 1Unit of Infection Models, German Primate Center, Göttingen, Germany.

Journal of Virology
|June 20, 2024

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View abstract on PubMed

Summary
This summary is machine-generated.

Monoclonal antibodies for SARS-CoV-2 are selected based on cell culture neutralization potency. However, resistance mutations can limit efficacy in vivo, highlighting the importance of the genetic barrier to resistance for effective antibody prophylaxis.

Area of Science:

  • Virology
  • Immunology
  • Pharmacology

Background:

  • Monoclonal antibodies are crucial for treating viral infections like SARS-CoV-2.
  • Antibody neutralization potency in cell culture is often the primary selection criterion for clinical development.
  • In vivo protection may be influenced by factors beyond cell culture neutralization.

Purpose of the Study:

  • To compare the in vivo efficacy of two neutralizing monoclonal antibodies (TRES6 and 4C12) against SARS-CoV-2.
  • To evaluate the influence of antibody epitope targeting and genetic barrier to resistance on prophylactic efficacy.
  • To assess antibody distribution in respiratory secretions and serum.

Main Methods:

  • Prophylactic administration of TRES6 and 4C12 monoclonal antibodies in rhesus monkeys.
Keywords:
SARS-CoV-2antibody therapybarrier to resistanceneutralizing monoclonal antibodies

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  • Challenge with the Alpha SARS-CoV-2 variant via naso-oropharyngeal route.
  • Quantification of viral loads in upper and lower respiratory tracts.
  • Analysis of viral mutations conferring antibody resistance.
  • Measurement of antibody concentrations in serum and respiratory secretions.

    • Main Results:

    • TRES6 initially reduced viral loads but resistance mutations emerged rapidly, compromising efficacy.
    • 4C12 showed less efficient initial viral load suppression but maintained lower viral loads in the lower respiratory tract long-term.
    • No resistance mutations to 4C12 were detected; it exhibited reduced distribution into respiratory secretions.
    • Viral genetic barrier to resistance emerged as a critical factor for antibody efficacy.

    Conclusions:

    • Cell culture neutralization potency is not the sole determinant of in vivo efficacy for SARS-CoV-2 monoclonal antibodies.
    • The genetic barrier to resistance significantly impacts the effectiveness of antibody prophylaxis.
    • Antibody distribution into respiratory secretions influences therapeutic outcomes.
    nonhuman primate model