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Monday, August 11, 2025

Antiviral monoclonal antibodies


Introduction

  • Antiviral monoclonal antibodies (mAbs) are laboratory-engineered immunoglobulins designed to target specific viral antigens.

  • They are part of passive immunotherapy, providing immediate but temporary immunity by delivering ready-made antibodies.

  • Used for prevention or treatment of viral infections by neutralizing viral particles, blocking entry into host cells, or marking infected cells for immune destruction.

  • Particularly valuable for high-risk populations, immunocompromised individuals, and in cases where vaccines are ineffective or unavailable.

  • Examples include therapies against SARS-CoV-2, RSV (respiratory syncytial virus), Ebola virus, and others.

Mechanism of Action

Neutralization of Virus

  • Bind directly to viral surface proteins critical for cell entry (e.g., spike protein in SARS-CoV-2, F protein in RSV).

  • Prevent virus-receptor interaction and membrane fusion.

Opsonization and Phagocytosis

  • Mark virus particles for destruction by immune cells via Fc receptor-mediated uptake.

Complement Activation

  • Engage complement pathways leading to viral particle lysis or opsonization.

Antibody-Dependent Cellular Cytotoxicity (ADCC)

  • Bind infected cells expressing viral antigens on their surface, directing natural killer (NK) cells to induce apoptosis.

Types of Antiviral Monoclonal Antibodies

1. Fully Human mAbs

  • Generated using transgenic mice or phage display libraries with human immunoglobulin genes.

  • Lower risk of immunogenicity compared to chimeric or humanized antibodies.

  • Example: Sotrovimab (SARS-CoV-2).

2. Humanized mAbs

  • Mostly human antibody sequence with only antigen-binding regions (complementarity-determining regions) from non-human species.

  • Reduced immune reaction compared to chimeric antibodies.

3. Chimeric mAbs

  • Combine murine variable regions with human constant regions.

  • Higher immunogenicity than fully human or humanized antibodies.

4. Bispecific Antibodies

  • Engineered to bind two distinct epitopes or antigens simultaneously, potentially enhancing neutralization and reducing escape mutants.

5. Antibody Cocktails

  • Combination of two or more mAbs targeting different viral epitopes.

  • Reduces risk of viral resistance.

  • Example: Casirivimab + Imdevimab for COVID-19.

Pharmacokinetics

  • Administration: Mostly intravenous (IV) or intramuscular (IM).

  • Absorption: IM administration results in slower absorption compared to IV infusion.

  • Distribution: Primarily in extracellular fluid; large molecular size limits tissue penetration.

  • Metabolism: Catabolized to peptides and amino acids via reticuloendothelial system.

  • Half-life: Varies widely (days to weeks); some engineered with Fc modifications for extended half-life (e.g., tixagevimab/cilgavimab).

Clinical Indications

Pre-exposure Prophylaxis

  • For high-risk individuals unable to mount adequate vaccine responses (e.g., severely immunocompromised).

Post-exposure Prophylaxis

  • Administered shortly after exposure to prevent infection or reduce severity.

Treatment of Active Infection

  • Given early in the course of infection to prevent disease progression.

  • Often indicated for mild to moderate disease in high-risk patients.

Examples of Approved or Authorized Antiviral mAbs

SARS-CoV-2 (COVID-19)

  • Sotrovimab: Targets a conserved epitope of the spike protein; retains activity against some variants.

  • Tixagevimab + Cilgavimab (Evusheld): Long-acting combination for pre-exposure prophylaxis.

  • Casirivimab + Imdevimab (REGEN-COV): Dual-targeted spike protein binding; many variants have reduced susceptibility.

  • Bebtelovimab: Potent against multiple Omicron subvariants (authorization status varies).

Respiratory Syncytial Virus (RSV)

  • Palivizumab: Targets RSV F protein; used for prophylaxis in high-risk infants.

  • Nirsevimab: Long-acting mAb with Fc modifications, providing season-long protection for infants.

Ebola Virus

  • Inmazeb (atoltivimab + maftivimab + odesivimab): Three-antibody cocktail against different glycoprotein epitopes.

  • Ebanga (ansuvimab): Targets Ebola glycoprotein; used in treatment of Zaire ebolavirus infection.

Cytomegalovirus (CMV)

  • Investigational mAbs in development for transplant recipients and congenital CMV prevention.

Advantages

  • Immediate onset of protection after administration.

  • High specificity for viral target; minimal off-target effects.

  • Potentially effective in immunocompromised patients.

  • Useful against viruses with limited or no effective vaccines.

Limitations

  • High production costs and limited availability.

  • Parenteral administration required.

  • Risk of viral resistance due to mutations in target epitopes.

  • Shorter duration of protection compared to active immunity from vaccination.

Adverse Effects

Common

  • Injection site reactions (IM) or infusion-related reactions (IV).

  • Fatigue, headache, nausea.

Serious

  • Hypersensitivity reactions, including anaphylaxis (rare).

  • Cytokine release syndrome in some cases.

Contraindications

  • Known hypersensitivity to the active substance or formulation components.

  • Caution in patients with history of severe allergic reactions to other monoclonal antibodies.

Precautions

  • Monitor during and after infusion for hypersensitivity reactions.

  • Consider local variant susceptibility before administration (especially for COVID-19 mAbs).

  • In pregnancy, weigh benefits against limited safety data.

Resistance Considerations

  • Viral mutations, especially in surface glycoproteins, can reduce mAb binding and neutralization.

  • Use of antibody cocktails or bispecific antibodies can reduce resistance risk.

  • Surveillance of circulating viral variants essential for continued efficacy.

Future Directions

  • Development of broadly neutralizing antibodies targeting highly conserved viral epitopes.

  • Engineering Fc modifications to enhance half-life and effector functions.

  • Expanding indications to other viral pathogens such as influenza, HIV, and emerging viruses.

  • Investigating intranasal formulations for mucosal immunity.



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