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Optimization of Anti-SARS-CoV-2 Neutralizing Antibody Therapies: Roadmap to Improve Clinical Effectiveness and
Karlijn van der Straten1,2, Marit J van Gils1, Steven W de Taeye1
1Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Abstract:
One of the major breakthroughs to combat the current Coronavirus Disease 2019 (COVID-19) pandemic has been the development of highly effective vaccines against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Still, alternatives are needed for individuals who are at high risk of developing severe COVID-19 and are not protected by vaccination. Monoclonal antibodies against the spike protein of SARS-CoV-2 have been shown to be effective as prophylaxis and treatment against COVID-19. However, the emergence of variants of concern (VOCs) challenges the efficacy of antibody therapies. This review describes the neutralization resistance of the clinically-approved monoclonal antibody therapies against the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1), Delta (B.1.617.2), and the Omicron (B.1.1.529) variants. To guide the development of monoclonal antibody therapies and to anticipate on the continuous evolution of SARS-CoV-2, we highlight different strategies to broaden the antibody activity by targeting more conserved epitopes and/or simultaneously targeting multiple sites of vulnerability of the virus. This review further describes the contribution of antibody Fc effector functions to optimize the antibody efficacy. In addition, the main route of SARS-CoV-2 antibody administration is currently intravenously and dictates a monthly injection when used as prophylactic. Therefore, we discusses the concept of long-acting antibodies (LAABs) and non-intravenously routes of antibody administration in order to broaden the clinical applicability of antibody therapies.
Insights
Monoclonal antibodies offer an alternative to COVID-19 vaccines, but emerging variants challenge their effectiveness. Strategies to broaden antibody activity and improve administration are crucial for continued therapeutic success against SARS-CoV-2.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- The COVID-19 pandemic spurred vaccine development, yet effective alternatives are needed for high-risk, unvaccinated individuals.
- Monoclonal antibodies targeting SARS-CoV-2 spike protein show promise for COVID-19 prophylaxis and treatment.
- Emerging variants of concern (VOCs) pose a significant challenge to the efficacy of current antibody therapies.
Purpose of the Study:
- To review the neutralization resistance of approved monoclonal antibodies against major SARS-CoV-2 variants (Alpha, Beta, Gamma, Delta, Omicron).
- To highlight strategies for developing broader-acting antibody therapies by targeting conserved epitopes or multiple viral vulnerabilities.
- To discuss the role of antibody Fc effector functions and novel administration routes (long-acting, non-intravenous) for enhanced clinical applicability.
Main Methods:
- Literature review of neutralization resistance data for clinically-approved monoclonal antibodies against SARS-CoV-2 VOCs.
- Analysis of strategies to broaden antibody activity, including targeting conserved epitopes and multiple viral sites.
- Discussion of antibody Fc effector functions and emerging long-acting antibody (LAAB) concepts and non-intravenous administration routes.
Main Results:
- Significant neutralization resistance of some monoclonal antibodies against variants like Omicron has been observed.
- Targeting conserved epitopes and multiple viral vulnerabilities offers a promising strategy to overcome resistance.
- Fc effector functions can enhance antibody efficacy, and LAABs/non-intravenous routes may improve patient compliance and applicability.
Conclusions:
- Continuous evolution of SARS-CoV-2 necessitates the development of broadly neutralizing antibodies.
- Optimizing antibody design through conserved epitope targeting and Fc effector function modulation is key.
- Innovative administration strategies, including long-acting and non-intravenous options, are essential for expanding antibody therapy use.
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