The insights from SARS-CoV-2 antibodytreatment for future emerging infectious diseases

Antibodies have pivotal roles in the immune response to infection. Laboratory-created SARS-CoV-2 antibody treatment is an emerging approach to treat COVID-19. Early treatment with these antibodies can reduce COVID-19-related hospitalisation or death in patients at high risk.1Weinreich DM Sivapalasingam S Norton T et al.REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19.N Engl J Med. 2021; 384: 238-251Crossref PubMed Scopus (1120) Google Scholar, 2Gupta A Gonzalez-Rojas Y Juarez E et al.Early treatment for COVID-19 with SARS-CoV-2 neutralizing antibody sotrovimab.N Engl J Med. 2021; 385: 1941-1950Crossref PubMed Scopus (616) Google Scholar, 3Dougan M Nirula A Azizad M et al.Bamlanivimab plus etesevimab in mild or moderate COVID-19.N Engl J Med. 2021; 385: 1382-1392Crossref PubMed Scopus (426) Google Scholar These antibodies can also provide targeted prophylaxis for individuals at high risk, and interrupt transmission of viruses in populations.4Marston HD Paules CI Fauci AS Monoclonal antibodies for emerging infectious diseases—borrowing from history.N Engl J Med. 2018; 378: 1469-1472Crossref PubMed Scopus (99) Google Scholar A major concern of SARS-CoV-2 antibodies is the limited commercial value compared with current small-molecule drugs, such as nirmatrelvir plus ritonavir (Paxlovid) and molnupiravir. Small-molecule drugs (typically 0·1–0·6 kilodalton) can penetrate the cell membrane and bind intracellular targets; they are generally more stable than biological drugs and can be administered orally. Therefore, the target population that would benefit from SARS-CoV-2 antibodies rather than small-molecule drugs needs to be identified. Currently, SARS-CoV-2 antibody treatment might be effective in immunocompromised patients with COVID-19.5Denkinger CM Janssen M Schäkel U et al.Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial.Nat Cancer. 2023; 4: 96-107PubMed Google Scholar However, large phase 3 trials are difficult to conduct to establish the efficacy of SARS-CoV-2 antibody treatment in the highest-risk patients, who have negligible ability to produce endogenous antibodies. Examples of such patients include those with haematological malignancies treated with anti-CD20 monoclonal antibodies (mAbs) or chimeric antigen receptor T-cell immunotherapy. For these patients, systemic administration would be more helpful than inhalation due to their almost non-existent humoral immunity. Another promising use of SARS-CoV-2 antibodies is in prophylactic treatment for patients at high risk. The necessary condition is that the antibodies require an extended half-life to be effective.6Abraham J Monoclonal antibodies with extended half-life to prevent Covid-19.N Engl J Med. 2022; 386: 2236-2238Crossref PubMed Scopus (2) Google Scholar It is reasonable to position the objective of the phase 1/3 trial of AZD3152 (NCT05648110), a combination of two mAbs (AZD1061 and AZD3152), as evaluating its safety and neutralising activity for pre-exposure prophylaxis of COVID-19. However, theoretically, inhaling the antibodies might not provide long-lasting exposure in the lungs. Therefore, the use of the inhalation route for antibodies needs to be explored for its potential value and scenarios for SARS-CoV-2 infection, because it might also be helpful for other infectious diseases. The evasion of mAb-induced protection to all SARS-CoV-2 antibodies is the biggest threat because of the evolution of the spike protein of new SARS-CoV-2 variants.7Cox M Peacock TP Harvey WT et al.SARS-CoV-2 variant evasion of monoclonal antibodies based on in vitro studies.Nat Rev Microbiol. 2023; 21: 112-124Crossref PubMed Scopus (61) Google Scholar At the time of writing, the omicron variant (BA.5) has evaded almost all available mAb-based drugs.8Wang Q Iketani S Li Z et al.Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants.Cell. 2023; 186: 279-286Summary Full Text Full Text PDF PubMed Scopus (226) Google Scholar Efforts are still being coordinated to quickly identify and develop better antibodies.9Chen Y Zhao X Zhou H Zhu H Jiang S Wang P Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses.Nat Rev Immunol. 2023; 23: 189-199Crossref PubMed Scopus (47) Google Scholar Maranda and colleagues10Maranda B Labbé SM Lurquin M et al.Safety and efficacy of inhaled IBIO123 for mild-to-moderate COVID-19: a randomised, double-blind, dose-ascending, placebo-controlled, phase 1/2 trial.Lancet Infect Dis. 2023; (published online Aug 21.)https://doi.org/10.1016/S1473-3099(23)00393-6Google Scholar did a phase 1/2 trial to test the safety and explore the efficacy of IBIO123. This treatment consists of a fully human, recombinant, monoclonal IgG in a mixture of two antibodies binding to the S1 subunit and one antibody binding to the S2 subunit of the receptor-binding domain. IBIO123 showed neutralisation potency against SARS-CoV-2 from the original strain isolated in Wuhan, China, up to XBB1.5. The authors raised a hypothesis that direct delivery of neutralising antibodies via inhalation might provide additional respiratory clinical benefits. Thus, in this phase 1/2 trial, IBIO123 and a placebo were administered via oral inhalation to outpatients with COVID-19. The main findings of the study indicate that oral inhalation of IBIO123 did not result in more adverse events or serious adverse events than the placebo. The results also showed that the proportion of participants with respiratory symptom resolution on day 8 was 33 (41%) of 81 in the IBIO123 group, compared with five (17%) of 29 in the placebo group (p=0·024) in the overall population. However, no significant reduction in viral load was observed on day 5. The study showed the safety of inhaling antibodies. However, several key questions remain unanswered, including whether inhalation of antibodies is more beneficial than systemic administration, how inhalation of antibodies neutralises SARS-CoV-2 in other organs, how antibody exposure should be evaluated in the lungs and plasma, and how the optimal dosage of antibody could be identified in phase 1 trials. The extended development time required for new small-molecule drugs makes it challenging for them to address emerging infectious diseases quickly. Although SARS-CoV-2 antibodies face the aforementioned challenges, the rapid development of mAbs is poised to contribute more substantially in the future. The insights gained from antibodies for SARS-CoV-2 will probably be applicable to the creation of antibodies for other infectious diseases too. We declare no competing interests. Safety and efficacy of inhaled IBIO123 for mild-to-moderate COVID-19: a randomised, double-blind, dose-ascending, placebo-controlled, phase 1/2 trialInhalation of IBIO123 was safe. Despite the lack of significant reduction of viral load at day 5, treatment with IBIO123 resulted in a higher proportion of participants with complete resolution of respiratory symptoms at day 6. This study supports further clinical research on inhaled monoclonal antibodies in COVID-19 and respiratory diseases in general. Full-Text PDF