Anti-SARS-CoV-2 and anti-cytokine storm neutralizing antibody therapies against COVID-19: Update, challenges, and perspectives

Abstract

Coronavirus disease 2019 (COVID-19) has been declared by the World Health Organization (WHO) as a pandemic since March 2020. This disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The only available tools to avoid contamination and transmission of this virus are physical distancing, the use of N95 and surgical masks, and hand hygiene. Vaccines are another essential tool to reduce the impact of the pandemic, though these present challenges in terms of production and logistics, particularly in underdeveloped and developing countries. One of the critical early research findings is the interaction of the spike virus protein with the angiotensin-converting enzyme 2 (ACE2) human receptor. Developing strategies to block this interaction has therefore been identified as a way to treat this infection. Neutralizing antibodies (nAbs) have emerged as a therapeutic approach since the pandemic started. Infected patients may be asymptomatic or present with mild symptoms, and others may evolve to moderate or severe disease, leading to death. An immunological phenomenon known as cytokine storm has been observed in patients with severe disease characterized by a proinflammatory cytokine cascade response that leads to lung injury. Thus, some treatment strategies focus on anti-cytokine storm nAbs. This review summarizes the latest advances in research and clinical trials, challenges, and perspectives on antibody-based treatments (ABT) as therapies against COVID-19.

Keywords: Antibody-based treatments; COVID-19; Cytokine storm; Neutralizing; Passive immunotherapy; SARS-CoV-2; Spike.

Graphical abstract

Fig. 1

General SARS-CoV-2 proteins and genomic RNA from an infected human. After coughing in the air, the virus droplets can infect another person. The figure shows the general ultrastructural protein and genomic RNA of SARS-CoV-2, including the nucleocapsid (N), envelope (E), membrane (M), spike (S), and genomic + RNA, respectively. The figure was generated using BioRender software.

Fig. 2

SARS-CoV-2 spike (S) glycoprotein interaction with ACE2 host receptor and antibodies against S protein can prevent virus entry. A) Spike has two conformational states: “up” and “down.” RDB only interacts and binds to ACE2 when spike is in the “up” conformation. B) Types of antibody-mediated blockage of virus entry: 1) nAbs bind to RBM, avoiding interaction with ACE2 and resulting in no entry and no infection; 2) nAbs bind to other spike domains, such as the N-terminal domain (NTD) and S2, with multiple mechanisms of action or with mechanisms of action that remain unknown; 3) nAbs bind to RBD (not RBM) and do not compete with ACE2 binding, with multiple mechanisms of action or with mechanisms of action that remain unknown; 4) nAbs bind to RBD (not RBM) and compete with ACE2 binding, resulting in no entry and no infection; and 5) nAbs bind to two or more regions (cocktails and polyclonal antibodies), resulting in no entry and no infection. The figure was generated using BioRender software.

Fig. 3

SARS-CoV-2 alveolar pneumonia induced by Cytokine Storm and antibody-based treatments against crucial cytokines. A) SARS-CoV-2 alveolar pneumonia induced by cytokine storm proinflammatory response caused by macrophages and other innate immune cells. The key cytokines are TNF-α IL-1β and IL-6. B) Antibody-based treatments against the key cytokines: TNF-α (adalimumab and infliximab), IL-1β (canakinumab), and IL-6 receptor (tocilizumab and sarilumab). The figure was generated using BioRender software.