== Representative of bispecific antibodies against SARS-CoV-2. Wildtype Escape variants of parent antibodies Omicron 7-GW01 (PDB:7EPX) 1-REGN10989 (PDB:7M42) Null Wildtype VOCs 4-n3113v (PDB:7VNB) 7-n3130v (PDB:7WHI,7WHJ) Preclinical China Mar 09, 2022 Wildtype Alpha Beta Gamma 2-C121 (PDB:7K8X) 5-C135 (PDB:7K8Z) Null Wildtype VOCs 5-CoV2-06 (PDB:7WPH) 1-CoV2-14 (PDB:7XXL) Preclinical US 27 Dec 2023 Wildtype Escape variants of parent antibodies Alpha Delta 1-B38 (PDB:7BZ5) 2-H4 (no PDB data) Preclinical China 28 Feb 2022 Yellow color indicates the epitope of antibody binding, number before antibody name is the antibody class. In conclusion, the intrinsic genomic instability of RNA viruses makes immune escape an inevitable scientific challenge. review presents analyses and discussions aimed at offering useful insights for shaping future strategies in bispecific antibody design to effectively confront the difficulties posed by SARS-CoV-2 and propel developments in antiviral therapeutic development. Keywords:SARS-CoV-2, Bispecific antibody, Function, Mechanism, Breadth == 1. Background == Despite more than four years having elapsed since the onset of the SARS-CoV-2 outbreak, the prolonged global impact and adversity inflicted by this computer virus endure (Zhu et al., 2020). Intensive efforts in vaccine development have aimed to provide proactive protection to the populations (Dai et al., 2020,2021;Wang et al., 2020b). Concurrently, the need for specific therapies for individuals infected with SARS-CoV-2 or ineligible for vaccination, such as the elderly and immunocompromised, has become paramount. Among these remedies, monoclonal antibodies, renowned for their high specificity and outstanding targeting effects, emerged as one of the most efficacious specific drugs (Barnes et al., 2020;Cao et al., 2020;Hassan et al., 2020;Joyce et al., 2020;Kreer et al., 2020;Petherick, 2020). Thus, the utilization of monoclonal antibodies for SARS-CoV-2 treatment, evolving from early convalescent plasma to the identification and purification of monoclonal antibodies, unequivocally underscores the feasibility and effectiveness of this treatment approach (Joyner et al., 2021;Libster et al., 2021;Wang et al., 2020c;Writing Committee et al., 2021). However, the scenery of SARS-CoV-2 remains in flux. Within a short span, a mutation occurring at position N501Y in para-iodoHoechst 33258 the spike protein emerged (Brown et al., 2021;Davies et al., 2021;Graham et al., 2021;Socher et al., 2021;Volz et al., 2021), setting off subsequent mutations at numerous sites, including the variants of concern (VOCs) and variants of interest (VOIs) as designated by the World Health Business (Aleem et al., 2022;Dejnirattisai et al., 2022;Hoffmann para-iodoHoechst 33258 et al., 2021;Zhou et al., 2021a). This progression culminated in the development of variants with unique serotypes (Tan et al., 2023). Consequently, the efficacy of a para-iodoHoechst 33258 singular therapeutic drug, including monoclonal antibodies, has become notably inconsistent (Baum et al., 2020a;Dejnirattisai et al., 2022;Shah et al., 2021;Starr et al., 2021). While cocktail (mix of more than two antibodies) therapy appears to offer relatively improved effectiveness against variants compared to monoclonal antibody therapy (Baum et al., 2020a;Baum et al., 2020b;Hansen et al., 2020;Wang et al., 2020a;Yao et al., 2020), this approach presents difficulties with higher costs and constraints on production and application due to its complex formulation ratios (Crowe, 2022). At this pivotal stage, bispecific antibodies (bsAbs) (designing more than two monoclonal antibodies into one molecule through biochemical process) emerge as a highly promising strategy in addressing SARS-CoV-2 and its evolving variants. Originating from the pioneering work by Nisonoff and colleagues, bispecific antibodies have developed into over a hundred design formats, widely used by scientists and pharmaceutical entities in combating malignancy and viral infections (Labrijn et al., 2019;Nisonoff et al., 1960). The bispecific antibody design strategies have been extensively applied in treating viruses such as HIV, ZIKA, Ebola, H5N1, CMV, with a particularly abundant number of cases targeting HIV (Bournazos et al., 2016;Frei et al., 2016;Huang et al., 2016;Steinhardt et al., 2018;Wang et al., 2017;Zanin et al., 2015). The success of these bispecific antibodies underscored their superior antiviral activity compared to monoclonal antibodies and heightened capability to prevent of immune escape. Compared to cocktail therapy, bispecific antibodies are designed as single-molecule drugs by integrating two or more monoclonal antibodies, streamlining their production formula and reducing the production cost. Moreover, due to their unique action mechanisms, bispecific antibodies often exhibit markedly superior efficacy compared to cocktails. Consequently, in the context of preventing and treating SARS-CoV-2, bispecific antibodies emerge as an evidently superior option over monoclonal antibodies or cocktails (De Gasparo et al., 2021;Hanke et al., 2022;Ku et al., 2022). In this review, we categorize and summarize bispecific antibodies targeting SARS-CoV-2, Rabbit Polyclonal to Stefin B outlining their design formats, mechanisms of action, and associated advantages and limitations, and aiming to provide insights that steers the development of novel approaches in the future design of bispecific antibodies. == 2. para-iodoHoechst 33258 Characteristics of representative bispecific antibodies targeting SARS-CoV-2 == Bispecific antibodies fuse two or more antibody drug molecules into one through biochemical processes, holding the potential to harness the combined therapeutic benefits of two antibodies concurrently. In the context of combatting SARS-CoV-2, the primary emphasis is usually on specific.