First-in-class trispecific VHH-Fc based antibody with potent prophylactic and therapeutic efficacy against SARS-CoV-2 and variants

• Published in: Scientific reports 2022-03, Vol.12 (1), p.4163-4163, Article 4163
• Main Authors: Titong, Allison, Gallolu Kankanamalage, Sachith, Dong, Jianbo, Huang, Betty, Spadoni, Nicholas, Wang, Bo, Wright, Meredith, Pham, Keegan L. J., Le, Anh Hai, Liu, Yue
• Format: Article
• Language: English
• Subjects: 631/154/51/1568; 631/326/596/4130; 631/61/51/1568; 692/308/153; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Antigen-Antibody Reactions - drug effects; Biomarkers - metabolism; Coronaviruses; COVID-19; COVID-19 - drug therapy; COVID-19 - virology; Disease prevention; Drug Stability; Epitopes; Humanities and Social Sciences; Humans; Immunocompromised Host; Mice; Mice, Transgenic; multidisciplinary; Pandemics; Prophylaxis; Safety; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - physiology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Single-Domain Antibodies - immunology; Single-Domain Antibodies - pharmacology; Single-Domain Antibodies - therapeutic use; Spike Glycoprotein, Coronavirus - immunology; Thermal stability; Viral Load
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-07952-4

SARS-CoV-2 and its variants have persisted in this ongoing COVID-19 pandemic. While the vaccines have greatly reduced the COVID-19 cases, hospitalizations, and death, about half of the world remain unvaccinated due to various reasons. Furthermore, the duration of the immunity gained from COVID-19 vaccination is still unclear. Therefore, there is a need for innovative prophylactic and treatment measures. In response to this need, we previously reported on the successful computer-aided development of potent VHH-based multispecific antibodies that were characterized in vitro. Here, we evaluated in vivo efficacy and safety of the lead trispecific VHH-Fc, ABS-VIR-001. Importantly, our data showed that ABS-VIR-001 treatment prevented SARS-CoV-2 infection and death when provided as an intranasal prophylaxis in a humanized ACE-2 mouse model. In addition, ABS-VIR-001 post-exposure treatment was shown to greatly reduce viral loads by as much as 50-fold. A detailed panel of metabolic and cellular parameters demonstrated that ABS-VIR-001 treatment was overall comparable to the PBS treatment, indicating a favorable safety profile. Notably, our inhibition studies show that ABS-VIR-001 continued to demonstrate unwavering efficacy against SARS-CoV-2 mutants, associated with key variants including Delta and Omicron, owing to its multiple epitope design. Lastly, we rigorously tested and confirmed the excellent thermostability of ABS-VIR-001 when heated to 45 °C for up to 4 weeks. Taken together, our study suggests that ABS-VIR-001 is an efficacious and durable prophylaxis and post-exposure treatment for COVID-19 with promising safety and manufacturability features for global distribution.