A recent study published in Cell Host & Microbe by Dr. Michael Diamond’s group at Washington University School of Medicine investigated ultrapotent miniproteins (LCB1) as a novel means of targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These specific miniproteins target the Receptor Binding Domain (RBD) on the spike protein of SARS-CoV-2. In this study, the potential prophylactic and post-infection therapeutic effects of two LCB1 miniproteins were studied; with (LCB1-fc) and without (LCB1v1.3) an Fc domain. LCB1-fc contains a longer half-life and ability to engage the effector arms of the immune system.
K18 human hACE2-expressing transgenic mice were exposed to LCB1 miniproteins via intranasal dosing. Following intranasal administration, lung mechanics, weight change, viral burden, survival cytokine and inflammatory factors were measured to quantify therapeutic effects of LCB1 against SARS-CoV-2 infection.
Results revealed that 4 to 7 days post-infection (dpi) after administering the LCB1-Fc, there was no detection of the virus in the lungs compared to the control proteins mice. When exposed to LCB1v1.3, an impressive 400-fold reduction was seen in viral RNA compared to control binder-treated mice at any day post-inoculation. Similar results were seen in LCB1-Fc and LCB1v1.3 at the heart, lung, spleen and brain when measuring viral RNA levels which were at or near the limit of detection in the assays at days 4 and 7 dpi.
Lung function results using the flexiVent system demonstrated a compromised lung function in SARS-CoV-2 infected mice without LCB1 treatment, such that a significant decrease in lung capacity and compliance as well as an increase in pulmonary resistance, elastance and tissue damping was seen. On the other hand, prophylactic LCB1-Fc treatment prevented this lung function decline in SARS-CoV-2 infected mice.
Additionally, to evaluate the efficacy of LCB1-Fc and LCB1v1.3, K18-hACE2 mice received a lethal dose of SARS-CoV-2, followed by administration of either the control binder protein or LCB1-Fc 2- or 3-dpi. Mice who received control binder proteins perished after 11-dpi, whereas mice treated with LCB1v1.3 or LCB1-Fc mice survived.
In conclusion, this important pre-clinical study established significant therapeutic potential for these LCB1 miniproteins to prevent or attenuate SARS-CoV-2 infection.
Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice. (2021). bioRxiv, doi: 10.1016/j.chom.2021.06.008