PT  - JOURNAL ARTICLE
AU  - Iwanaga, Naoki
AU  - Cooper, Laura
AU  - Rong, Lijun
AU  - Beddingfield, Brandon
AU  - Crabtree, Jackelyn
AU  - Tripp, Ralph A.
AU  - Qin, Xuebin
AU  - Kolls, Jay K.
TI  - Novel ACE2-IgG1 fusions with improved <em>in vitro</em> and <em>in vivo</em> activity against SARS-CoV2
AID  - 10.1101/2020.06.15.152157
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.15.152157
4099  - http://biorxiv.org/content/early/2020/07/24/2020.06.15.152157.short
4100  - http://biorxiv.org/content/early/2020/07/24/2020.06.15.152157.full
AB  - SARS-CoV2, the etiologic agent of COVID-19, uses ACE2 as a cell entry receptor. Soluble ACE2 has been shown to have neutralizing antiviral activity but has a short half-life and no active transport mechanism from the circulation into the alveolar spaces of the lung. To overcome this, we constructed an ACE2-human IgG1 fusion protein with mutations in the catalytic domain of ACE2. This fusion protein contained a LALA mutation that abrogates Fcrγ binding, but retains FcRN binding to prolong the half-life, as well as achieve therapeutic concentrations in the lung lavage. Interestingly, a mutation in the catalytic domain of ACE2, MDR504, completely abrogated catalytic activity, but significantly increased binding to SARS-CoV2 spike protein in vitro. This feature correlated with more potent viral neutralization in a plaque assay. Parental administration of the protein showed stable serum concentrations with a serum half-life of ∼ 145 hours with excellent bioavailability in the epithelial lining fluid of the lung. Prophylactic administration of MDR504 significantly attenuated SARS-CoV2 infection in a murine model. These data support that the MDR504 hACE2-Fc is an excellent candidate for pre or post-exposure prophylaxis or treatment of COVID-19.Competing Interest StatementTulane University has filed a provisional patent listing Drs. Kolls and Iwanaga as inventors of MDR504