Methods of inhibiting MASP-2 for the treatment and/or prevention of coronavirus-induced acute respiratory distress syndrome
Inventors
Demopulos, Gregory A. • Quinton, Tineka J.
Assignees
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Publication Number
US-12351648-B2
Publication Date
2025-07-08
Expiration Date
Abstract
In one aspect, the invention provides methods for treating, inhibiting, alleviating, or preventing acute respiratory distress syndrome, pneumonia, or some other pulmonary or other manifestation of coronavirus infection, such as thrombosis, in a mammalian subject infected with coronavirus, such as SARS-CoV-2. The methods comprise the step of administering to a subject infected with coronavirus an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation. In one embodiment, the MASP-2 inhibitory agent is a MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ ID NO:6. In one embodiment, the MASP-2 inhibitory agent is a small molecule MASP-2 inhibitory compound. In one embodiment, the subject is a human subject suffering from COVID-19-induced acute respiratory distress syndrome (ARDS) and requires supplemental oxygen prior to treatment and the MASP-2 inhibitory agent is administered in an amount sufficient to discontinue the need for supplemental oxygen.
Core Innovation
The invention concerns improving respiratory function in a human subject suffering from COVID-19 induced acute respiratory distress syndrome (ARDS) requiring mechanical ventilation by administering a MASP-2 inhibitory monoclonal antibody or antigen-binding fragment thereof. The monoclonal antibody or antigen-binding fragment comprises a heavy chain variable region including CDR-H1, CDR-H2 and CDR-H3 of SEQ ID NO:67 and a light chain variable region including CDR-L1, CDR-L2 and CDR-L3 of SEQ ID NO:69. The administration is provided in an amount and for a time period sufficient to discontinue the need for mechanical ventilation.
The invention targets MASP-2 inhibition to address lectin-pathway complement activation and downstream complement deposition, with selective inhibition of lectin pathway complement activation while not substantially inhibiting C1q-dependent complement activation. The disclosure also describes quantitative evaluation of complement inhibition, including inhibition of C3b deposition in 10% human serum with an IC50 of 30 nM or less.
The disclosure further includes MASP-2 inhibitory compounds and related structures, including exemplary small-molecule compounds and structural depictions of small-molecule forms with indicated salts, counterions, and structural features. The compounds are presented as discrete molecular entities.
Claims Coverage
The consolidated claim coverage centers on methods for improving respiratory function in COVID-19 induced ARDS with mechanical ventilation, using a MASP-2 inhibitory monoclonal antibody or antigen-binding fragment defined by specific heavy- and light-chain CDR sequence sets, administered for a time sufficient to discontinue mechanical ventilation. Dependent claims further add selective lectin-pathway inhibition relative to C1q-dependent activation, quantitative potency criteria for C3b deposition inhibition, and selected antibody format categories.
Improving respiratory function in COVID-19 induced ARDS requiring mechanical ventilation by administering a MASP-2 inhibitory monoclonal antibody defined by SEQ ID NO:67 and SEQ ID NO:69
A method for improving respiratory function in a human subject suffering from COVID-19 induced acute respiratory distress syndrome (ARDS) wherein the subject requires mechanical ventilation, comprising administering an amount of a MASP-2 inhibitory monoclonal antibody or antigen-binding fragment thereof and for a time period sufficient to discontinue the need for mechanical ventilation, wherein the MASP-2 inhibitory monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising CDR-H1, CDR-H2 and CDR-H3 of SEQ ID NO:67 and a light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 of SEQ ID NO:69.
Selective inhibition of lectin pathway complement activation without substantial C1q-dependent activation
A MASP-2 inhibitory antibody selectively inhibits lectin pathway complement activation while not substantially inhibiting C1q-dependent complement activation.
Quantitative inhibition of C3b deposition in 10% human serum
A MASP-2 inhibitory antibody inhibits C3b deposition in 10% human serum with an IC50 of 30 nM or less.
Selected antibody format categories
The antibody or fragment is selected from recombinant, reduced-effector-function, chimeric, humanized, or human antibodies.
Overall, the claim coverage is anchored by a COVID-19 induced ARDS treatment method requiring mechanical ventilation, using a MASP-2 inhibitory monoclonal antibody or antigen-binding fragment with specified SEQ ID NO:67 and SEQ ID NO:69 CDR sequences and administered for a time sufficient to discontinue mechanical ventilation. Dependent claims further narrow the approach by adding lectin-pathway selectivity over C1q-dependent activation, an IC50 potency threshold for C3b deposition in 10% human serum, and selected antibody format categories.
Stated Advantages
Improving respiratory function in a human subject suffering from COVID-19 induced acute respiratory distress syndrome (ARDS) requiring mechanical ventilation.
Discontinue the need for mechanical ventilation.
Stops supplemental oxygen use.
Selective inhibition of lectin pathway complement activation while not substantially inhibiting C1q-dependent complement activation.
Inhibits C3b deposition in 10% human serum with an IC50 of 30 nM or less.
Reduces circulating endothelial cells and inflammatory biomarkers, with reported clinical improvements/discharge in compassionate-use experience.
Documented Applications
Treating COVID-19 induced acute respiratory distress syndrome (ARDS) requiring mechanical ventilation to improve respiratory function and discontinue mechanical ventilation, optionally including discontinuing supplemental oxygen.
Phase 2 clinical results in steroid-dependent IgA nephropathy with reduced uACR and 24-hour urine protein.
Phase 2 clinical results in membranous nephropathy with reduced uACR and 24-hour urine protein.
Renal fibrosis/injury mouse models including unilateral ureteric obstruction (UUO), protein-overload proteinuria model, and Adriamycin-induced nephropathy, reported as showing reduced collagen, macrophage infiltration, inflammation markers, and apoptosis.
Compassionate-use experience in severe COVID-19/ARDS patients, reporting decreases in circulating endothelial cells and inflammatory biomarkers and reported clinical improvements/discharge.
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