Methods of treating pneumonia or respiratory failure associated with COVID-19 by administering an anti-LIGHT antibody
Inventors
Neil, Garry A. • Zafir-Lavie, Inbal
Assignees
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Publication Number
US-12331107-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The present disclosure relates to methods of detecting free (active) LIGHT in biological samples to diagnose conditions associated with elevated free LIGHT, as well as to predict the effectiveness of anti-LIGHT therapies. The disclosure also relates to treating such conditions with anti-LIGHT antibodies. Conditions include acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), optionally wherein the ALI and ARDS are associated with viral infection, including coronavirus infection. Conditions also include Crohn's Disease or an inflammatory condition associated with Crohn's Disease.
Core Innovation
The disclosure is directed to diagnosing and treating diseases associated with elevated free (active) LIGHT (TNFSF14). It links elevated free LIGHT to cytokine storm, T-cell activation, pulmonary fibrosis, and disease course, and uses free LIGHT as a disease-associated biomarker and companion diagnostic. The disclosure also addresses detection concepts intended to measure free LIGHT rather than receptor-bound or total LIGHT, including capture-based detection approaches using anti-LIGHT antibody.
For therapy, the disclosure provides treatment of pneumonia associated with COVID-19 and respiratory failure associated with COVID-19 pneumonia by administering an anti-LIGHT antibody to a human subject in need thereof. The anti-LIGHT antibody comprises a heavy chain and a light chain variable region with CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences corresponding to SEQ ID NOs 2 to 7. The disclosure further describes evaluation in a randomized placebo-controlled Phase 2 trial in COVID-19 pneumonia/ALI/ARDS/respiratory failure, with clinical endpoints including survival and freedom from respiratory failure.
The disclosure also covers treatment of Crohn’s disease and inflammatory conditions associated with Crohn’s disease through targeting free LIGHT. It reports example study design elements where free LIGHT levels are elevated in COVID-19 and Crohn’s disease cohorts and where anti-LIGHT therapy rapidly reduces serum free LIGHT. The disclosure further describes assay implementation concepts, including sandwich immunoassay and single molecule array-style detection (Simoa), with capture antibodies and detection antibodies for free-light measurement.
Claims Coverage
The partial content includes two independent claims, both centered on administering an anti-LIGHT antibody with specific CDR-defined heavy-chain and light-chain variable regions to treat COVID-19-associated lung disease and respiratory failure. Across the independent claims, the inventive features are the use of the anti-LIGHT antibody with defined CDR sequences and the disease context of COVID-19 pneumonia/respiratory failure; additional inventive features are provided in one independent-claim family by refinements on clinical constraints and quantified outcomes.
CDR-defined anti-LIGHT antibody composition
An anti-LIGHT antibody comprising a heavy chain and a light chain variable region comprising a CDR-H1 having the sequence of SEQ ID NO: 2, CDR-H2 having the sequence of SEQ ID NO: 3, CDR-H3 having the sequence of SEQ ID NO: 4, CDR-L1 having the sequence of SEQ ID NO: 5, CDR-L2 having the sequence of SEQ ID NO: 6, and CDR-L3 having the sequence of SEQ ID NO: 7.
Treating COVID-19-associated pneumonia with the anti-LIGHT antibody
A method of treating pneumonia associated with COVID-19 comprising administering to a human subject in need thereof an effective amount of an anti-LIGHT antibody having the CDR-defined heavy chain and light chain variable region sequences (SEQ ID NOs 2 to 7).
Treating respiratory failure associated with COVID-19 pneumonia with the anti-LIGHT antibody
A method of treating respiratory failure associated with COVID-19 pneumonia comprising administering to a human subject in need thereof an effective amount of an anti-LIGHT antibody having the CDR-defined heavy chain and light chain variable region sequences (SEQ ID NOs 2 to 7).
Reducing serum free LIGHT and related clinical risk in COVID-19 pneumonia
The method further provides that administering the anti-LIGHT antibody reduces serum free LIGHT levels, reduces risk of mortality by equal to or greater than 50% at 28 days and/or 60 days after administration, and reduces risk of respiratory failure (as stated in the dependent claim refinements associated with the COVID-19 pneumonia treatment).
Patient-treatment context constraints for the COVID-19 pneumonia method
The COVID-19 pneumonia treatment method further includes administering as a single dose of about 16 mg/kg and administering to a subject who has received or is currently receiving anti-COVID-19 therapy comprising corticosteroid and/or remdesivir, and the subject is 60 years of age or older (as stated in dependent claim refinements).
The claim coverage provided here protects two COVID-19 lung-disease treatment approaches that both require administering an effective amount of an anti-LIGHT antibody with CDR-H1/CDR-H2/CDR-H3 and CDR-L1/CDR-L2/CDR-L3 sequences defined by SEQ ID NOs 2 to 7. The COVID-19 pneumonia family additionally refines treatment by specifying biomarker-level reduction of serum free LIGHT and quantitative clinical risk reduction at defined timepoints, together with contextual constraints including single-dose amount, concomitant corticosteroid and/or remdesivir therapy, and subject age threshold.
Stated Advantages
Rapid reduction of serum free LIGHT after anti-LIGHT therapy is described.
Reduced risk of mortality by equal to or greater than 50% at 28 days and/or 60 days after administration (as stated in the dependent claim refinements).
Reduced risk of respiratory failure is described (as stated in the dependent claim refinements).
Shows reduced plasma free LIGHT and correlation with clinical improvement, supporting LIGHT as a therapeutic target and companion diagnostic.
Provides an antibody competition/recovery check on Quanterix HD-1 demonstrating unspecific binding within an acceptance range.
Documented Applications
Treating pneumonia associated with COVID-19 in a human subject, including evaluation in a randomized placebo-controlled Phase 2 trial with endpoints including survival and freedom from respiratory failure.
Treating respiratory failure associated with COVID-19 pneumonia in a human subject.
Treating Crohn’s disease and inflammatory conditions associated with Crohn’s disease by targeting elevated free (active) LIGHT.
Treating Crohn’s disease in adults with moderate-to-severe active disease after anti-TNFα failure using an anti-LIGHT monoclonal antibody in a Phase 1b open-label dose-escalation study.
Using free LIGHT as a companion diagnostic by measuring plasma free LIGHT levels that correlate with disease course and clinical improvement in Crohn’s disease.
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