Method of treating acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) associate with COVID-19 by administering an anti-LIGHT antibody
Inventors
Neil, Garry A. • Zafir-Lavie, Inbal
Assignees
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Publication Number
US-11708406-B2
Publication Date
2023-07-25
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
LIGHT (TNFSF14) is presented as a key mediator of free/active inflammatory signaling, and the disclosure motivates measuring free LIGHT in patient samples to support diagnosis and monitoring related to LIGHT biology. It defines free, bound, and total LIGHT and discusses LIGHT signaling components including DcR3, HVEM, and LTβR in the context of LIGHT activity.
The disclosure provides a free-LIGHT immunoassay using an antibody-based capture/detection format, including a Simoa sandwich format, to determine serum free LIGHT. It links assay measurement of free LIGHT to clinical interpretation for LIGHT-driven inflammatory conditions and reports assay validation elements and performance controls, including DcR3 interference and spike-recovery and linearity elements.
The disclosure describes anti-LIGHT antibody therapy and presents therapeutic antibodies with specified heavy and light chain variable regions comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 sequence sets. It also reports serum free LIGHT elevated in COVID-19 compared with controls, elevated free LIGHT in Crohn’s disease-associated inflammation compared with controls, and a rapid reduction in free LIGHT after single anti-LIGHT dosing.
The disclosure includes clinical evaluation of anti-LIGHT in COVID-19 pneumonia/ALI/ARDS, including a placebo-controlled phase 2 trial, and also describes a Phase 1b, multi-center, open-label dose-escalation signal-finding clinical study in adults with moderate-to-severe active Crohn’s disease who failed prior anti-TNFα therapy. The document frames the clinical rationale around modulation of free LIGHT and the inflammatory signaling role of LIGHT in acute lung injury.
Claims Coverage
The available claim coverage centers on defined anti-LIGHT antibodies with specified CDR sequence sets for treating COVID-19-associated ARDS or ALI. The partial content also supports treatment context for anti-LIGHT use and biomarker-linked effects.
Anti-LIGHT antibody with defined CDR sequences for COVID-19-associated ARDS or ALI treatment
Administering to a human subject an effective amount of an anti-LIGHT antibody comprising a heavy chain and a light chain variable region, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 have the sequences of SEQ ID NOs 2, 3, 4, 5, 6, and 7, for treating acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) associated with COVID-19.
The claim set centers on an anti-LIGHT antibody defined by specific heavy- and light-chain CDR sequence assignments for use in treating COVID-19-associated ARDS or ALI, with biomarker and clinical outcome context supporting the disclosure.
Stated Advantages
Reduced risk of respiratory failure.
Lowering of serum free-LIGHT levels.
Reduced mortality risk by at least 50% at 28 days and/or 60 days.
A clinical improvement measure defined as being alive and free of respiratory failure at day 28.
Subcutaneous anti-LIGHT decreased plasma free LIGHT into the normal range at days 28 and 56.
Corresponding clinical improvement was indicated by SES-CD score reduction.
Documented Applications
Diagnosis/monitoring support for LIGHT-associated inflammatory conditions using a free-LIGHT immunoassay (serum free LIGHT measurement).
Treatment of COVID-19-associated acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) with anti-LIGHT antibody therapy, evaluated in a placebo-controlled phase 2 trial.
Monitoring/biomarker observation in COVID-19, including elevated serum free LIGHT compared with controls and rapid free-LIGHT reduction after single anti-LIGHT dosing.
Evaluation of LIGHT-related inflammation in Crohn’s disease, reporting elevated free LIGHT compared with controls.
Phase 1b, multi-center, open-label dose-escalation signal-finding study of anti-LIGHT monoclonal antibody in adults with moderate-to-severe active Crohn’s disease who failed prior anti-TNFα therapy.
ARDS testing context measuring LIGHT levels in ARDS patients versus healthy donors, together with a free LIGHT assay reference.
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