ApoM-Fc fusion proteins for treating lung diseases
Inventors
Hla, Timothy T. • Swendeman, Steven L. • Puder, Mark • Smith, Lois
Assignees
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Publication Number
US-12415847-B2
Publication Date
2025-09-16
Expiration Date
Abstract
Provided herein are methods of treating lung disease using fusion proteins comprising ApoM (e.g., human or murine ApoM) fused to a constant region (Fc) of a immunoglobulin G (IgG, e.g., human IgG or murine IgG).
Core Innovation
The invention concerns ApoM–Fc fusion proteins, including an apolipoprotein M (ApoM) fused to a constant region (Fc) of an immunoglobulin G (IgG), for use in decreasing the severity of one or more symptoms associated with bronchopulmonary dysplasia (BPD) or congenital diaphragmatic hernia (CDH). ApoM is provided with defined amino acid sequences using SEQ ID options, and the Fc sequence is specified with stated sequence identity ranges to defined Fc SEQ IDs.
The invention addresses treating lung diseases by administering a therapeutically effective amount of the ApoM–Fc fusion protein to a subject in need thereof. Administration includes defined subject stages, including in utero, shortly after birth, or adulthood, and includes multiple delivery routes. The approach is described as decreasing BPD/CDH symptom severity and as supporting lung-related outcomes including restoration of lung architecture.
The invention provides a mechanistic rationale involving ApoM and sphingosine-1-phosphate (S1P), including activation of S1P receptor signaling. The described signaling includes S1P receptor activation and coupling to downstream pathways associated with S1P receptors, and the document includes functional and biological assays to assess S1P loading and receptor activation, endothelial barrier protection using TEER, and receptor competition or blocking.
The invention also describes documented biological effects in disease models, including reduced BPD severity in a hyperoxia mouse model with increased intact alveoli, and improved lung function and proliferation-related readouts in a partial pneumonectomy model for CDH consistent with enhanced lung regeneration.
Claims Coverage
The independent claims cover methods that administer a therapeutically effective amount of a specifically defined ApoM–Fc fusion protein to decrease severity of symptoms associated with BPD or CDH, with inventive features centered on defined ApoM/Fc sequences and targeted therapeutic outcomes. Independent inventive features are specified for three independent claims addressing BPD broadly, BPD in a human subject context, and CDH in a human subject context.
Administering ApoM–Fc fusion protein for BPD or CDH symptom severity
A method of decreasing the severity of one or more symptoms associated with bronchopulmonary dysplasia (BPD) or congenital diaphragmatic hernia (CDH) by administering to a subject in need thereof a therapeutically effective amount of a fusion protein comprising an apolipoprotein M (ApoM) fused to a constant region (Fc) of an immunoglobulin G (IgG), wherein the ApoM comprises the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6, and wherein the Fc comprises an amino acid sequence that is 96% identical to SEQ NO 7 or SEQ NO 8.
Administering defined ApoM–Fc fusion protein to a human for BPD severity
A method of decreasing the severity of one or more symptoms associated with Bronchopulmonary Dysplasia (BPD) by administering to a human subject in need thereof a therapeutically effective amount of a fusion protein comprising an apolipoprotein M (ApoM) fused to a constant region (Fc) of an immunoglobulin G (IgG), wherein the ApoM comprises the amino acid sequence of SEQ ID NO: 5, and wherein the Fc comprises the amino acid sequence of SEQ ID NO 7.
Administering defined ApoM–Fc fusion protein to a human for CDH severity
A method of decreasing the severity of one or more symptoms associated with Congenital Diaphragmatic Hernia (CDH) by administering to a human subject in need thereof a therapeutically effective amount of a fusion protein comprising an apolipoprotein M (ApoM) fused to a constant region (Fc) of an immunoglobulin G (IgG), wherein the ApoM comprises the amino acid sequence of SEQ ID NO: 5, and wherein the Fc comprises the amino acid sequence of SEQ ID NO 7.
Across the independent claims, the methods are distinguished by specifying therapeutically effective administration of ApoM–Fc fusion proteins with defined ApoM SEQ ID and Fc SEQ ID, including an Fc identity range for one claim. The claimed therapeutic purpose is decreasing severity of symptoms associated with BPD or CDH, with additional claim coverage refining subject context, administration timing, administration routes, and lung-related functional outcomes.
Stated Advantages
Decreases the severity of one or more symptoms associated with bronchopulmonary dysplasia (BPD) or congenital diaphragmatic hernia (CDH).
Restores lung architecture.
Increases lung regeneration and growth and/or restores lung development.
Provides enhanced lung regeneration consistent with improved lung function and proliferation-related readouts in a partial pneumonectomy model for CDH.
Reduces BPD severity in a hyperoxia mouse model with increased intact alveoli.
Documented Applications
Decreasing severity of one or more symptoms associated with bronchopulmonary dysplasia (BPD) by administering an ApoM–Fc fusion protein.
Decreasing severity of one or more symptoms associated with congenital diaphragmatic hernia (CDH) by administering an ApoM–Fc fusion protein.
Use in disease-model contexts including a hyperoxia mouse model for BPD and a partial pneumonectomy model for CDH, with reported lung architecture/regeneration-related outcomes.
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