Methods for inhibiting fibrosis in a subject in need thereof
Inventors
Brunskill, Nigel John • Demopulos, Gregory A. • Dudler, Thomas A. • Schwaeble, Hans-Wilhelm
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12005117-B2
Publication Date
2024-06-11
Expiration Date
Abstract
In one aspect, the invention provides methods for treating, inhibiting, alleviating or preventing fibrosis in a mammalian subject suffering, or at risk of developing a disease or disorder caused or exacerbated by fibrosis and/or inflammation. In one embodiment, the invention provides methods of treating a subject suffering from renal fibrosis. In one embodiment, the invention provides methods of reducing proteinuria in a subject suffering from a renal disease or condition associated with proteinuria. The methods comprise the step of administering, to a subject in need thereof, an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation.
Core Innovation
The invention relates to MASP-2 inhibitory antibodies and antigen-binding fragments, including antibody formats that extend to Fab, F(ab')2, scFv, Fv, and diabodies, and to fusion constructs based on the OMS646 scaffold and SGMI-2 peptide inhibitors. MASP-2 inhibitory agents are configured in humanized and chimeric formats and can include Fc effector function reduction.
A key aspect of the invention is inhibiting lectin-pathway complement activation associated with MASP-2, including C3 convertase activity, C4 cleavage, and deposition of C3b and C4b. Functional assays using human serum with mannan-coated beads assess C3b deposition and C4b deposition, and the fusion format shows increased lectin-pathway inhibition compared with a naked scaffold, with reported IC50 improvements, while not substantially inhibiting the classical pathway.
The invention is further supported by preclinical models linking MASP-2 to renal fibrosis and inflammation, including unilateral ureteric obstruction and protein-overload proteinurea models, with reductions in collagen deposition and macrophage infiltration and altered fibrosis and inflammation gene expression. In vivo efficacy with OMS646-SGMI-2 in unilateral ureteric obstruction is described as reducing fibrosis and hydroxyproline, and the document further cites clinical Phase 2 data in steroid-dependent IgA nephropathy and membranous nephropathy with reductions in urine albumin-to-creatinine ratio and 24-hour protein with steroid tapering.
Claims Coverage
The document includes one independent claim covering kidney protection from drug-induced nephropathy by administering a MASP-2 inhibitory antibody or antigen-binding fragment. Dependent claim coverage refines functional complement effects, administration timing, target agent categories, quantitative efficacy thresholds, and sequence-defined antibody variable-region features.
Kidney protection from drug-induced nephropathy using a MASP-2 inhibitory antibody
A method of protecting a kidney from renal injury in a subject that has undergone, is undergoing, or will undergo treatment with one or more nephrotoxic agents by administering a MASP-2 inhibitory antibody or antigen-binding fragment effective to prevent or ameliorate the incidence of drug-induced nephropathy.
C3b deposition inhibition threshold in human serum
The MASP-2 inhibitory antibody inhibits C3b deposition in 90% human serum with an IC50 of 30 nM or less.
Reduction in 24-hour urine protein excretion
Administering the MASP-2 inhibitory antibody or antigen-binding fragment in an effective amount and duration to achieve at least a 20% reduction in 24-hour urine protein excretion versus baseline before treatment.
Administration before the nephrotoxic agent
Administering the MASP-2 inhibitory antibody before the nephrotoxic agent.
Nephrotoxic agent as a radiocontrast dye
The nephrotoxic agent is a radiocontrast dye.
Sequence-defined heavy- and light-chain CDRs
A MASP-2 inhibitory monoclonal antibody or antigen-binding fragment in which the heavy-chain variable region contains CDR-H1, CDR-H2, and CDR-H3 defined by SEQ ID NO:67, and the light-chain variable region contains CDR-L1, CDR-L2, and CDR-L3 defined by SEQ ID NO:69.
Overall claim coverage focuses on preventing or ameliorating drug-induced nephropathy by administering MASP-2 inhibitory antibody or antigen-binding fragments, with further refinements that define potency for inhibiting C3b deposition in human serum, quantify improvement by reductions in 24-hour urine protein, specify pre-treatment timing, specify radiocontrast dye as the nephrotoxic agent, and define antibody variable-region specificity using SEQ ID-defined CDRs.
Stated Advantages
Prevents or ameliorates the incidence of drug-induced nephropathy.
Inhibits C3b deposition in human serum with reported IC50 potency (IC50 of 30 nM or less in 90% human serum).
Achieves at least a 20% reduction in 24-hour urine protein excretion versus baseline before treatment.
Reduces incidence of renal injury associated with exposure to one or more nephrotoxic agents.
Provides lectin-pathway selectivity by blocking MASP-2-dependent complement activation while largely preserving C1q/classical pathway activity.
Documented Applications
Protecting a kidney from renal injury in a subject undergoing treatment with one or more nephrotoxic agents, including radiocontrast dye, to prevent or ameliorate drug-induced nephropathy.
Renal fibrosis and inflammation contexts supported by MASP-2-mediated lectin-pathway contribution in unilateral ureteric obstruction and protein-overload proteinurea models, with reduced collagen deposition and macrophage infiltration reported for MASP-2 modulation and OMS646-SGMI-2 efficacy.
Steroid-dependent IgA nephropathy (Phase 2), with reductions in urine albumin-to-creatinine ratio and 24-hour protein with steroid tapering reported.
Membranous nephropathy (Phase 2), with reductions in urine albumin-to-creatinine ratio and 24-hour protein with steroid tapering reported.
Protecting against drug-induced nephropathy associated with radiocontrast dye nephrotoxic agents.
Protecting renal function and alleviating renal fibrosis and proteinuria in contexts that include renal injury and drug-induced nephropathy.
Treating or preventing fibrosis and proteinuria in clinical contexts described as IgA nephropathy, including steroid-dependent IgA nephropathy, and membranous nephropathy, including steroid-dependent membranous nephropathy.
Ongoing Phase 2 clinical trial results are referenced for IgA nephropathy and membranous nephropathy.
Interested in licensing this patent?