Methods for treating conditions associated with MASP-2 dependent complement activation
Inventors
Demopulos, Gregory A. • Dudler, Thomas A. • Schwaeble, Hans-Wilhelm
Assignees
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Publication Number
US-11981749-B2
Publication Date
2024-05-14
Expiration Date
Abstract
In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a human subject suffering from TMA associated with hematopoietic stem cell transplant. 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 thereof comprising specified heavy chain variable region and light chain variable region sets forth as SEQ ID NO:67 and SEQ ID NO:70, including CDR-defined variants and ≥90% identity variants. The described antibodies inhibit MASP-2 activity and lectin-pathway-mediated complement functions associated with thrombus formation, including effects on complement-mediated deposition such as C3b deposition and C5b-9 deposition.
The disclosed problem addressed in the patent is persistent TMA associated with hematopoietic stem cell transplant (HSCT-TMA), including cases in which TMA persists despite a reduction or discontinuation of an immunosuppressive agent, or persists at least 30 days after transplant. The patent links lectin-pathway activation and MASP-2 to endothelial injury and prothrombotic complement activity, which supports therapeutic intervention to improve clinical parameters associated with persistent TMA.
The claimed and described solution is a method of treating a human subject with persistent HSCT-TMA by administering an MASP-2 inhibitory monoclonal antibody composition, or an antigen-binding fragment, having the specified variable regions, at a dosage and frequency effective to improve selected clinical parameters associated with persistent TMA. MASP-2 functions as a molecular bridge between complement and coagulation, including cleavage of prothrombin, thereby contributing to thrombotic microangiopathy and related coagulopathies such as TA-TMA and related thrombotic conditions in cancer chemotherapy and transplantation contexts.
Claims Coverage
The independent claim covers a treatment method for persistent HSCT-TMA using a MASP-2 inhibitory antibody composition with specified variable regions and a regimen defined by dose and duration, where treatment improves defined clinical parameters. The claim set includes dependent refinements that add potency/serum deposition constraints, administration wording, and further narrowing of patient and antibody formats and context.
Treating persistent HSCT-TMA with MASP-2 inhibitory antibody composition
A method of treating a human subject suffering from persistent TMA associated with hematopoietic stem cell transplant (HSCT-TMA) comprising identifying a human subject with persistent HSCT-TMA wherein the subject has TMA that persists despite a reduction or discontinuation of an immunosuppressive agent, or wherein the subject has TMA that persists at least 30 days after transplant, and administering a composition comprising a MASP-2 inhibitory antibody, or antigen-binding fragment thereof.
Specified variable regions comprising SEQ ID NO:67 and SEQ ID NO:70
The MASP-2 inhibitory monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth as SEQ ID NO:67 and a light chain variable region set forth as SEQ ID NO:70.
Weekly dosing at at least 4 mg/kg for at least three weeks to improve clinical parameters
The composition is administered at a dosage of at least 4 mg/kg at least once a week for a time period of at least three weeks, wherein the administration is effective to improve at least one or more of the following clinical parameters associated with persistent TMA associated with hematopoietic stem cell transplant: increase in platelet count, increase in haptoglobin, decrease in lactate dehydrogenase (LDH), and/or decrease in creatinine.
MASP-2 antibody potency constraint for inhibiting C3b deposition in human serum
The method includes using a MASP-2 inhibitory antibody that inhibits C3b deposition in 90% human serum, with an IC50 of 30 nM or less.
Systemic administration of the MASP-2 inhibitory antibody
The method includes systemically delivering a MASP-2 inhibitory antibody to a subject system.
Antibody format selected from recombinant, reduced-effector-function, chimeric, humanized, or human
The method is performed using an antibody (or fragment thereof) selected from recombinant, reduced-effector-function, chimeric, humanized, or human antibodies.
Patient selection based on persistence window after immunosuppression reduction/discontinuation
The method is applied to a subject with persistent HSCT-TMA whose TMA persists for at least two weeks after reduction or discontinuation of an immunosuppression agent.
Immunosuppression agent is a calcineurin inhibitor
The immunosuppression agent is a calcineurin inhibitor.
Overall, the claim coverage is focused on treating persistent HSCT-TMA by administering an MASP-2 inhibitory antibody composition defined by specific variable regions (SEQ ID NO:67 and SEQ ID NO:70) and a weekly dosing regimen for at least three weeks, with therapeutic effect measured by improvements in platelet count, haptoglobin, LDH, and/or creatinine. Dependent claims further specify a C3b deposition inhibition potency threshold, systemic delivery wording, allowable antibody formats, and narrowed patient/immunosuppression-context selection.
Stated Advantages
Improves one or more clinical parameters associated with persistent TMA associated with hematopoietic stem cell transplant, including increase in platelet count, increase in haptoglobin, decrease in LDH, and/or decrease in creatinine.
Improves clinical parameters associated with persistent HSCT-TMA.
Suppresses lectin-pathway-driven complement activation and downstream complement deposition, including C5b-9 deposition.
Safety and improvements in platelet-related and hemolysis-related parameters over weeks were reported for early Phase 2 clinical outcomes for OMS646 in thrombotic microangiopathy.
Documented Applications
Treatment of a human subject suffering from persistent thrombotic microangiopathy associated with hematopoietic stem cell transplant (persistent HSCT-TMA), including cases where TMA persists despite reduction/discontinuation of immunosuppressive agents or persists at least 30 days after transplant.
Treating persistent HSCT-TMA in human subjects, including TMA that persists despite reduction/discontinuation of immunosuppressive agents and TMA persisting at least 30 days after transplant.
Treating and preventing TMA in cancer chemotherapy and transplantation contexts via MASP-2/lectin-pathway inhibition (including TA-TMA and related thrombotic microangiopathy contexts mentioned).
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