Methods for treating and/or preventing graft-versus-host disease and/or diffuse alveolar hemorrhage and/or veno-occlusive disease associated with hematopoietic stem cell transplant
Inventors
Demopulos, Gregory A. • Dudler, Thomas • Schwaeble, Hans-Wilhelm
Assignees
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Publication Number
US-11896621-B2
Publication Date
2024-02-13
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 graft-versus-host disease and/or diffuse alveolar hemorrhage and/or veno-occlusive disease associated with a 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 disclosure describes MASP-2 as an essential enzyme for lectin-pathway complement activation and identifies MASP-2 inhibitory antibodies and antigen-binding fragments that inhibit MASP-2-dependent complement activation. The described agents selectively inhibit C3 convertase formation and C4 cleavage while preserving classical-pathway complement activity and blocking lectin-pathway-mediated prothrombin cleavage into thrombin.
The independent claim describes a method of treating or preventing diffuse alveolar hemorrhage associated with hematopoietic stem cell transplant in a human subject suffering from, or at risk of developing, the condition. The method comprises administering a composition comprising an amount of a MASP-2 inhibitory antibody or antigen-binding fragment effective to inhibit MASP-2-dependent complement activation.
Dependent claims further provide refinements concerning subject identification prior to administration, systemic delivery, selective complement inhibition without classical pathway impairment, and antibody characteristics. Experimental reports and clinical observations describe concentration-dependent complement inhibition and resolution of diffuse alveolar hemorrhage, thrombotic microangiopathy, and hemolysis following hematopoietic stem cell transplant, permitting cessation of oxygen therapy, transfusions, and hemodialysis.
Claims Coverage
The claims identify one independent claim and five inventive features that refine the treatment method through subject identification, systemic delivery, pathway selectivity, and antibody characteristics.
Treatment of diffuse alveolar hemorrhage associated with hematopoietic stem cell transplant
The independent claim specifies administering a composition comprising an amount of a MASP-2 inhibitory antibody or antigen-binding fragment effective to inhibit MASP-2-dependent complement activation to a human subject suffering from, or at risk of developing, diffuse alveolar hemorrhage associated with hematopoietic stem cell transplant.
Identification of the subject before administration
A dependent claim specifies identifying the subject as suffering from, or at risk of, diffuse alveolar hemorrhage before administering the composition.
Systemic delivery
A dependent claim specifies systemic delivery of the MASP-2 inhibitory antibody to the subject.
Selective inhibition of complement activation
A dependent claim specifies that the MASP-2 inhibitory antibody does not substantially inhibit the classical pathway.
Antibody characteristics
Dependent claims specify antibody CDRs by sequence identifiers and potency characteristics for inhibiting C3b deposition.
The claim coverage focuses on administering a MASP-2 inhibitory antibody or antigen-binding fragment to treat or prevent hematopoietic stem cell transplant-associated diffuse alveolar hemorrhage, with dependent claims specifying subject identification, systemic delivery, antibody characteristics, and pathway selectivity.
Stated Advantages
Administration of the inhibitory antibody, including OMS646, was associated with clinical resolution of transplant-associated diffuse alveolar hemorrhage and thrombotic microangiopathy, allowing discontinuation of oxygen therapy, hemodialysis, and transfusions.
MASP-2 deficiency or antibody blockade produced protective effects in animal models of renal ischemia/reperfusion injury, macular degeneration, disseminated coagulation, meningococcal infection, radiation injury, and erythrocyte lysis.
MASP-2 inhibition blocks thrombin activation and provides protective effects in experimental thrombotic microangiopathy and disseminated intravascular coagulation models, showing reduced or delayed thrombotic microvascular occlusion and inhibition of lectin-pathway activity while classical- and alternative-pathway readouts remain largely unchanged.
MASP-2 deficiency or inhibitory anti-MASP-2 antibodies reduce infection-associated illness and improve survival in an STX/LPS-induced HUS model.
Documented Applications
Treatment or prevention of diffuse alveolar hemorrhage in a human subject suffering from, or at risk of developing, the condition associated with hematopoietic stem cell transplant.
Treatment or prevention of cancer-associated, chemotherapy-associated, or transplantation-associated thrombotic microangiopathy, graft-versus-host disease, and neurological symptoms.
Administration of a MASP-2 inhibitor alongside C5 inhibitors in thrombotic thrombocytopenic purpura.
Treatment or prevention of sepsis, complement-related renal conditions, and other blood disorders.
Intervention or testing in models of renal ischemia/reperfusion injury, macular degeneration, disseminated coagulation, meningococcal infection, radiation injury, erythrocyte lysis, and STX/LPS-induced HUS.
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