Methods for treating conditions associated with MASP-2 dependent complement activation
Inventors
Schwaeble, Hans-Wilhelm • Tedford, Clark E. • Parent, James B. • Dudler, Thomas • Demopulos, Gregory A.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11884742-B2
Publication Date
2024-01-30
Expiration Date
Abstract
In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject. 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. In some embodiments, the MASP-2 inhibitory agent inhibits cellular injury associated with MASP-2-mediated alternative complement pathway activation, while leaving the classical (C1q-dependent) pathway component of the immune system intact. In another aspect, the invention provides compositions for inhibiting the effects of lectin-dependent complement activation, comprising a therapeutically effective amount of a MASP-2 inhibitory agent and a pharmaceutically acceptable carrier.
Core Innovation
The disclosure describes a method of inhibiting adverse effects of transplantation in a subject who has undergone, is undergoing, or will undergo a liver transplant procedure. The method comprises administering to the subject, or pretreating the liver to be transplanted with, a composition comprising a monoclonal MASP-2 inhibitory antibody or antigen-binding fragment thereof. The antibody or fragment specifically binds to a portion of SEQ ID NO:6 and inhibits MASP-2-dependent complement activation.
The approach reduces complement-mediated and inflammatory injury while preserving C1q-dependent classical pathway function. MASP-2 links lectin complement activation and coagulation by cleaving prothrombin to generate thrombin, with inhibition decreasing C3 convertase formation, C4 cleavage, and thrombin generation. Documented results show MASP-2 deficiency or antibody inhibition lowers blood urea nitrogen, decreases infarct size, and protects against ischemia/reperfusion injury and complement-mediated tissue damage.
Claims Coverage
The claims identify one independent claim directed to inhibiting adverse effects of liver transplantation, comprising three inventive features reciting all elements of the claim.
Inhibition of adverse effects of liver transplantation
The claim provides a method of inhibiting adverse effects of transplantation in a subject who has undergone, is undergoing, or will undergo a liver transplant procedure.
Administration or liver pretreatment
The composition is administered to the subject or used to pretreat the liver to be transplanted.
MASP-2 inhibitory antibody composition
The composition comprises a monoclonal MASP-2 inhibitory antibody, or antigen-binding fragment thereof, that specifically binds a portion of SEQ ID NO:6 and inhibits MASP-2-dependent complement activation.
The independent claim centers on inhibiting adverse effects of liver transplantation through subject administration or graft pretreatment with a monoclonal MASP-2 inhibitory antibody or antigen-binding fragment that inhibits MASP-2-dependent complement activation.
Stated Advantages
The method reduces complement-mediated tissue injury and inflammatory adverse effects after liver transplantation while preserving C1q-dependent classical pathway function.
MASP-2 deficiency and inhibition protect against ischemia/reperfusion injury, reduce infarct size, and associate with lower blood urea nitrogen and improved graft function.
Documented Applications
Liver transplant procedures in a subject who has undergone, is undergoing, or will undergo transplantation, encompassing subject administration or pretreatment of the liver to be transplanted.
Organ allotransplantation and tissue grafts, including renal transplantation and evaluation of kidney graft function.
Treatment of pathology in models of ischemia/reperfusion injury and complement-mediated damage.
Potential applications for MASP-2 inhibition in sepsis, blood and urogenital disorders, diabetes complications, malignancy treatment effects, radiation syndrome, endocrine and ophthalmologic disorders, coagulopathies, and DIC and related thrombosis.
Interested in licensing this patent?