Methods of inhibiting MASP-2-dependent complement activation in a subject suffering from catastrophic antiphospholipid syndrome
Inventors
Demopulos, Gregory A. • Dudler, Thomas • Schwaeble, Hans-Wilhelm
Assignees
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Publication Number
US-11525011-B2
Publication Date
2022-12-13
Expiration Date
Abstract
In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject suffering from, or at risk for developing a thrombotic microangiopathy (TMA). 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.
Core Innovation
The disclosure describes a method of inhibiting MASP-2-dependent complement activation in a subject suffering from Catastrophic Antiphospholipid Syndrome (CAPS). The method comprises administering a composition comprising a MASP-2 inhibitory monoclonal antibody or antigen-binding fragment that specifically binds a portion of MASP-2 and comprises specified heavy-chain and light-chain variable-region CDRs. The antibody selectively inhibits MASP-2-dependent complement activation without substantially inhibiting classical pathway activity.
The disclosure reports inhibition of lectin-pathway activity, including C3 convertase formation, C4 cleavage, and a MASP-2-dependent C4-bypass route of C3 activation. Preclinical evaluations show reduced complement-mediated hemolysis, delayed microvascular occlusion, and delayed thrombus formation across thrombotic microangiopathy models. In tested patient samples, MASP-2 inhibition reduces atypical hemolytic uremic syndrome serum-induced endothelial C5b-9 deposition, thrombus formation, and apoptosis-related effects.
Claims Coverage
The provided claim set identifies one independent claim containing three inventive features directed to CAPS treatment using a specified MASP-2 inhibitory antibody.
Inhibition of MASP-2-dependent complement activation in CAPS
Administering a composition comprising an amount of a MASP-2 inhibitory monoclonal antibody or antigen-binding fragment effective to inhibit MASP-2-dependent complement activation in a subject suffering from Catastrophic Antiphospholipid Syndrome (CAPS).
Specified MASP-2 inhibitory antibody or fragment
The composition comprises a MASP-2 inhibitory monoclonal antibody or antigen-binding fragment that specifically binds to a portion of MASP-2, such as SEQ ID NO:6, and comprises specified heavy-chain and light-chain variable-region CDRs; [procedural detail omitted for safety].
Classical pathway selectivity
The MASP-2 inhibitory monoclonal antibody or antigen-binding fragment does not substantially inhibit the classical pathway.
The independent claim combines treatment of CAPS via inhibition of MASP-2-dependent complement activation using a specified antibody or antigen-binding fragment with the limitation that the antibody does not substantially inhibit the classical pathway.
Stated Advantages
Selectively inhibits MASP-2-dependent complement activation without substantially inhibiting the classical pathway, reducing lectin-pathway C3 and MAC deposition while leaving classical-pathway activity comparatively intact.
Anti-MASP-2 treatment maintained 100% survival in an STX/LPS-induced HUS model compared to 0% in untreated controls, and reduced radiation-associated and infection-related mortality in preclinical models.
Delays microvascular occlusion and thrombus formation in thrombotic microangiopathy models while reducing complement-mediated hemolysis.
Reduces aHUS serum-induced endothelial C5b-9 deposition, thrombus formation, and apoptosis-related effects in tested patient samples.
Documented Applications
Inhibiting MASP-2-dependent complement activation in subjects suffering from Catastrophic Antiphospholipid Syndrome (CAPS) by administering the claimed composition.
Treatment and evaluation of blood disorders and thrombotic microangiopathies (TMAs), including sepsis, disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), and thrombotic thrombocytopenic purpura (TTP).
Preclinical assays and models evaluating lectin-pathway MAC deposition, thrombus formation, and vascular occlusion in atypical hemolytic uremic syndrome (aHUS)-related contexts.
Outcomes reported for MASP-2-deficient animal models in transplantation, infection, and sepsis.
Potential combination therapy with terminal C5 inhibitors.
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