MASP-2 and MASP-3 Inhibitors for Upstream Complement Control
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current complement inhibitors, such as Eculizumab, target downstream molecules like C5, failing to inhibit the initiation steps of complement activation, leading to indiscriminate tissue damage and inflammation in various disease states, while the lectin and alternative pathways' initiators remain poorly understood.
Innovation Solution
Development of MASP-3 and MASP-2 inhibitory agents to target the initiation steps of the lectin and alternative complement pathways, providing a therapeutic approach to inhibit complement activation in conditions like PNH, AMD, and ischemia-reperfusion injury.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If downstream complement inhibitors like Eculizumab targeting C5 are used, then complement-mediated tissue damage and inflammation are reduced, but the initiation steps of complement activation remain uninhibited leading to continued downstream activation
Solution Approach 1:
The patent applies preliminary action by targeting MASP-2, an upstream initiator of the lectin pathway, before complement activation proceeds downstream. By inhibiting MASP-2 with small molecule compounds, the patent prevents the initiation of complement activation at its source, rather than merely blocking downstream effects. This upstream intervention ensures more complete inhibition of the complement cascade.
2Reliability
If MASP-2 inhibitory agents are used to target initiation steps, then complement activation is more effectively inhibited, but the complexity of the therapeutic approach increases
Solution Approach 1:
The patent employs small molecule compounds as disposable, orally administrable inhibitors of MASP-2. These small molecules serve as simple, transient inhibitors that can be easily administered and metabolized, avoiding the complexity of biologics while providing effective inhibition. The small molecule nature allows for oral delivery and simpler manufacturing compared to antibody-based therapies.
3Ease of manufacture
If small molecule MASP-2 inhibitors are used, then oral administration and easier manufacturing are achieved, but the potency and selectivity requirements increase
Solution Approach 1:
The patent applies local quality by designing small molecule inhibitors with specific structural features that confer selectivity for MASP-2 over other complement proteins. The molecular structure is locally optimized with functional groups and spatial arrangements that specifically recognize and bind to unique epitopes on MASP-2, ensuring selective inhibition despite the structural similarities among complement proteins.
Data Source
AI summary
In one aspect, the invention provides methods and compositions for inhibiting MASP-3-dependent complement activation in a subject suffering from or at risk for developing, a disease or disorder selected from the group consisting of paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, arthritis, disseminated intravascular coagulation, thrombotic microangiopathy, asthma, dense deposit disease, pauci-immune necrotizing crescentic glomerulonephritis, traumatic brain injury, aspiration pneumonia, endophthalmitis, neuromyelitis optica and Behcet's disease by administering to the subject a composition comprising an amount of a MASP-3 inhibitory agent in an amount effective to inhibit MASP-3-dependent complement activation. In some embodiments, the subject is administered a MASP-2 inhibitory agent and a MASP-1 inhibitory agent, a MASP-2 inhibitory agent and a MASP-3 inhibitory agent administered, a MASP-3 inhibitory agent and a MASP-1 inhibitory agent, or a MASP-1 inhibitory agent, a MASP-2 inhibitory agent and a MASP-3 inhibitory agent.