by The complement system is an important part of the innate immune system that helps defend the body against infection and foreign pathogens. It consists of over 30 proteins that are produced mainly by the liver but also by other tissues such as leukocytes. When activated, the complement system works to eliminate pathogens in three ways: opsonization, inflammatory response recruitment, and direct cell lysis.
Opsonization tags pathogens for removal by macrophages and neutrophils. Complement proteins coat the surface of pathogens, marking them for phagocytosis. The inflammatory response is triggered when complement activation fragments attract immune cells to sites of infection. Direct cell lysis uses the membrane attack complex to punch holes in the membranes of pathogen cells, lysing them directly.
While important for immune defense, improper regulation of the complement system can lead to damage of healthy host tissues. This has been implicated in many inflammatory and degenerative diseases. Inhibiting specific components of the complement cascade now shows therapeutic potential for treating various conditions.
Targeting The Alternative Pathway For Disease Treatment
A major area of focus for Global Complement Inhibitors is the alternative pathway, which can be activated independently of the classical and lectin pathways. Unlike the other pathways, it lacks tight regulation and thus is more prone to inappropriate activation. Excessive alternative pathway activity has been linked to many inflammatory and autoimmune disorders.
Several therapies aim to block C3 and C5 cleavage in this pathway. For example, Eculizumab (Soliris) is a monoclonal antibody approved for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). It binds C5 and prevents its cleavage into pro-inflammatory C5a and C5b. This inhibits membrane attack complex formation and lysis of blood cells seen in these diseases.
Other alternative pathway inhibitors in development target C3. Pegcetacoplan (APL-2) blocks C3 cleavage and showed similar efficacy to eculizumab in aHUS trials. It has the advantage of being administered subcutaneously rather than intravenously. Ravulizumab (Ultomiris) is a long-acting C5 inhibitor recently approved for PNH and aHUS like eculizumab.
Potential For Treating Musculoskeletal Conditions
Excessive complement activation may play a role in inflammatory joint diseases such as rheumatoid arthritis. Preclinical evidence suggests blocking C5a signaling could reduce joint inflammation and damage. Several Global Complement Inhibitors are now in clinical trials for RA.
AVD-001 is a bi-specific monoclonal antibody blocking both C5a and IL-17A, another proinflammatory mediator. A recent phase 2 trial showed beneficial effects on clinical scores in RA patients compared to placebo. similar phase 2 study is ongoing for ABP 959, a monoclonal blocking C5a alone.
Studies implicate the alternative pathway in osteoarthritis pathology as well. AMY-101 is a short peptide inhibitor of C3 cleavage advancing through Phase 1 testing for knee OA. If further trials are positive, Global Complement Inhibitors may offer an alternative to NSAIDs for treating pain from these common joint conditions.
Potential For Neurological And Eye Disease
In the central nervous system, alternative pathway activation has been linked to neurodegenerative conditions like Alzheimer’s disease as well as acute disorders such as stroke and traumatic brain injury. Preclinical data suggests complement inhibition could help prevent neuronal cell death.
A trend toward reduced atrophy rates was seen with an anti-C3 therapy in an Alzheimer’s trial. A phase 2 study is ongoing for ABP 938, an antibody blocking C5, for acute brain injuries. Success in these areas could open major new opportunities for modulating neuroinflammation and neurodegeneration.
In ophthalmology, genetic studies demonstrate alternative pathway risk factors for age-related macular degeneration, a leading cause of blindness. Complement deposition is prevalent in choroidal neovascularization lesions. Systemic administration of lampalizumab, an anti-factor D monoclonal antibody, slowed vision loss in a phase 3 AMD trial before being discontinued for commercial reasons. Topical drop formulations may provide an alternative approach.
The emergence of Global Complement Inhibitors therapies targeting key proteins such as C3, C5 and factor D represents an exciting new avenue for treating inflammatory and autoimmune conditions. Success so far in PNH, aHUS and potentially other areas lays the foundation for wider application across rheumatology, ophthalmology, neurology and other fields where complement dysregulation takes place. As our understanding of complement system involvement in disease pathogenesis grows, inhibition strategies will likely expand to benefit many patient populations.
*Note:
1. Source: Coherent Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
About Author - Vaagisha Singh
Vaagisha brings over three years of expertise as a content editor in the market research domain. Originally a creative writer, she discovered her passion for editing, combining her flair for writing with a meticulous eye for detail. Her ability to craft and refine compelling content makes her an invaluable asset in delivering polished and engaging write-ups. LinkedIn
