Exploring the Complement System.

The complement system, a complex network of proteins renowned for its role in immune responses, is a significant yet often neglected player in drug development. Its significant impact on drug development outcomes warrants a closer examination of its potential as either a friend aiding development or a foe complicating results. This blog explores the complexities, challenges, and opportunities of the complement system in drug development, as well as methods for evaluating it. 

Understanding the Complement System

The complement system, a part of the innate immune system, comprises around 50 plasma and cellular proteins. It enhances (complements) the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is involved in various immune processes, including opsonization (marking pathogens for destruction), inflammation induction, and formation of the membrane attack complex (MAC) to lyse pathogens. 

While the complement system is essential for defense against pathogens, its activation must be carefully balanced. Overactivation can lead to tissue damage and inflammation, contributing to various diseases, whereas under activation might increase susceptibility to infections. This delicate balance presents both challenges and opportunities for drug development. 

But is it a Friend? Aiding in Drug Discovery

The complement system modulates disease processes, including autoimmune diseases, neurodegenerative diseases, and cancer. Understanding how complement components interact with disease pathology can aid the design of drugs that inhibit or enhance complement activity, depending on the therapeutic goal. For instance, in cancer, specific complement components might promote tumour growth by suppressing the immune response, suggesting that complement inhibitors could have therapeutic benefits. 

On the other hand, during the early stages of drug development, researchers use the complement system’s ability to identify and eliminate foreign substances to screen for potential drug candidates. Understanding how drugs influence complement activation can guide lead optimization, ensuring the development of safer and more efficacious therapeutics. Furthermore, the complement system is a valuable biomarker in preclinical and clinical studies, providing insights into drug-induced immune responses and potential adverse effects. 

Or a Foe? The Challenge of Unintended Activation

The complement system’s role extends beyond drug discovery to drug safety assessment. A significant challenge in drug development is avoiding unintended complement activation, which can trigger inflammatory responses and adverse reactions, constituting challenges in clinical development. Biological therapeutics, including monoclonal antibodies, can activate the complement system, leading to infusion reactions or other side effects. Understanding therapeutic agents’ immunogenicity, including their potential to induce complement activation-related adverse events, is critical for predicting and mitigating safety risks. Incorporating complement-related endpoints into preclinical safety assessments enables early detection of potential adverse effects, guiding informed decision-making and ensuring patient safety throughout drug development. 

Assays for Exploring the Complement System

Understanding the basic functions and implications of the complement system in drug development is essential, as is knowing the available methods for studying its activity and modulation.  

• Enzyme-linked immunosorbent assays (ELISAs) can quantify specific complement components or activation products in biological samples, allowing researchers to monitor complement activation levels in response to drug treatments.  
• Flow cytometry assays enable the analysis of complement receptor expression on immune cells, providing information on cellular interactions with complement proteins. 
• Functional assays such as the hemolytic assay measure the membrane attack complex’s (MAC) activity, offering insights into the effectiveness of drugs in inhibiting complement-mediated cytotoxicity. Additionally, complement deposition assays assess the ability of therapeutic agents to trigger complement activation and subsequent immune responses. 

Researchers can gain a comprehensive understanding of the complement system’s involvement in drug development by incorporating these assays into preclinical and clinical studies. These assays facilitate the identification of potential drug candidates, evaluation of safety profiles, and optimization of therapeutic strategies. 

It is increasingly important to understand the impact of the complement system, as it is likely to be the foundation of new pharmaceutical innovations, leading to transformative healthcare and breakthroughs in drug development.