Complement activation in drug development

Navigating the Challenges of Complement Activation
Unpredictable hypersensitivity reactions are a major concern for drug companies and regulatory agencies emphasize the need for new, non-standard toxicity tests that enable the prediction of adverse immune events of therapeutic agents. One significant challenge in preclinical drug development is the unintended activation of the complement system. This ancient part of the immune system, while crucial for defending against pathogens, can cause serious adverse effects in patients when activated by therapeutic agents. Understanding these risks is essential for developing safe and effective drugs.
Understanding Complement Activation
The complement system is a complex network of over 50 plasma and cell surface proteins organized into three interconnected activation pathways: the classical, alternative, and lectin. Each pathway plays a crucial role in immune surveillance, recognizing and eliminating pathogens. The complement system cannot only cross-talk with the activation cascades of plasma but also serves as a bridge between innate and adaptive immunity 1. When therapeutic agents unintentionally trigger any of these pathways, they can cause significant harm to the patient.
Undesired Effects of Complement Activation in Drug Development
Complement Activation-Related Pseudo-Allergy (CARPA): Complement activation can lead to hypersensitivity reactions known as CARPA, with occasional lethal outcomes in humans.  Anaphylatoxins like C3a, C5a, and Bb split products are generated, binding to immune cells such as mast cells, basophils, and macrophages. This binding releases vasoactive mediators that can cause severe allergic reactions in humans 2. Examples include monoclonal antibodies (e.g., Rituximab), liposome-encapsulated drugs (e.g., Doxorubicin, Amfotericin B), and micellarized anti-cancer agents (e.g., paclitaxel), all of which have been associated with CARPA 3.
Platelet activation, thrombosis, and inflammation: The complement and coagulation systems are genetically and functionally related. Activation of complement can activate platelets and promote coagulation and lead to thrombotic complications 4. Complement-derived anaphylatoxins contribute to a vicious circle of complement activation, enhancing local inflammation, thrombosis, tissue injury, and damage to healthy cells 5.
Compromised efficacy of therapies: In cancer treatments, such as with the drug Doxorubicin, complement activation correlates with the severity of hypersensitivity reactions. The infusion rate of the drug significantly impacts both the extent of complement activation and the risk of adverse reactions 6.
The Complexity of Complement Activation Assessment
Species-Specific Differences: Since complement response to foreign antigens is a phylogenetically ancient, highly conserved process, it occurs in many animal species. However, different species show different sensitivity 7.  Although Non-human Primates (NHP) has proven to be an effective toxicological model for ASOs, monkeys appear to be more sensitive to Antisense oligonucleotide (ASO)-induced complement activation than humans and other species. For example, the effects of Inotersen on complement in NHPs were not observed in humans. NHPs over-predicted risk of complement activation and effects on platelets 8.
Diverse Modes of Action: Different drugs activate the complement system through various mechanisms. Antibodies may trigger the classical pathway, while oligonucleotides, particularly those with phosphorothioate backbones, can activate the alternative pathway 9
Context of the Test Environment:The interaction between drugs and the complement system can vary significantly depending on whether the testing environment is in vitro or in vivo. Factors such as drug concentration, antigen density, and local microenvironment conditions also influence complement activation dynamics. Whole blood assays provide a physiologically relevant test environment, replicating in-human complement activation.
Conclusion
The unintended activation of the complement system presents a significant challenge in drug development. Understanding the mechanisms behind this activation and recognizing the potential for adverse effects is crucial for developing safer therapies. In the next part of this blog series, we will explore the solutions, best practices, and analytical methods that can help mitigate these risks and ensure the safety of new drugs. Coming fall 2024.