Science

Modulating the Alternative Pathway of the Complement System to Treat Inflammatory Diseases

A Novel Approach to Treating Inflammatory Conditions and Diseases

Taligen’s product development programs are based on recent advances in our understanding of the alternative complement pathway that modulates complement-induced inflammation.

The Complement System

The complement system is a series of proteins that make up part of the innate immune system, which acts as an “early warning” to recognize tissue damage and to initiate the inflammation process.

Once initiated, inflammation proceeds as a cascade in which a single injury or insult triggers a complex and highly redundant process that includes the recruitment of inflammatory cells and release of effector molecules such as cytokines and enzymes, which lead to tissue damage (see figure below). Current anti-inflammatory agents target inflammation by blocking mediators far down in the inflammatory cascade (eg: IL-4, IL-13, etc.), leaving many other inflammatory mediators unaffected. In contrast, Taligen has demonstrated that the regulation of complement activation early in the cascade results in the down-regulation of multiple downstream effectors of inflammation. This provides a more complete control of the inflammatory response.

The complement system can be activated by one of three pathways: the classical, lectin or alternative pathways (see figure below). Activation of complement by any of the three pathways leads to cleavage of the major serum complement component (C3) and initiation of a cascade of activation in which a number of pro-inflammatory molecules, including C3a, C5a and the membrane attack complex (MAC), are released. In this process, C3b becomes covalently bound to nearby tissues and serves as a ligand for complement receptors (CR) that are present on a variety of immune cells. The CR-mediated binding of these cells to tissue-bound C3b further contributes to the generation of the inflammatory response.

Of the three pathways of complement activation, the alternative pathway is unique in that it acts as a potent amplification mechanism for the complement system. Driven by the presence of small amounts of activated C3, the alternative pathway is capable of amplifying the generation of pro-inflammatory complement activation products by 50-100 fold. This amplification of complement activation has been shown to be critical in driving inflammatory disease processes.

Taligen’s Novel Approach: Modulating the Alternative Pathway

Recent research has shown that the alternative complement pathway, also known as the complement amplification loop (see figure below), is an active component of many inflammatory diseases. Taligen’s approach is directed at controlling this amplification pathway of complement activation. The control of this amplification regulates excessive activation of complement, which characterizes many disease processes, while low levels of physiologically important complement activation are maintained.

 

Taligen’s approach is unique because its goal is not to completely block complement activation, but rather to modulate it to prevent excessive activation while allowing low levels of physiologically important complement activation to proceed. Taligen’s research is directed at both (1) inhibiting the actions of Factor B, an essential component of the alternative pathway of complement and a critical step in the amplification of complement activation (see figure below) and (2) providing increased amounts of functional Factor H, an endogenous regulator of complement amplification to specific sites where complement is activated. These approaches disrupt the amplification “loop,” dampening the inflammatory response. Taligen’s lead development programs are protein therapeutics designed to target complement inhibitors specifically at sites where excessive complement activation is occurring, controlling inflammation at a specific tissue site. This strategy differentiates Taligen’s approach from other complement therapeutics that indiscriminately block activation systemically.

Figure Legend: Green arrows indicate “on” or amplification of complement activation. Red arrows indicate inhibitory pathways to down-regulate the amplification loop.

Protein Therapeutics in Development

Taligen is leveraging its deep and extensive knowledge of the alternative complement pathway to discover and develop protein therapeutic candidates to treat diseases that are caused or exacerbated by the alternative pathway. Taligen’s lead product candidates are monoclonal antibodies and recombinant fusion proteins that target Factors B and H, key factors in the alternative pathway. These products are in preclinical stages of development for the treatment of systemic as well as local inflammatory conditions and diseases. Examples include TA106 a monoclonal antibody against Factor B and TT30, a Factor H recombinant fusion protein that targets sites of complement activation.

TA106 is a Fab fragment of a monoclonal antibody that inhibits complement Factor B. The initial clinical applications for TA106 will be for inflammatory diseases known to have an alternative pathway etiology and are amenable to localized delivery such as age-related macular degeneration and asthma.

Taligen is developing novel compounds, such as TT30 or targeted Factor H, that are intended to selectively deliver complement inhibitors to sites where complement activation is occurring and driving inflammation. Taligen scientists have demonstrated that targeting delivery of complement inhibitors to these sites is more efficacious, requires a lower dose of product and is safer than untargeted inhibitors.

The company has proof-of-concept data using this technology in animal models of choroidal neovascularization, inflammatory arthritis, ischemia-reperfusion injury, lupus nephritis, stroke and spinal cord injury. Ongoing experiments in animal models of human disease are further expanding and refining the list of potential indications. In addition, Taligen has data that demonstrate that targeted delivery of the complement inhibitory portion of Factor H to sites of complement activation with TT30 (CR2~factor H) is equally efficacious in animal models of choroidal neovascularization when given by systemic or by intraocular injection.

This targeting technology is designed to provide local regulation of complement activation without triggering systemic complement inhibition, potentially allowing application to a broad range of autoimmune and inflammatory diseases.