Pipeline

Complement

Overview

CB 4332 – SQ Enhanced Complement Factor I
Complement system disorders

Deficient or excessive activation of the complement system may lead to severe disorders, including micro thrombotic, autoimmune, and severe infectious diseases.

Diseases of the Classical Complement Pathway

In healthy individuals, the classical complement pathway is triggered by antibody-pathogen interactions. Specifically, antibodies bind to pathogens and mark them as targets for destruction by the complement system. This lets the complement system know that an unwanted pathogen is present and needs to be destroyed and cleared. In disease, however, the antibody mediated targeting affects an individual’s own cells and the classical complement system triggers an uncontrolled self-destructive process, which can have dire consequences. This response involves complement proteins C1, C2, and C4, and modulating these factors could potentially treat disorders of the classical complement pathway in a way that leaves the alternative and lectin as well as common pathways intact to carry out their normal physiological functions.

Catalyst protease programs in complement

We believe that engineered proteases hold a unique potential to address disorders driven by dysregulated biological processes and are differentiated by circumventing certain limitations of small molecule and antibody based therapeutics. Two examples of biological processes/systems that can be targeted by engineered proteases are the coagulation and complement systems. In both systems one protease molecule can modulate tens, hundreds, thousands, or even more target molecules to either activate or inactivate them. This is because a protease therapeutic does not become consumed in the process of engaging its target.

Therefore, smaller amounts of protease-based drug molecules can have profound impact on biological regulatory pathways. In comparison, small molecule drugs normally only inhibit a single target molecule per drug molecule and antibodies inhibit two at best. Proteases do not have this inherent limitation.

Moreover, proteases lend themselves well to half-life extension allowing infrequent convenient administration. We currently have several protease programs in preclinical discovery or early non-clinical development. Common to the programs is that they target diseases caused by deficient regulation of the complement system.

Click or tap the “Expand” buttons below to learn more about our programs.

CB 4332 is a wholly-owned first-in-class improved CFI intended for lifelong prophylactic SQ administration in individuals with CFI deficiency.

A key regulation of the classical pathway occurs at the level of C2/C4. Specifically, CFI together with cofactors, cleave and inactivate C4b to appropriately limit the downstream response. However, in diseases of the classical complement pathway, this regulatory step can be overwhelmed by too much upstream activity leading to uncontrolled downstream complement activation, even in people with normal CFI, ultimately resulting in destruction of the patient’s own cells.

We are engineering specific and potent C4b degraders to counteract this imbalance to alleviate disease in disorders of classical pathway hyperactivity by engineering an existing regulatory mechanism to become more effective and thereby applicable in individuals with normal CFI levels. By taking this approach we leverage existing biological functions and aim to specifically address fundamental deficiencies in the way current and future antibody and small molecule-based therapeutics work. Notably, although we have not chosen a disorder for our first clinical trial with a C4b degrader, the concept is designed to work across disorders of the classical pathway irrespective of the patients CFI genotype.

CB 2782-PEG is an engineered pegylated C3 degrader that we designed with a best-in-class anti-C3 profile for dry AMD. Dry AMD is an ocular disease leading to vision loss and blindness for which there is currently no approved therapies. Complement hyperreactivity plays an important role in dry AMD. Using the protease CB 2782-PEG to degrade C3 allows for the neutralization of C3 activity. It is expected that maintaining low C3 in the eye can significantly slow disease progression in dry AMD in patients who would otherwise lose their vision over time.

The global market potential in dry AMD has been estimated to be $8.6 billion which could grow to over $18.0 billion by 2028.

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