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Development and Optimization of Bifunctional Fusion Proteins to Locally Modulate Complement Activation in Diseased
Kelly C Fahnoe1, Fei Liu1, Jennifer G Morgan1
1Preclinical Research Q32 Bio Inc., Waltham, MA, United States.
Frontiers in Immunology
|July 5, 2022
Summary
Researchers developed targeted fusion proteins to inhibit complement activation in diseased tissues. This approach aims to reduce systemic side effects associated with current broad-acting anti-complement therapies.
Area of Science:
- Immunology
- Biochemistry
- Drug Development
Background:
- Sustained complement activation drives inflammatory and autoimmune diseases.
- Current anti-complement therapies cause systemic inhibition, impacting essential immune functions.
- There is a need for localized complement inhibition in diseased tissues.
Purpose of the Study:
- To develop novel fusion proteins for tissue-targeted complement inhibition.
- To deliver complement negative regulators specifically to sites of complement activation.
- To improve therapeutic potency, duration, and safety profiles.
Main Methods:
- Created a library of bifunctional fusion proteins linking complement receptor type 1 (CR1) to anti-C3d antibodies.
- Engineered fusion proteins to bind C3 fragments (iC3b, C3dg, C3d) deposited on injured tissues.
- Performed biochemical, in vitro, and preclinical in vivo characterization of fusion proteins.
Main Results:
- Identified fusion proteins that inhibit complement activation while retaining C3d binding.
- Demonstrated effective tissue distribution of anti-C3d fusion proteins in vivo.
- Showed sustained reduction of C3 fragment deposition in injured tissues for over 14 days.
Conclusions:
- Anti-C3d fusion proteins offer a promising strategy for localized complement inhibition.
- This approach may restore proper complement regulation in diseased tissues without systemic blockade.
- Further evaluation of C3d mAb-CR1_1-10 is warranted for treating complement-mediated diseases.
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