Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation.

The complement system is a key component of the innate immune system, and its aberrant activation underlies the pathophysiology of various diseases. Zilucoplan is a macrocyclic peptide that binds and inhibits the cleavage/activation of human complement component 5 (C5). We present The interaction of zilucoplan with C5, including for clinical C5 R885 variants, was investigated using surface plasmon resonance (SPR), hemolysis assays, and ELISA. The interference of C5b6 formation by zilucoplan was investigated by native gel analysis and hemolysis assay. The permeability of zilucoplan in a reconstituted basement membrane was assessed by the partition of zilucoplan on Matrigel-coated transwell chambers. Zilucoplan specifically bound human complement C5 with high affinity, competitively inhibited the binding of C5 to C3b, and blocked C5 cleavage by C5 convertases and the assembly of the cytolytic membrane attack complex (MAC, or C5b9). Zilucoplan fully prevented the Our findings demonstrate that zilucoplan uses a dual mode of action to potently inhibit the activation of C5 and terminal complement pathway including wild-type and clinical R885 variants that do not respond to eculizumab treatment. These data may be relevant to the clinically demonstrated benefits of zilucoplan.

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Copyright © 2023 Tang, Tang, Dhamnaskar, Hoarty, Vyasamneni, Vadysirisack, Ma, Zhu, Wang, Bu, Cong, Palmer, Duda, Sayegh and Ricardo.

Déclaration de conflit d'intérêts

All authors are employees or former employees of Ra Pharmaceuticals or UCB Pharma. KD is currently employed by Nurix Therapeutics, San Francisco, CA, USA. MH is currently employed by Dyne Therapeutics, Waltham, MA, USA. RV is currently employed by BioNTech SE, Cambridge, USA. ZM is currently employed by Mariana Oncology, Watertown, MA, USA. DV is currently employed by Dianthus Therapeutics, Waltham, MA, USA. NZ is currently employed by Avilar Therapeutics, Waltham, MA, USA. CS is currently employed by Mitochondria Emotion, Cambridge, MA, USA. AR is currently employed by Mariana Oncology, Watertown, MA, USA. The authors declare that this study received funding from UCB Ra Pharmaceuticals. The funder had the following involvement: study design, collection, analysis and interpretation of data, review of this article and the decision to submit it for publication.