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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Overactivation of the lectin pathway of complement plays a pathogenic role in a broad range of immune-mediated and inflammatory disorders; mannan-binding lectin-associated serine protease-2 (MASP-2) is the key effector enzyme of the lectin pathway. We developed a fully human monoclonal antibody, narsoplimab, to bind to MASP-2 and specifically inhibit lectin pathway activation. Herein, we describe the preclinical characterization of narsoplimab that supports its evaluation in clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>ELISA binding studies demonstrated that narsoplimab interacted with both zymogen and enzymatically active forms of human MASP-2 with high affinity (K<jats:sub>D<\/jats:sub> 0.062 and 0.089 nM, respectively) and a selectivity ratio of &amp;gt;5,000-fold relative to closely related serine proteases C1r, C1s, MASP-1, and MASP-3. Interaction studies using surface plasmon resonance and ELISA demonstrated approximately 100-fold greater binding affinity for intact narsoplimab compared to a monovalent antigen binding fragment, suggesting an important contribution of functional bivalency to high-affinity binding. In functional assays conducted in dilute serum under pathway-specific assay conditions, narsoplimab selectively inhibited lectin pathway-dependent activation of C5b-9 with high potency (IC<jats:sub>50<\/jats:sub> ~ 1 nM) but had no observable effect on classical pathway or alternative pathway activity at concentrations up to 500 nM. In functional assays conducted in 90% serum, narsoplimab inhibited lectin pathway activation in human serum with high potency (IC<jats:sub>50<\/jats:sub> ~ 3.4 nM) whereas its potency in cynomolgus monkey serum was approximately 10-fold lower (IC<jats:sub>50<\/jats:sub> ~ 33 nM). Following single dose intravenous administration to cynomolgus monkeys, narsoplimab exposure increased in an approximately dose-proportional manner. Clear dose-dependent pharmacodynamic responses were observed at doses &amp;gt;1.5 mg\/kg, as evidenced by a reduction in lectin pathway activity assessed <jats:italic>ex vivo<\/jats:italic> that increased in magnitude and duration with increasing dose. Analysis of pharmacokinetic and pharmacodynamic data revealed a well-defined concentration-effect relationship with an <jats:italic>ex vivo<\/jats:italic> EC<jats:sub>50<\/jats:sub> value of approximately 6.1 \u03bcg\/mL, which was comparable to the <jats:italic>in vitro<\/jats:italic> functional potency (IC<jats:sub>50<\/jats:sub> 33 nM; ~ 5 \u03bcg\/mL).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Based on these results, narsoplimab has been evaluated in clinical trials for the treatment of conditions associated with inappropriate lectin pathway activation, such as hematopoietic stem cell transplantation-associated thrombotic microangiopathy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1297352","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T16:11:37Z","timestamp":1699546297000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Development and characterization of narsoplimab, a selective MASP-2 inhibitor, for the treatment of lectin-pathway\u2013mediated disorders"],"prefix":"10.3389","volume":"14","author":[{"given":"Thomas","family":"Dudler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadam","family":"Yaseen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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