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It was a long\u2010acting monoclonal antibody (aka 5G1\u20101, 5G1.1, h5G1.1, and now known as eculizumab) that targets C5, specifically preventing the generation of C5a, a potent anaphylatoxin, and C5b, the first step in the eventual formation of membrane attack complex. The enormous clinical and financial success of eculizumab across four diseases (PNH, atypical hemolytic uremic syndrome (aHUS), myasthenia gravis (MG), and anti\u2010aquaporin\u20104 (AQP4) antibody\u2010positive neuromyelitis optica spectrum disorder (NMOSD)) has fueled a surge in complement therapeutics, especially targeting diseases with an underlying complement pathophysiology for which anti\u2010C5 therapy is ineffective. Intensive research has also uncovered challenges that arise from C5 blockade. For example, PNH patients can still face extravascular hemolysis or pharmacodynamic breakthrough of complement suppression during complement\u2010amplifying conditions. These \u201cside\u201d effects of a stoichiometric inhibitor like eculizumab were unexpected and are incompatible with some of our accepted knowledge of the complement cascade. And they are not unique to C5 inhibition. Indeed, \u201cexceptions\u201d to the rules of complement biology abound and have led to unprecedented and surprising insights. In this review, we will describe initial, present and future aspects of protein inhibitors of the complement cascade, highlighting unexpected findings that are redefining some of the mechanistic foundations upon which the complement cascade is organized.<\/jats:p>","DOI":"10.1111\/imr.13164","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T03:57:32Z","timestamp":1668743852000},"page":"376-401","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Protein therapeutics and their lessons: Expect the unexpected when inhibiting the multi\u2010protein cascade of the complement system"],"prefix":"10.1111","volume":"313","author":[{"given":"Christoph Q.","family":"Schmidt","sequence":"first","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products University of Ulm Medical Center  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J. 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