title: Design and development of TT30, a novel C3d-targeted C3/C5 convertase inhibitor for treatment of human complement alternative pathway-mediated diseases.
abstract: To selectively modulate human complement alternative pathway (CAP) activity implicated in a wide range of acute and chronic inflammatory conditions and to provide local cell surface and tissue-based inhibition of complement-induced damage, we developed TT30, a novel therapeutic fusion protein linking the human complement receptor type 2 (CR2/CD21) C3 fragment (C3frag = iC3b, C3dg, C3d)-binding domain with the CAP inhibitory domain of human factor H (fH). TT30 efficiently blocks ex vivo CAP-dependent C3frag accumulation on activated surfaces, membrane attack complex (MAC) formation and hemolysis of RBCs in a CR2-dependent manner, and with a ∼ 150-fold potency gain over fH, without interference of C3 activation or MAC formation through the classic and lectin pathways. TT30 protects RBCs from hemolysis and remains bound and detectable for at least 24 hours. TT30 selectively inhibits CAP in cynomolgus monkeys and is bioavailable after subcutaneous injection. Using a unique combination of targeting and effector domains, TT30 controls cell surface CAP activation and has substantial potential utility for the treatment of human CAP-mediated diseases.
authors.affiliation: Alexion Pharmaceuticals, Cambridge, MA, USA. fridkis-harelim@alxn.com
authors.forename: Masha
authors.initials: M
authors.lastname: Fridkis-Hareli
authors.forename: Michael
authors.initials: M
authors.lastname: Storek
authors.forename: Istvan
authors.initials: I
authors.lastname: Mazsaroff
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Risitano
authors.forename: Ante S
authors.initials: AS
authors.lastname: Lundberg
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Horvath
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
mesh_terms: D000818:Animals; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015933:Complement C3d / Q000378:metabolism*; D017242:Complement Factor H / Q000008:administration & dosage / Q000627:therapeutic use*; D003170:Complement Pathway, Alternative / Q000276:immunology*; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D018448:Models, Immunological; D058990:Molecular Targeted Therapy / Q000379:methods; D011817:Rabbits; D017464:Receptors, Complement 3d / Q000008:administration & dosage / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D017464:Receptors, Complement 3d; D011993:Recombinant Fusion Proteins; C574810:TT30 fusion protein, human; D015933:Complement C3d; D017242:Complement Factor H; D050577:Complement C3-C5 Convertases