Factor XII(a) inhibitors: a review of the patent literature

References

• Weidmann H, Heikaus L, Long AT, et al. The plasma contact system, a protease cascade at the nexus of inflammation, coagulation and immunity. Bba-Mol Cell Res. 2017;1864:2118–2127.
   PubMed Web of Science ®Google Scholar
• Schmaier AH, Stavrou EX. Factor XII – what’s important but not commonly thought about. Res Pract Thromb Haemost. 2019;3(4):599–606.
   PubMed Web of Science ®Google Scholar
• Renne T, Stavrou EX. Roles of factor xii in innate immunity. Front Immunol. 2011;2019(10). DOI: https://doi.org/10.3389/fimmu.2019.02011.
   Google Scholar
• Davoine C, Bouckaert C, Fillet M, et al. Factor XII/XIIa inhibitors: their discovery, development, and potential indications. Eur J Med Chem. 2020;208:112753.
   PubMed Web of Science ®Google Scholar
• Doolittle RF. Coagulation in vertebrates with a focus on evolution and inflammation. J Innate Immun. 2011;3(1):9–16.
   PubMed Web of Science ®Google Scholar
• Renne T, Schmaier AH, Nickel KF, et al. In vivo roles of factor XII. Blood. 2012;120(22):4296–4303.
   PubMed Web of Science ®Google Scholar
• Didiasova M, Wujak L, Schaefer L, et al. Factor XII in coagulation, inflammation and beyond. Cell Signal. 2018;80:257–265.
   Google Scholar
• Cool DE, Edgell CJ, Louie GV, et al. Characterization of human blood coagulation factor XII cDNA. Prediction of the primary structure of factor XII and the tertiary structure of beta-factor XIIa. J Biol Chem. 1985;260(25):13666–13676.
   PubMed Web of Science ®Google Scholar
• Dementiev A, Silva A, Yee C, et al. Structures of human plasma β–factor XIIa cocrystallized with potent inhibitors. Blood Adv. 2018;2(5):549–558.
   PubMed Web of Science ®Google Scholar
• Kohs TCL, Lorentz CU, Johnson J, et al. Development of coagulation factor XII antibodies for inhibiting vascular device-related thrombosis. Cell Mol Bioeng. 2021.
   PubMed Web of Science ®Google Scholar
• Kleinschnitz C, Stoll G, Bendszus M, et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med. 2006;203(3):513–518.
   PubMed Web of Science ®Google Scholar
• Renne T, Pozgajova M, Gruner S, et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med. 2005;202(2):271–281.
   PubMed Web of Science ®Google Scholar
• Renne T, Nieswandt B, Gailani D. The intrinsic pathway of coagulation is essential for thrombus stability in mice. Blood Cell Mol Dis. 2006;36(2):148–151. .
   PubMed Web of Science ®Google Scholar
• Kuijpers MJ, van der Meijden PE, Feijge MA, et al. Factor XII regulates the pathological process of thrombus formation on ruptured plaques. Arterioscler Thromb Vasc Biol. ;2014;34(8):1674–1680.
   Google Scholar
• Maas C, Renne T. Coagulation factor XII in thrombosis and inflammation. Blood. 2018;131(17):1903–1909.
   PubMed Web of Science ®Google Scholar
• Xu Y, Cai TQ, Castriota G, et al. Factor XIIa inhibition by Infestin-4: in vitro mode of action and in vivo antithrombotic benefit. Thromb Haemost. 2014;111(4):694–704.
   PubMed Web of Science ®Google Scholar
• Barbieri CM, Wang X, Wu W, et al. Factor XIIa as a novel target for thrombosis: target engagement requirement and efficacy in a rabbit model of microembolic signals. J Pharmacol Exp Ther. 2017;360(3):466–475.
   PubMed Web of Science ®Google Scholar
• Yau JW, Liao P, Fredenburgh JC, et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood. 2014;123(13):2102–2107.
   PubMed Web of Science ®Google Scholar
• Larsson M, Rayzman V, Nolte MW, et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med. 2014;6(222):222ra17.
   PubMed Web of Science ®Google Scholar
• Matafonov A, Leung PY, Gailani AE, et al. Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood. 2014;123(11):1739–1746.
   Google Scholar
• Wilbs J, Kong XD, Middendorp SJ, et al. Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs. Nat Commun. 2020;11(1):3890.
   PubMed Web of Science ®Google Scholar
• Kenne E, Nickel KF, Long AT, et al. Factor XII: a novel target for safe prevention of thrombosis and inflammation. J Intern Med. 2015;278(6):571–585.
   PubMed Web of Science ®Google Scholar
• Howl J, Payne SJ. Bradykinin receptors as a therapeutic target. Expert Opin Ther Tar. 2003;7(2):277–285.
   PubMed Web of Science ®Google Scholar
• Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med (Lond). 2019;80(7):391–398.
   PubMed Web of Science ®Google Scholar
• Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005;139(3):379–394.
   PubMed Web of Science ®Google Scholar
• Bjorkqvist J, de Maat S, Lewandrowski U, et al. Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. J Clin Invest. 2015;125(8):3132–3146.
   PubMed Web of Science ®Google Scholar
• Nickel KF, Long AT, Fuchs TA, et al. Factor XII as a therapeutic target in thromboembolic and inflammatory diseases. Arterioscl Throm Vas. 2017;37(1):13–20.
   Google Scholar
• Bork K. Pasteurized C1 inhibitor concentrate in hereditary angioedema: pharmacology, safety, efficacy and future directions. Expert Rev Clin Immunol. 2008;4(1):13–20.
   PubMed Web of Science ®Google Scholar
• Bender L, Weidmann H, Rose-John S, et al. Factor XII-driven inflammatory reactions with implications for anaphylaxis. Front Immunol. 2017;8:1115.
   PubMed Web of Science ®Google Scholar
• Cao H, Biondo M, Lioe H, et al. Antibody-mediated inhibition of FXIIa blocks downstream bradykinin generation. J Allergy Clin Immunol. 2018;142(4):1355–1358.
   PubMed Web of Science ®Google Scholar
• Nicola S, Rolla G, Brussino L. Breakthroughs in hereditary angioedema management: a systematic review of approved drugs and those under research. Drugs Context. 2019;8:212605.
   PubMedGoogle Scholar
• Liu J, Qin J, Borodovsky A, et al. An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema. RNA. 2019;25(2):255–263.
   PubMed Web of Science ®Google Scholar
• Chen ZL, Revenko AS, Singh P, et al. Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice. Blood. 2017;129(18):2547–2556.
   PubMed Web of Science ®Google Scholar
• Gobel K, Pankratz S, Asaridou CM, et al. Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. Nat Commun. 2016;7(1):11626.
   PubMedGoogle Scholar
• Raghunathan V, Zilberman-Rudenko J, Olson SR, et al. The contact pathway and sepsis. Res Pract Thromb Haemost. 2019;3(3):331–339.
   PubMed Web of Science ®Google Scholar
• Jansen PM, Pixley RA, Brouwer M, et al. Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase. Blood. 1996;87(6):2337–2344.
   PubMed Web of Science ®Google Scholar
• Pixley RA, De La Cadena R, Page JD, et al. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons. J Clin Invest. 1993;91(1):61–68.
   PubMed Web of Science ®Google Scholar
• Bouckaert C, Serra S, Rondelet G, et al. Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors. Eur J Med Chem. 2016;110:181–194.
   PubMed Web of Science ®Google Scholar
• Breslow JL, Ponda MP, Selnick H, et al.; The Rockefeller University. USA. Aminotriazole immunomodulators for treating autoimmune diseases. WO2017123518. 2107.
   Google Scholar
• Short KM, Pham SM, Williams DC, et al.; Verseon Inc. USA. Multisubstituted aromatic compounds as inhibitors of thrombin. WO2011126903. 2011.
   Google Scholar
• Korff M, Imberg L, Will JM, et al. Acylated 1H-1,2,4-Triazol-5-amines targeting human coagulation factor xiia and thrombin: conventional and microscale synthesis, anticoagulant properties, and mechanism of action. J Med Chem. 2020;63(21):13159–13186.
   PubMed Web of Science ®Google Scholar
• Ponda MP, Breslow JL, Selnick H, et al.; The Rockefeller University. USA. Aminoacylindazole immunomodulators for treatment of autoimmune diseases. WO2017205296. 2017.
   Google Scholar
• Ponda MP, Selnick H, Egbertson M, et al.; The Rockefeller University. USA. Pyranopyrazole and pyrazolopyridine immunomodulators for treatment of autoimmune diseases. WO2019108565. 2019.
   Google Scholar
• Rao A, Mckittrick BA, Lombardo M, et al. Merck Sharp & Dohme corp. USA. Factor XIIa inhibitors. WO 2018093695. 2018.
   Google Scholar
• Hicks J, Mckittrick BA, Whitehead B, et al.; Merck Sharp & Dohme corp. USA. Factor XIIa inhibitors. WO2018093716. 2018.
   Google Scholar
• Philippou H, Foster R, Fishwick C, et al.; University of Leeds. USA. Factor XIIa inhibitors. WO2019211585. 2019.
   Google Scholar
• Philippou H, Foster R, Fishwick C, et al.; University of Leeds. USA. Factor XIIa inhibitors. WO2019186164. 2019.
   Google Scholar
• Kalvins I, Birmans A, Veveris M. TETRA, SIA. Latvia. Novel factor XII inhibitor. WO2012158003. 2012.
   Google Scholar
• Middendorp SJ, Wilbs J, Quarroz C, et al. Peptide macrocycle inhibitor of coagulation factor XII with subnanomolar affinity and high target selectivity. J Med Chem. 2017;60(3):1151–1158.
   PubMed Web of Science ®Google Scholar
• Hansson KM, Nielsen S, Elg M, et al. The effect of corn trypsin inhibitor and inhibiting antibodies for FXIa and FXIIa on coagulation of plasma and whole blood. J Thromb Haemost. 2014;12(10):1678–1686.
   Google Scholar
• Rajapakse N, Jung WK, Mendis E, et al. A novel anticoagulant purified from fish protein hydrolysate inhibits factor XIIa and platelet aggregation. Life Sci. 2005;76(22):2607–2619.
   PubMed Web of Science ®Google Scholar
• Krupka J, May F, Weimer T, et al. The coagulation factor XIIa Inhibitor rHA-Infestin-4 improves outcome after cerebral ischemia/reperfusion injury in rats. PLoS One. 2016;11(1):e0146783.
   PubMed Web of Science ®Google Scholar
• Ulmer JS, Lindquist RN, Dennis MS, et al. Ecotin is a potent inhibitor of the contact system proteases factor XIIa and plasma kallikrein. FEBS Lett. 1995;365(2–3):159–163.
   PubMed Web of Science ®Google Scholar
• Hackeng TM, Suijlen DPL, Hemker HC, et al.; Maastricht University. Netherlands. Thermostable inhibitors of activation of the blood clotting system through contact with foreign surfaces. WO2013028069. 2013.
   Google Scholar
• Heitz A, Hernandez JF, Gagnon J, et al. Solution structure of the squash trypsin inhibitor MCoTI-II. A new family for cyclic knottins. Biochemistry. 2001;40(27):7973–7983.
   PubMed Web of Science ®Google Scholar
• Heinis C, Baeriswyl V, Middendorp S, et al. Ecole Polytechnique Fédérale De Lausanne (EPFL). Switzerland. Novel inhibitors of the enzyme activated factor XII (FXIIa). WO2016174103. 2016.
   Google Scholar
• Baeriswyl V, Calzavarini S, Chen S, et al. A synthetic factor XIIa inhibitor blocks selectively intrinsic coagulation initiation. ACS Chem Biol. 2015;10(8):1861–1870.
   Web of Science ®Google Scholar
• Rimphanitchayakit V, Tassanakajon A. Structure and function of invertebrate Kazal-type serine proteinase inhibitors. Dev Comp Immunol. 2010;34(4):377–386.
   PubMed Web of Science ®Google Scholar
• Campos IT, Amino R, Sampaio CA, et al. Infestin, a thrombin inhibitor presents in Triatoma infestans midgut, a Chagas’ disease vector: gene cloning, expression and characterization of the inhibitor. Insect Biochem Mol Biol. 2002;32(9):991–997.
   PubMed Web of Science ®Google Scholar
• Campos IT, Souza TA, Torquato RJ, et al. The Kazal-type inhibitors infestins 1 and 4 differ in specificity but are similar in three-dimensional structure. Acta Crystallogr D Biol Crystallogr. 2012;68(6):695–702.
   PubMedGoogle Scholar
• Campos IT, Tanaka-Azevedo AM, Tanaka AS. Identification and characterization of a novel factor XIIa inhibitor in the hematophagous insect, Triatoma infestans (Hemiptera: reduviidae). FEBS Lett. 2004;577(3):512–516.
   PubMed Web of Science ®Google Scholar
• Pathak M, Manna R, Li C, et al. Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics. Acta Crystallogr D Struct Biol. 2019;75(6):578–591.
   PubMedGoogle Scholar
• Schulte S, Kronthaler U, Schmidbauer S, et al., CSL Behring GmbH. Germany. Therapeutic application of kazal-type serine protease inhibitors. WO2008098720. 2008.
   Google Scholar
• Hagedorn I, Schmidbauer S, Pleines I, et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation. 2010;121(13):1510–1517.
   PubMed Web of Science ®Google Scholar
• May F, Krupka J, Fries M, et al. FXIIa inhibitor rHA-Infestin-4: safe thromboprotection in experimental venous, arterial and foreign surface-induced thrombosis. Br J Haematol. 2016;173(5):769–778.
   PubMed Web of Science ®Google Scholar
• Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood. 2008;112(9):3555–3562.
   PubMed Web of Science ®Google Scholar
• Hopp S, Nolte MW, Stetter C, et al. Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa. J Neuroinflammation. 2017;14(1):39.
   PubMedGoogle Scholar
• Zeitler S, Nolte M, Schulte S, et al.; CSL Behring GmbH; U.S. Factor XII inhibitors for the administration with medical procedures comprising contact with artificial surfaces. WO2012120128. 2012.
   Google Scholar
• Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood1990;76(9):1680–1697.
   Google Scholar
• Kolyadko VN, Lushchekina SV, Vuimo TA, et al. New Infestin-4 mutants with increased selectivity against factor XIIa. PLoS One. 2015;10(12):e0144940.
   PubMed Web of Science ®Google Scholar
• Kolyadko VN, Ataullakhanov FI, Panteleev MA, et al.; HemaCore LLC. Russian Federation. High-selectivity contact activation inhibitor based on infestin-4. WO2015080629. 2015.
   Google Scholar
• Vorobev II, Orlova NA, Koljadko VN; HemaCore LLC. Russian Federation. Fused protein of thioredoxin and infestin 4 domain, method for preparing it, expression plasmid DNA coding fused protein, and bacterium Escherichia Coli transformed by this plasmid DNA. RU2528251. 2014.
   Google Scholar
• Meuth S, Goebel K, Kleinschnitz C, et al., CSL Ltd, CSL Behring GmbH, Julius-Maximilians-Universitaet Wuerzburg and Westfaelische Wilhelms Universitaet Muenster; U.S. Factor XII inhibitors for the treatment of neurological inflammatory disorders. WO2013113774. 2013.
   Google Scholar
• Decrem Y, Rath G, Blasioli V, et al. Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis. J Exp Med. 2009;206(11):2381–2395.
   PubMed Web of Science ®Google Scholar
• Louahed J, Ruti B, Louahed J, et al. Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding. Am J Trop Med Hyg. 2002;66(3):225–233.
   PubMed Web of Science ®Google Scholar
• Godfroid E,DY, Vanhamme L, Bollen A, et al. Identification and molecular characterisation of proteins, expressed in the ixodes ricinus salivary glands. US20080219970A1. 2008.
   Google Scholar
• Pireaux V, Tassignon J, Demoulin S, et al. Anticoagulation with an inhibitor of factors XIa and XIIa during cardiopulmonary bypass. J Am Coll Cardiol. 2019;74(17):2178–2189.
   PubMed Web of Science ®Google Scholar
• A study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of Ir-CPI in healthy male subjects. [cited 2021 Feb 9]. Available from: https://ClinicalTrials.gov/show/NCT04653766
   Google Scholar
• de Maat S, Sanrattana W, Mailer RK, et al. Design and characterization of alpha1-antitrypsin variants for treatment of contact system-driven thromboinflammation. Blood. 2019;134(19):1658–1669.
   Web of Science ®Google Scholar
• Maas C, de Maat S; UMC Utrecht Holding B.V. Netherlands. Modified serpins for the treatment of bradykinin-mediated disease. WO2018154044. 2018.
   Google Scholar
• Heestermans M, van Vlijmen BJM. Oligonucleotides targeting coagulation factor mRNAs: use in thrombosis and hemophilia research and therapy. Thromb J. 2017;15(1):7.
   PubMedGoogle Scholar
• Tatiparti K, Sau S, Kashaw SK, et al. siRNA delivery strategies: a comprehensive review of recent developments. Nanomaterials (Basel). 2017;7(4):7.
   Google Scholar
• Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19:673–694.
   PubMed Web of Science ®Google Scholar
• Monia BP, Macleod RA, Crosby JR ISIS Pharmaceuticals Inc. USA. Methods for modulating factor 12 expression. WO2012064758. 2012.
   Google Scholar
• Kanner SB, Lewis DL, Wakefield DH, et al.; Arrowhead Research Corp. USA. Compositions and methods for inhibiting gene expression of factor XII. WO2016149331. 2016.
   Google Scholar
• Rozema DB, Lewis DL, Wakefield DH, et al. Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc Natl Acad Sci U S A. 2007;104(32):12982–12987.
   PubMed Web of Science ®Google Scholar
• Arrowhead Pharmaceuticals. Progress in RNAi-based Therapeutics at Arrowhead Pharmaceuticals. [cited 2021 Feb 4]. Available from: https://ir.arrowheadpharma.com/static-files/2be69c62-184c-4024-bde6-c0caf127cdf8
   Google Scholar
• Arrowhead Pharmaceuticals. Arrowhead Pharmaceuticals, Pipeline. [cited 2021 Feb 9]. Available from: https://arrowheadpharma.com/pipeline/
   Google Scholar
• Huang Y. Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics. Mol Ther Nucleic Acids. 2017;6:116–132.
   PubMedGoogle Scholar
• Melquist S, Wakefield D, Hamilton H, et al. Targeting Factor 12 (F12) with a novel RNAi delivery platform as a prophylactic treatment for Hereditary Angioedema (HAE). J Allergy Clin Immunol. 2016;137(2):AB251.
   Web of Science ®Google Scholar
• Akinc A, Hinkle G, Maier M, et al.; Alnylam Pharmaceuticals Inc. USA. Factor XII (Hageman factor) (F12), kallikrein B, plasma (Fletcher factor) 1 (KLKB1), and Kininogen 1 (KNG1) iRNA compositions and methods of use thereof. WO2016179342. 2016.
   Google Scholar
• Liu J, Cooley BC, Akinc A, et al. Knockdown of liver-derived factor XII by GalNAc-siRNA ALN-F12 prevents thrombosis in mice without impacting hemostatic function. Thromb Res. 2020;196:200–205. .
   PubMed Web of Science ®Google Scholar
• Alnylam Pharmaceuticals. Early Stage RNAi therapeutics pipeline. [cited 2021 Feb 9]. Available from: https://www.alnylam.com/wp-content/uploads/2020/07/RNAi-Roundtable_Early-Pipeline_FINAL_07172020.pdf
   Google Scholar
• Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–497.
   PubMed Web of Science ®Google Scholar
• Pixley RA, Colman RW; Temple University. USA. Monoclonal antibodies to the light chain region of human factor XII and methods of preparing and using the same. WO1989011865. 1989.
   Google Scholar
• Esnouf MP, Coagen Ltd GB Blood-coagulation factor XIIa beta monoclonal antibody and immunoassay. WO9008835. 1990.
   Google Scholar
• Nuijens JH, Huijbregtsc CCM, Hack CE; Cetus Corp. USA. Inhibitors of factor XII activation and applications thereof. WO1991017258. 1991.
   Google Scholar
• Esnouf MP, Burgess AI, Dodds AW, et al. A monoclonal antibody raised against human β-factor XIIa which also recognizes α-factor XIIa but not Factor XII or complexes of factor XIIa with C1 esterase inhibitor. Thromb Haemost. 2000;83(6):874–881.
   PubMed Web of Science ®Google Scholar
• Panousis C, Rayzman V, Nash A, et al.; Behring Gmbh. Germany. Inhibitory anti-factor XII/XIIa monoclonal antibodies and their uses. WO2013014092. 2013.
   Google Scholar
• Gruber A, Gailani D, Leung P, et al.; Vanderbilt University, Aronora Inc., Oregon Health & Science University. USA. Antibodies against factor XII and uses thereof. WO2014089493. 2014.
   Google Scholar
• Matafonov A, Gailani AE, Grach SL, et al. Antibodies to human factor XII with antithrombotic properties. Blood. 2012;120(21):1106.
   Google Scholar
• Wygrecka M, Nolte M, Panousis C; Csl Limited. Australia. Use of a FXIIa-inhibitor in the treatment of renal fibrosis and/or chronic kidney disease. WO2019113642. 2019.
   Google Scholar
• A study to investigate CSL312 in subjects with hereditary angioedema (HAE). [cited 2021 Feb 9]. Available from: https://ClinicalTrials.gov/show/NCT03712228
   Google Scholar
• CSL Behring. CSL behring presents results for garadacimab as preventive treatment in hereditary angioedema. [cited 2021 Jan 29]. Available from: https://www.cslbehring.com/newsroom/2020/eaaci-2020-garadacimab-data
   Google Scholar
• A clinical study to test the efficacy and safety of CSL312 on catheter-associated blood clot formation in subjects with cancer who receive chemotherapy through a PICC Line. [cited 2021 Feb 9]. Available from: https://ClinicalTrials.gov/show/NCT04281524
   Google Scholar
• Treatment With CSL312 in adults with coronavirus disease 2019 (COVID-19). [cited 2021 Feb 9]. Available from: https://ClinicalTrials.gov/show/NCT04409509
   Google Scholar
• Mason S, Kenniston JA, Nixon A, et al.; Dyax Corp. USA. A monoclonal antibody inhibitor of factor XIIa. WO2017015431. 2017.
   Google Scholar
• Mason SD, Kenniston J, Comeau SR, et al. Discovery and characterization of a highly specific antibody inhibitor of factor XIIa, and the subsequent generation of a factor XIIa/plasma kallikrein bispecific antibody. Blood. 2015;126(23):2268.
   Web of Science ®Google Scholar
• Sexton DJ, Dyax Corp. USA. Plasma kallikrein binding proteins. WO2012094587. 2012.
   Google Scholar
• Comeau SR, Nixon A, Kastrapeli N, et al. Dyax Corp. USA. Bispecific antibodies against plasma kallikrein and factor XII. WO2016109774. 2016.
   Google Scholar
• Jamsa A, Spronk HMH, Govers-Riemslag JWP, et al. An essential role of factor XI-feedback activation for hemostasis in embryonic development. J Thromb Haemost. 2013;11:128.
   Web of Science ®Google Scholar
• Pedicord DL, Seiffert D, Blat Y. Feedback activation of factor XI by thrombin does not occur in plasma. Proc Natl Acad Sci U S A. 2007;104(31):12855–12860.
   PubMed Web of Science ®Google Scholar
• Spronk HMH, Wilhelm S, Van Oerle R, et al. Feedback activation of factor XI by thrombin is essential for hemostasis in Vivo. Blood. 2009;114(22):838.
   Web of Science ®Google Scholar
• Tillman B, Gailani D. Inhibition of Factors XI and XII for prevention of thrombosis induced by artificial surfaces. Semin Thromb Hemost. 2018;44(1):60–69.
   PubMed Web of Science ®Google Scholar
• Lu RM, Hwang YC, Liu IJ, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27(1):1–30.
   Web of Science ®Google Scholar
• Hernandez I, Bott SW, Patel AS, et al. Pricing of monoclonal antibody therapies: higher if used for cancer? Am J Manag Care. 2018;24(2):109–112.
   PubMed Web of Science ®Google Scholar
• Sivaraja M, Pozzi N, Rienzo M, et al. Reversible covalent direct thrombin inhibitors. PLoS One. 2018;13(8):e0201377.
   PubMed Web of Science ®Google Scholar
• Sivaraja M, Clemens DM, Sizikov S, et al. VE-1902—A direct thrombin inhibitor with reversible covalent mechanism of action shows efficacy with reduced bleeding in rodent models of thrombosis. Thromb Res. 2020;190:112–121.
   PubMed Web of Science ®Google Scholar
• Datta A, Xu CP, Clemens D, et al. An improved potent direct thrombin inhibitor shows efficacy with low bleeding risk. Circulation. 2017;136:A19503.
   Web of Science ®Google Scholar