SKY59, A Novel Recycling Antibody for Complement-mediated Diseases

Author(s): Taku Fukuzawa, Junichi Nezu*

Journal Name: Current Medicinal Chemistry

Volume 27 , Issue 25 , 2020

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Background: The complement system usually helps protect against microbial infection, but it could also be involved in the onset of various diseases. Inhibition of complement component 5 (C5) with eculizumab has resulted in a significant reduction of hemolysis, reduction of thromboembolic events, and increased survival in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). However, eculizumab requires frequent intravenous infusions due to the abundance of C5 in plasma and some patients may still experience breakthrough hemolysis. This review introduces the recent body of knowledge on recycling technology and discusses the likely therapeutic benefits of SKY59, a novel recycling antibody, for PNH and complement-mediated disorders.

Methods: By using recycling technology, we created a novel anti-C5 antibody, SKY59, capable of binding to C5 pH-dependently.

Results: In cynomolgus monkeys, SKY59 robustly inhibited C5 and complement activity for significantly longer than a conventional antibody. SKY59 also showed an inhibitory effect on C5 variant p.Arg885His, whereas eculizumab does not suppress complement activity in patients with this type of mutation.

Conclusion: SKY59 is a promising anti-C5 biologic agent that has significant advantages over current therapies such as long duration of action and efficacy against C5 variants.

Keywords: Recycling technology, antibody therapeutics, pharmacokinetics, complement system, C5, paroxysmal nocturnal hemoglobinuria.

Serruto, D.; Rappuoli, R.; Scarselli, M.; Gros, P.; van Strijp, J.A. Molecular mechanisms of complement evasion: learning from staphylococci and meningococci. Nat. Rev. Microbiol., 2010, 8(6), 393-399.
[] [PMID: 20467445]
Holers, V.M. Complement and its receptors: new insights into human disease. Annu. Rev. Immunol., 2014, 32, 433-459.
[] [PMID: 24499275]
Merle, N.S.; Church, S.E.; Fremeaux-Bacchi, V.; Roumenina, L.T. Complement system part I - molecular mechanisms of activation and regulation. Front. Immunol., 2015, 6, 262.
[] [PMID: 26082779]
Hill, A.; DeZern, A.E.; Kinoshita, T.; Brodsky, R.A. Paroxysmal nocturnal haemoglobinuria. Nat. Rev. Dis. Primers, 2017, 3, 17028.
[] [PMID: 28516949]
Jokiranta, T.S. HUS and atypical HUS. Blood, 2017, 129(21), 2847-2856.
[] [PMID: 28416508]
Sharma, V.R. Paroxysmal nocturnal hemoglobinuria: pathogenesis, testing, and diagnosis. . Clinical advances in hematology & oncology: H&O, 2013, 11(Suppl)13(9), 2-8.
Hillmen, P.; Young, N.S.; Schubert, J.; Brodsky, R.A.; Socié, G.; Muus, P.; Röth, A.; Szer, J.; Elebute, M.O.; Nakamura, R.; Browne, P.; Risitano, A.M.; Hill, A.; Schrezenmeier, H.; Fu, C.L.; Maciejewski, J.; Rollins, S.A.; Mojcik, C.F.; Rother, R.P.; Luzzatto, L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med., 2006, 355(12), 1233-1243.
[] [PMID: 16990386]
Zuber, J.; Fakhouri, F.; Roumenina, L.T.; Loirat, C.; Frémeaux-Bacchi, V. French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat. Rev. Nephrol., 2012, 8(11), 643-657.
[] [PMID: 23026949]
Igawa, T.; Ishii, S.; Tachibana, T.; Maeda, A.; Higuchi, Y.; Shimaoka, S.; Moriyama, C.; Watanabe, T.; Takubo, R.; Doi, Y.; Wakabayashi, T.; Hayasaka, A.; Kadono, S.; Miyazaki, T.; Haraya, K.; Sekimori, Y.; Kojima, T.; Nabuchi, Y.; Aso, Y.; Kawabe, Y.; Hattori, K. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat. Biotechnol., 2010, 28(11), 1203-1207.
[] [PMID: 20953198]
Henne, K.R.; Ason, B.; Howard, M.; Wang, W.; Sun, J.; Higbee, J.; Tang, J.; Matsuda, K.C.; Xu, R.; Zhou, L.; Chan, J.C.; King, C.; Piper, D.E.; Ketchem, R.R.; Michaels, M.L.; Jackson, S.M.; Retter, M.W. Anti-PCSK9 antibody pharmacokinetics and low-density lipoprotein-cholesterol pharmacodynamics in nonhuman primates are antigen affinity-dependent and exhibit limited sensitivity to neonatal Fc receptor-binding enhancement. J. Pharmacol. Exp. Ther., 2015, 353(1), 119-131.
[] [PMID: 25653417]
Lammerts van Bueren, J.J.; Bleeker, W.K.; Bøgh, H.O.; Houtkamp, M.; Schuurman, J.; van de Winkel, J.G.; Parren, P.W. Effect of target dynamics on pharmacokinetics of a novel therapeutic antibody against the epidermal growth factor receptor: implications for the mechanisms of action. Cancer Res., 2006, 66(15), 7630-7638.
[] [PMID: 16885363]
Cosson, V.F.; Ng, V.W.; Lehle, M.; Lum, B.L. Population pharmacokinetics and exposure-response analyses of trastuzumab in patients with advanced gastric or gastroesophageal junction cancer. Cancer Chemother. Pharmacol., 2014, 73(4), 737-747.
[] [PMID: 24519752]
Okimura, K.; Maeta, K.; Kobayashi, N.; Goto, M.; Kano, N.; Ishihara, T.; Ishikawa, T.; Tsumura, H.; Ueno, A.; Miyao, Y.; Sakuma, S.; Kinugasa, F.; Takahashi, N.; Miura, T. Characterization of ASKP1240, a fully human antibody targeting human CD40 with potent immunosuppressive effects. Am. J. Transplant., 2014, 14(6), 1290-1299.
[] [PMID: 24731050]
Martin, P.L.; Cornacoff, J.; Prabhakar, U.; Lohr, T.; Treacy, G.; Sutherland, J.E.; Hersey, S.; Martin, E. Reviews preclinical safety and immune-modulating effects of therapeutic monoclonal antibodies to interleukin-6 and tumor necrosis factor-alpha in Cynomolgus macaques. J. Immunotoxicol., 2005, 1(3), 131-139.
[] [PMID: 18958646]
Haringman, J.J.; Gerlag, D.M.; Smeets, T.J.; Baeten, D.; van den Bosch, F.; Bresnihan, B.; Breedveld, F.C.; Dinant, H.J.; Legay, F.; Gram, H.; Loetscher, P.; Schmouder, R.; Woodworth, T.; Tak, P.P. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum., 2006, 54(8), 2387-2392.
[] [PMID: 16869001]
Byrd, J.C.; O’Brien, S.; Flinn, I.W.; Kipps, T.J.; Weiss, M.; Rai, K.; Lin, T.S.; Woodworth, J.; Wynne, D.; Reid, J.; Molina, A.; Leigh, B.; Harris, S. Phase 1 study of lumiliximab with detailed pharmacokinetic and pharmacodynamic measurements in patients with relapsed or refractory chronic lymphocytic leukemia. Clin. Cancer Res., 2007, 13(15 Pt 1), 4448-4455.
Xiao, J.J.; Krzyzanski, W.; Wang, Y.M.; Li, H.; Rose, M.J.; Ma, M.; Wu, Y.; Hinkle, B.; Perez-Ruixo, J.J. Pharmacokinetics of anti-hepcidin monoclonal antibody Ab 12B9m and hepcidin in cynomolgus monkeys. AAPS J., 2010, 12(4), 646-657.
[] [PMID: 20737261]
Jayson, G.C.; Mulatero, C.; Ranson, M.; Zweit, J.; Jackson, A.; Broughton, L.; Wagstaff, J.; Hakansson, L.; Groenewegen, G.; Lawrance, J.; Tang, M.; Wauk, L.; Levitt, D.; Marreaud, S.; Lehmann, F.F.; Herold, M.; Zwierzina, H. European Organisation for Research and Treatment of Cancer (EORTC). Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer. Eur. J. Cancer, 2005, 41(4), 555-563.
[] [PMID: 15737560]
Finkelman, F.D.; Madden, K.B.; Morris, S.C.; Holmes, J.M.; Boiani, N.; Katona, I.M.; Maliszewski, C.R. Anti-cytokine antibodies as carrier proteins. Prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes. J. Immunol., 1993, 151(3), 1235-1244.
[PMID: 8393043]
Rathanaswami, P.; Roalstad, S.; Roskos, L.; Su, Q.J.; Lackie, S.; Babcook, J. Demonstration of an in vivo generated sub-picomolar affinity fully human monoclonal antibody to interleukin-8. Biochem. Biophys. Res. Commun., 2005, 334(4), 1004-1013.
[] [PMID: 16038881]
Bradbury, A.R.; Sidhu, S.; Dübel, S.; McCafferty, J. Beyond natural antibodies: the power of in vitro display technologies. Nat. Biotechnol., 2011, 29(3), 245-254.
[] [PMID: 21390033]
Dall’Acqua, W.F.; Kiener, P.A.; Wu, H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J. Biol. Chem., 2006, 281(33), 23514-23524.
[] [PMID: 16793771]
Mircic, M.; Kavanaugh, A. The clinical efficacy of tocilizumab in rheumatoid arthritis. Drugs Today (Barc), 2009, 45(3), 189-197.
[] [PMID: 19436841]
Ghetie, V.; Ward, E.S. Multiple roles for the major histocompatibility complex class I- related receptor FcRn. Annu. Rev. Immunol., 2000, 18, 739-766.
[] [PMID: 10837074]
Yeung, Y.A.; Leabman, M.K.; Marvin, J.S.; Qiu, J.; Adams, C.W.; Lien, S.; Starovasnik, M.A.; Lowman, H.B. Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J. Immunol., 2009, 182(12), 7663-7671.
[] [PMID: 19494290]
Zalevsky, J.; Chamberlain, A.K.; Horton, H.M.; Karki, S.; Leung, I.W.; Sproule, T.J.; Lazar, G.A.; Roopenian, D.C.; Desjarlais, J.R. Enhanced antibody half-life improves in vivo activity. Nat. Biotechnol., 2010, 28(2), 157-159.
[] [PMID: 20081867]
Robbie, G.J.; Criste, R.; Dall’acqua, W.F.; Jensen, K.; Patel, N.K.; Losonsky, G.A.; Griffin, M.P. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob. Agents Chemother., 2013, 57(12), 6147-6153.
[] [PMID: 24080653]
Fukuzawa, T.; Sampei, Z.; Haraya, K.; Ruike, Y.; Shida-Kawazoe, M.; Shimizu, Y.; Gan, S.W.; Irie, M.; Tsuboi, Y.; Tai, H.; Sakiyama, T.; Sakamoto, A.; Ishii, S.; Maeda, A.; Iwayanagi, Y.; Shibahara, N.; Shibuya, M.; Nakamura, G.; Nambu, T.; Hayasaka, A.; Mimoto, F.; Okura, Y.; Hori, Y.; Habu, K.; Wada, M.; Miura, T.; Tachibana, T.; Honda, K.; Tsunoda, H.; Kitazawa, T.; Kawabe, Y.; Igawa, T.; Hattori, K.; Nezu, J. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci. Rep., 2017, 7(1), 1080.
[] [PMID: 28439081]
Davda, J.P.; Hansen, R.J. Properties of a general PK/PD model of antibody-ligand interactions for therapeutic antibodies that bind to soluble endogenous targets. MAbs, 2010, 2(5), 576-588.
[] [PMID: 20676036]
Wang, W.; Wang, X.; Doddareddy, R.; Fink, D.; McIntosh, T.; Davis, H.M.; Zhou, H. Mechanistic pharmacokinetic/target engagement/pharmacodynamics (PK/TE/PD) modeling in deciphering interplay between a monoclonal antibody and its soluble target in cynomolgus monkeys. AAPS J., 2014, 16(1), 129-139.
[] [PMID: 24287601]
Sissons, J.G.; Liebowitch, J.; Amos, N.; Peters, D.K. Metabolism of the fifth component of complement, and its relation to metabolism of the third component, in patients with complement activation. J. Clin. Invest., 1977, 59(4), 704-715.
[] [PMID: 845257]
Morgan, B.P.; Harris, C.L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov., 2015, 14(12), 857-877.
[] [PMID: 26493766]
Gatault, P.; Brachet, G.; Ternant, D.; Degenne, D.; Récipon, G.; Barbet, C.; Gyan, E.; Gouilleux-Gruart, V.; Bordes, C.; Farrell, A.; Halimi, J.M.; Watier, H. Therapeutic drug monitoring of eculizumab: Rationale for an individualized dosing schedule. MAbs, 2015, 7(6), 1205-1211.
[] [PMID: 26337866]
Nishimura, J.; Yamamoto, M.; Hayashi, S.; Ohyashiki, K.; Ando, K.; Brodsky, A.L.; Noji, H.; Kitamura, K.; Eto, T.; Takahashi, T.; Masuko, M.; Matsumoto, T.; Wano, Y.; Shichishima, T.; Shibayama, H.; Hase, M.; Li, L.; Johnson, K.; Lazarowski, A.; Tamburini, P.; Inazawa, J.; Kinoshita, T.; Kanakura, Y. Genetic variants in C5 and poor response to eculizumab. N. Engl. J. Med., 2014, 370(7), 632-639.
[] [PMID: 24521109]
Langemeijer, S.; Nishimura, J-I.; Weston-Davies, W.; Nunn, A. Miles.; Kanakura, Y.; Mackie, J., Ian.; Muss, P. C5 Polymorphism in a Dutch patient with paroxysmal nocturnal hemoglobinuria (PNH) and no Asian ancestry, resistant to eculizumab, but in vitro sensitive to coversin. Blood, 2015, 126, 1209.
Schatz-Jakobsen, J.A.; Zhang, Y.; Johnson, K.; Neill, A.; Sheridan, D.; Andersen, G.R. Structural basis for eculizumab-mediated inhibition of the complement terminal pathway. J. Immunol., 2016, 197(1), 337-344.
[] [PMID: 27194791]

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Article Details

Year: 2020
Published on: 22 July, 2020
Page: [4157 - 4164]
Pages: 8
DOI: 10.2174/0929867326666191016115853
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