Allergy Asthma Immunol Res.  2019 Mar;11(2):291-298. 10.4168/aair.2019.11.2.291.

Higher Binding Affinity and In Vitro Potency of Reslizumab for Interleukin-5 Compared With Mepolizumab

Affiliations
  • 1R&D, Biologics Lead Antibody Discovery, Teva Pharmaceuticals Australia, Sydney, NSW, Australia. mark.liddament@tevapharm.com
  • 2R&D, Biologics, Teva Pharmaceuticals USA, West Chester, PA, USA.

Abstract

Reslizumab and mepolizumab are recently approved monoclonal antibodies for the treatment of severe (uncontrolled) eosinophilic asthma. Both are effective in neutralizing the function of interleukin-5 (IL-5). This study is the first to compare the binding affinity and in vitro potency of both antibodies in head-to-head assays. Two assays assessed binding affinity (using the equilibrium dissociation constant [K(D)]) of each drug for human IL-5. In the Biacore surface plasmon resonance assay, the association constant (k(on)) values for human IL-5 for reslizumab and mepolizumab were 3.93 × 10⁶ and 1.83 × 10⁵, respectively. The dissociation constant (k(off)) values were 4.29 × 10⁻⁴ and 2.14 × 10⁻⁴, respectively. Calculated K(D) values for human IL-5 for reslizumab and mepolizumab were 109 and 1,170 pM, respectively, representing an approximately 11-fold stronger binding affinity with reslizumab. In the Kinetic Exclusion Assay, the k(on) values for human IL-5 for reslizumab and mepolizumab were 3.17 × 10⁶ and 1.32 × 10⁵, respectively. The k(off) values were 1.36 × 10⁻⁵ and 1.48 × 10⁻⁵, respectively. Measured K(D) values for human IL-5 for reslizumab and mepolizumab were 4.3 and 112 pM, respectively, representing an approximately 26-fold stronger binding affinity for reslizumab. A human-IL-5-dependent cell proliferation assay was developed to assess in vitro potency, based on a human cell line selected for enhanced surface expression of IL-5 receptor-alpha and consistent proliferation response to IL-5. The concentration at which 50% inhibition occurred (IC₅₀) was determined for both antibodies. Reslizumab and mepolizumab inhibited IL-5-dependent cell proliferation, with IC₅₀ values of approximately 91.1 and 286.5 pM, respectively, representing on average 3.1-fold higher potency with reslizumab. In conclusion, comparative assays show that reslizumab has higher affinity binding for and in vitro potency against human IL-5 compared with mepolizumab. However, these results do not take into consideration the different methods of administration of reslizumab and mepolizumab.

Keyword

Reslizumab; mepolizumab; antibody affinity; interleukin-5; drug evaluation, preclinical

MeSH Terms

Antibodies
Antibodies, Monoclonal
Antibody Affinity
Asthma
Cell Line
Cell Proliferation
Drug Evaluation, Preclinical
Eosinophils
Humans
In Vitro Techniques*
Interleukin-5*
Surface Plasmon Resonance
Antibodies
Antibodies, Monoclonal
Interleukin-5

Figure

  • Figure Inhibition of IL-5-induced proliferation by reslizumab and mepolizumab in the presence of 45 pM human IL-5. Two independent experimental replicates were made for each antibody and the fits for the calculated IC50 values showed high R2 values (> 0.99) in each replicate, indicating high confidence. Data shown for the dose-response curves were from a single representative experiment. IC50, concentration at which 50% inhibition occurred; IL-5, interleukin-5.


Cited by  1 articles

Update on the Management of Nonsteroidal Anti-Inflammatory Drug Hypersensitivity
Wan Yin Winnie Yeung, Hae Sim Park
Yonsei Med J. 2020;61(1):4-14.    doi: 10.3349/ymj.2020.61.1.4.


Reference

1. Aleman F, Lim HF, Nair P. Eosinophilic endotype of asthma. Immunol Allergy Clin North Am. 2016; 36:559–568.
Article
2. Zeiger RS, Schatz M, Li Q, Chen W, Khatry DB, Gossage D, et al. High blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. J Allergy Clin Immunol Pract. 2014; 2:741–750.
Article
3. Ulrik CS. Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma. Clin Exp Allergy. 1995; 25:820–827.
Article
4. Yamaguchi Y, Suda T, Suda J, Eguchi M, Miura Y, Harada N, et al. Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors. J Exp Med. 1988; 167:43–56.
Article
5. Warringa RA, Schweizer RC, Maikoe T, Kuijper PH, Bruijnzeel PL, Koendermann L. Modulation of eosinophil chemotaxis by interleukin-5. Am J Respir Cell Mol Biol. 1992; 7:631–636.
Article
6. Carlson M, Peterson C, Venge P. The influence of IL-3, IL-5, and GM-CSF on normal human eosinophil and neutrophil C3b-induced degranulation. Allergy. 1993; 48:437–442.
7. Kips JC, O'Connor BJ, Langley SJ, Woodcock A, Kerstjens HA, Postma DS, et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med. 2003; 167:1655–1659.
8. Smith DA, Minthorn EA, Beerahee M. Pharmacokinetics and pharmacodynamics of mepolizumab, an anti-interleukin-5 monoclonal antibody. Clin Pharmacokinet. 2011; 50:215–227.
Article
9. Teva Respiratory, LLC (US). CINQAIR®: highlights of prescribing information [Internet]. Frazer (PA): Teva Respiratory, LLC;2016. cited 2017 Oct 26. Available from: http://cinqair.com/pdf/PrescribingInformation.pdf.
10. GlaxoSmithKline. NUCALA: highlights of prescribing information [Internet]. Philadelphia (PA): GlaxoSmithKline;2017. cited 2018 Apr 5. Available from: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Nucala/pdf/NUCALA-PI-PIL.PDF.
11. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015; 3:355–366.
Article
12. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009; 360:973–984.
Article
13. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380:651–659.
Article
14. Cabon Y, Molinari N, Marin G, Vachier I, Gamez AS, Chanez P, et al. Comparison of anti-interleukin-5 therapies in patients with severe asthma: global and indirect meta-analyses of randomized placebo-controlled trials. Clin Exp Allergy. 2017; 47:129–138.
Article
15. Drake AW, Tang ML, Papalia GA, Landes G, Haak-Frendscho M, Klakamp SL. Biacore surface matrix effects on the binding kinetics and affinity of an antigen/antibody complex. Anal Biochem. 2012; 429:58–69.
Article
16. Jaworowicz D, Fiedler-Kelly J, Rabinovich-Guilatt L, Bond M. The steady-state pharmacokinetic (pk) profile across a range of patient body weight categories supports weight-based dosing for intravenous (iv) reslizumab. Am J Respir Crit Care Med. 2016; 193:A1389.
17. Alexander AG, Barkans J, Moqbel R, Barnes NC, Kay AB, Corrigan CJ. Serum interleukin 5 concentrations in atopic and non-atopic patients with glucocorticoid-dependent chronic severe asthma. Thorax. 1994; 49:1231–1233.
Article
18. Huang CD, Wang CH, Liu CY, Lin SM, Chou CL, Liu WT, et al. Eosinophils from asthmatics release IL-5 in an autocrine fashion to prevent apoptosis through upregulation of Bcl-2 expression. J Asthma. 2005; 42:395–403.
Article
19. Bates JT, Keefer CJ, Utley TJ, Correia BE, Schief WR, Crowe JE Jr. Reversion of somatic mutations of the respiratory syncytial virus-specific human monoclonal antibody Fab19 reveal a direct relationship between association rate and neutralizing potency. J Immunol. 2013; 190:3732–3739.
Article
20. European Medicines Agency. ICH topic Q 6 B. Specifications: test procedures and acceptance criteria for biotechnological/biological products [Internet]. London: European Medicines Agency;1999. cited 2018 Apr 11. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002824.pdf.
21. Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016; 150:789–798.
22. Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016; 150:799–810.
23. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371:1198–1207.
Article
Full Text Links
  • AAIR
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr