2. Academic Validation
  3. Elarekibep (PRS-060/AZD1402): a new class of inhaled Anticalin medicine targeting IL-4Ra for T2 endotype asthma

Elarekibep (PRS-060/AZD1402): a new class of inhaled Anticalin medicine targeting IL-4Ra for T2 endotype asthma

  • J Allergy Clin Immunol. 2022 Dec 30;S0091-6749(22)02588-X. doi: 10.1016/j.jaci.2022.12.815.
Gabriele Matschiner 1,  Mary F Fitzgerald 2,  Ulrich Moebius 2,  Andreas M Hohlbaum 2,  Hendrik Gille 2,  Kristian Jensen 2,  Klaus Kirchfeld 2,  Barbara Rattenstetter 2,  Alice Laforge 2,  Rachida S Bel Aiba 2,  Joe Ciccotosto 3,  Hong Nyugen 3,  Martyn I Foster 4,  John N Snouwaert 5,  MyTrang Nguyen 5,  Beverly H Koller 5,  Louis Matis 6,  Gary P Anderson 7,  Shane A Olwill 2
Affiliations

Affiliations

  • 1 Pieris Pharmaceuticals GmbH, Zeppelinstrasse 3, 85399 Hallbergmoos - Germany; Corresponding Author: Dr Gabriele Matschiner PhD; Zeppelinstrasse 3, 85399 Hallbergmoos, Germany, Phone +4916097819624. Email: [email protected].
  • 2 Pieris Pharmaceuticals GmbH, Zeppelinstrasse 3, 85399 Hallbergmoos - Germany.
  • 3 Lung Health Research Centre, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville 3010 VIC, Australia.
  • 4 Experimental Pathology Consultancy, 45 Hope Road, Benfleet, Essex SS7 5 JQ.
  • 5 University of North Carolina, 120 Mason Farm Road, 5073 Genetic Medicine Building, CB# 7264 Chapel Hill - North Carolina.
  • 6 Pieris Pharmaceuticals, Inc. 255 State Street, Boston, MA 02109, USA.
  • 7 Lung Health Research Centre, Department of Biochemistry and Pharmacology, University of Melbourne, Parkville 3010 VIC, Australia. Electronic address: [email protected].
PMID: 36592703 DOI: 10.1016/j.jaci.2022.12.815
Abstract

Background: T2 endotype asthma is driven by IL-4 and IL-13 signaling via IL-4Ra, which is highly expressed on airway epithelium, airway smooth muscle and immunocytes in the respiratory mucosa, suggesting potential advantages of an inhalable antagonist. Lipocalin 1 (Lcn1), a 16kD protein abundant in human periciliary fluid, has a robust drug-like structure well-suited to protein engineering, but has never been used to make an inhaled "Anticalin" protein therapeutic.

Objectives: To re-engineer Lcn1 into an inhalable IL-4Ra antagonist and assess its pharmacodynamic/kinetic profile.

Methods: Lcn1 was systematically modified by directed protein mutagenesis yielding a high affinity, slowly dissociating, long-acting full antagonist of IL-4Ra designated 'PRS-060' with properties analogous to dupilumab, competitively antagonizing IL-4Ra dependent cell proliferation, mucus induction and eotaxin expression in vitro. As PRS-060 displayed exquisite specificity for human IL-4Ra, with no cross-reactivity to rodents or higher primates, we created a new triple-humanized mouse model substituting hIL-4Ra, hIL-4, and hIL-13 at their correct syntenic murine loci to model clinical dosing.

Results: Inhaled PRS-060 strongly suppressed acute allergic inflammation indices in triple humanized mice with a duration of action longer than its bulk clearance suggesting it may act locally in the lung.

Conclusion: Lcn1 can be re-engineered into the Anticalin antagonist PRS-060, exemplifying a new class of inhaled topical, long-acting therapeutic with potential to treat T2 endotype asthma.

Keywords

Anticalin protein therapeutic; T2 endotype asthma; inhaled IL-4Ra antagonist; topical.

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