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
  • 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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