ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 1768

A First-in-class Selective and Potent IRAK4 Degrader Demonstrates Robust in Vitro and in Vivo Inhibition of TLR/IL-1R Activation and Inflammation

Veronica Campbell1, Joseph Kelleher 1, Jesse Chen 1, Jared Gollob 2, Nan Ji 2, Christine Klaus 2, Christine Loh 2, Michelle mayo 2, Alice McDonald 2, Haojing Rong 2, Scott Rusin 2, Kirti Sharma 2, Matt Weiss 2, Karen Yuan 2, Duncan Walker 2, Xiaozhang Zheng 2, Anthony Slavin 2 and Nello Mainolfi 2, 1Kymera Therapeutics, cambridge, MA, 2Kymera Therapeutics, Cambridge

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Autoinflammatory Disease, inflammatory cytokines and gout, interleukins (IL), Toll Like receptors

  • Tweet
  • Email
  • Print
Session Information

Date: Monday, November 11, 2019

Session Title: 4M088: Cytokines & Cell Trafficking (1764–1769)

Session Type: ACR Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: IL-1R/TLR activation plays a central role in the pathophysiology of multiple autoimmune and inflammatory diseases driven by the IL-1 family of cytokines and by TLR ligands.   Full signaling from IL-1Rs and TLRs through the Myddosome is dependent on both the kinase and scaffolding functions of Interleukin-1 receptor associated kinase 4 (IRAK4) (De Nardo et al. JBC 2018, De et al. JBC 2018). Therefore, hetero-bifunctional molecules that selectively target IRAK4 for degradation and elimination by the ubiquitin proteasome pathway have greatest potential to abrogate IL-1R/TLR signaling and shut down both the production of and response to TLR and IL-1 family cytokines.

Methods: Heterobifunctional degraders were designed to selectively target IRAK4 protein.  Degradation selectivity was assessed in relevant human PBMC population by unbiased tandem mass tag proteomics.   In vitro, PBMC flow cytometry and cytokine release assays were established to determine degradation potency (DC50) and inhibition of R848, LPS and IL-1β induced pro-inflammatory cytokines.  IRAK4 degrader was dosed orally in the mouse monosodium urate (MSU) air pouch model of gouty arthritis. In vivo, degradation was measured in mouse spleen tissues by targeted mass spectrometry.

Results: Unbiased proteomics with a depth >10,000 proteins showed exclusive degradation of IRAK4 in human PBMCs.  In vitro, selective IRAK4 degraders led to potent and greater than 90% degradation in both lymphocytes (DC50= 1.5nM) and monocytes (DC50=0.4nM).  Pre-treatment with IRAK4 degraders achieved potent single digit nanomolar inhibition of R848, LPS and IL-1β induced pro-inflammatory cytokines (TNF-α, IL-6) and chemokines (CCL3).  Importantly, IRAK4 degradation led to more effective inhibition of cytokine and chemokine induction compared to a selective IRAK4 kinase inhibitor.  Oral administration of an IRAK4 degrader in the mouse MSU air pouch model led to dose-dependent IRAK4 degradation in spleen tissue and a marked decrease in neutrophil infiltration (p=0.002 unpaired t test, two-tailed).

Conclusion: Selective and potent targeted IRAK4 degradation led to marked inhibition of both TLR- and IL-1R-mediated pro-inflammatory cytokine and chemokine production.  By removal of both scaffolding and kinase functions, IRAK4 degradation demonstrated greater activity compared to kinase inhibition alone across multiple TLR/IL-1R stimuli.  Promising in vivo mouse data showed that oral administration of an IRAK4 degrader can be achieved and have an effect on TLR/IL-1β-driven inflammation in a gouty arthritis model. Together, these data show the potential for IRAK4 degraders to treat TLR/IL-1R-driven inflammatory and autoimmune diseases.


Disclosure: V. Campbell, Kymera Therapeutics, 1, 3; J. Kelleher, Kymera Therapeutics, 1, 3; J. Chen, Kymera Therapeutics, 1, 3; J. Gollob, Kymera Therapeutics, 1, 3, 6, Kymera Therapeutics, 1, 3, 6; N. Ji, Kymera Therapeutics, 1, 3; C. Klaus, Kymera Therapeutics, 1, 3; C. Loh, Kymera Therapeutics, 1, 3; M. mayo, Kymera Therapeutics, 1, 3; A. McDonald, Kymera Therapeutics, 1, 3; H. Rong, Kymera Therapeutics, 1, 3; S. Rusin, Kymera Therapeutics, 1, 3; K. Sharma, Kymera Therapeutics, 1, 3; M. Weiss, Kymera Therapeutics, 1, 3; K. Yuan, Kymera Therapeutics, 1, 3; D. Walker, Kymera Therapeutics, 1, 3; X. Zheng, Kymera Therapeutics, 1, 3, Kymera Therapeutics, 1, 3; A. Slavin, Kymera Therapeutics, 1, 3; N. Mainolfi, Kymera Therapeutics, 1, 3, 6.

To cite this abstract in AMA style:

Campbell V, Kelleher J, Chen J, Gollob J, Ji N, Klaus C, Loh C, mayo M, McDonald A, Rong H, Rusin S, Sharma K, Weiss M, Yuan K, Walker D, Zheng X, Slavin A, Mainolfi N. A First-in-class Selective and Potent IRAK4 Degrader Demonstrates Robust in Vitro and in Vivo Inhibition of TLR/IL-1R Activation and Inflammation [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-first-in-class-selective-and-potent-irak4-degrader-demonstrates-robust-in-vitro-and-in-vivo-inhibition-of-tlr-il-1r-activation-and-inflammation/. Accessed January 28, 2023.
  • Tweet
  • Email
  • Print

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-first-in-class-selective-and-potent-irak4-degrader-demonstrates-robust-in-vitro-and-in-vivo-inhibition-of-tlr-il-1r-activation-and-inflammation/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2023 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences