Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor

Abstract

Interleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers. As such, blocking the inflammatory signals inherent to IL-1 family signaling is an established and expanding therapeutic strategy. While several FDA-approved IL-1 inhibitors exist, including an Fc fusion protein, a neutralizing antibody, and an antagonist cytokine, none specifically targets the co-receptor IL-1 receptor accessory protein (IL-1RAcP). Most IL-1 family cytokines form productive signaling complexes by binding first to their cognate receptors – IL-1RI for IL-1α and IL-1β; ST2 for IL-33; and IL-36R for IL-36α, IL-36β and IL-36γ – after which they recruit the shared secondary receptor IL-1RAcP to form a ternary cytokine/receptor/co-receptor complex. Recently, IL-1RAcP was identified as a biomarker for both AML and CML. IL-1RAcP has also been implicated in tumor progression in solid tumors and an anti-IL1RAP antibody (nadunolimab, CAN04) is in phase II clinical studies in pancreatic cancer and non-small cell lung cancer (NCT03267316). As IL-1RAcP is common to all of the abovementioned IL-1 family cytokines, targeting this co-receptor raises the possibility of selective signaling inhibition for different IL-1 family cytokines. Indeed, previous studies of IL-1β and IL-33 signaling complexes have revealed that these cytokines employ distinct mechanisms of IL-1RAcP recruitment even though their overall cytokine/receptor/co-receptor complexes are structurally similar. Here, using functional, biophysical, and structural analyses, we show that antibodies specific for IL-1RAcP can differentially block signaling by IL-1 family cytokines depending on the distinct IL-1RAcP epitopes that they engage. Our results indicate that targeting a shared cytokine receptor is a viable therapeutic strategy for selective cytokine signaling inhibition.

Computational Structure Prediction for Antibody-Antigen Complexes From Hydrogen-Deuterium Exchange Mass Spectrometry: Challenges and Outlook

“…The calculation of HDX data from a protein atomic models based on the phenomenological expression is now feasible for researchers using a software package called HDX ensemble reweighing (HDXer) developed by Bradshaw et al (93). In a recent study, this technique was applied to simulate the deuterium uptake of the top docking poses to compare with the experimental data (36). The simulated HDX profiles of the two docking complexes aligned well with the empirical data, further validating the selected models, and highlighting the advances being made in the field of HDX prediction.…”

“…HDX-MS has been used successfully in the past to map Ab epitopes to Ag surfaces (e.g., 14,20,22,28,[31][32][33][34][35][36]. A typical HDX-MS epitope mapping experiment (Figure 1) is performed on the Ag alone as a reference and then in complex with the Ab.…”

“…simulations in different protein modeling suites (i.e., MOE, PatchDock, ZDOCK, RosettaDock (102,103,112,123) to derive Ab-Ag complex structures in several epitope mapping studies (e.g., 11,14,27,32,36). A summary of their protocols and docking performance is presented in Table 2.…”

“…To propel the presence of HDX-MS predicted epitope peptides at the interface, these peptides are assigned as favorable docking sites (11,14,32,36). This is accomplished by applying fixed distance restraints between residues in HDXdetected epitope peptides and residues in the Ab.…”

The Controversial Role of IL-33 in Lung Cancer

“…However, the specific role of IL-33/ST2 axis that might predominate in tumor remains to be further studied. Ongoing phase II clinical studies (NCT03267316 and NCT05116891) on IL-1RAcP antibody CAN04, which showed the potency of selective cytokine signaling inhibition of IL-1 family cytokines in NSCLC ( 62 ), may hopefully find a new method to treat lung cancer.…”