Preprint Watch 2026-07-27: 1 Clinical Failures Flagged for IL13 | Claidex

Claidex Preprint Watch

doi:10.64898/2026.07.24.740376

Preprint WatchModerateJuly 27th, 2026

IL-13 Induces a Tuft Cell-Intrinsic CD45 Checkpoint to Limit Intestinal Type 2 Immunity

Sochen, C.; Lebon, S.; Habshush-Menachem, A.; Sarusi-Portuguez, A.; Holiar, V.; Rudenko, V.; Toval, B.; Liu, J.; Levin, Y.; Vaaknin, E.; Rosenthal, N.; Tiferet, N.; Orr, I.; Ben-Dor, S.; Haffner-Krausz, R.; Grencis, R.; Munitz, A.; Karo-Atar, D.; Shulman, Z.; Biton, M.

The receptor tyrosine phosphatase CD45, encoded by Ptprc, is expressed in a subset of intestinal tuft cells, is induced by IL-13, and restrains IL-13 responsive transcriptional programs, forming an IL-13 induced negative feedback circuit that limits type 2 immunity.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The Claidex record holds one IL-13 failure, lebrikizumab in asthma, which missed on efficacy in phase 3 (lebrikizumab-il13-asthma-lavolta-phase3-efficacy-failure). This preprint describes an epithelium-intrinsic brake on IL-13 signalling, a CD45 dependent negative feedback circuit that IL-13 itself induces. The tissue is intestine rather than airway, so the finding does not transfer directly. It does supply a candidate explanation for why blocking a cytokine that already carries its own feedback brake produced smaller clinical effects than the preclinical biology implied. Any new IL-13 directed program should account for endogenous negative feedback when sizing the expected effect, rather than modelling IL-13 blockade as removal of an unopposed driver.

Abstract excerpt

Tuft cells initiate intestinal type 2 immunity, yet the mechanisms that restrain excessive tuft cell activation remain poorly understood. Here, we identify the receptor tyrosine phosphatase CD45 (Ptprc), previously considered a hematopoietic marker, as a regulator of intestinal tuft cell function. CD45 expression is restricted to a subset of tuft cells and is induced by helminth infection and IL-13. Epithelial-specific deletion of Ptprc activated a tuft cell inflammatory program, promoted an epithelial inflammatory state, and increased eosinophil accumulation at homeostasis. During Heligmosomoides polygyrus bakeri infection, CD45 deficiency enhanced ILC2 and Th2 responses and reduced parasite burden, demonstrating that epithelial CD45 limits type 2 immunity in vivo. Accordingly, in intestinal organoids, CD45 was dispensable for IL-13-driven tuft cell differentiation but restrained IL-13-responsive transcriptional programs. Mechanistically, CD45-deficient tuft cells exhibited altered protein abundance of STAT5 and IL17RB, implicated in tuft cell immune regulation. Together, these findings identify CD45 as a tuft cell-intrinsic regulatory checkpoint that restrains intestinal type 2 immunity through an IL-13-induced negative-feedback circuit.

Matching Claidex post-mortems

1 of 1 indexed

Jun 30, 2026Lebrikizumab in asthma: an anti-IL-13 effect that would not replicateLebrikizumabEfficacyMRS 37

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.