Preprint Watch 2026-09-07: 1 Clinical Failures Flagged for C3 | Claidex

Claidex Preprint Watch

doi:10.1101/2025.05.29.656912

Preprint WatchMildSeptember 7th, 2026

A Transcriptionally Distinct Intermediate Activation State Precedes Langerhans Cell Migration from the Epidermis

Kiselev, A.; Schmitter-Sanchez, A. D.; Mishra, S.; Kim, H.; Williams, S.; Park, S.

Single-cell transcriptomics of more than 22,000 epidermal Langerhans cells identifies an intermediate activation state preceding migration, and integration with homeostatic and injured skin datasets identifies wound-specific fibroblasts as the major source of complement C3.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The overlap here is at the level of the target only. This preprint locates complement C3 production in wound-specific fibroblasts during epidermal Langerhans cell activation, a setting with no clinical relationship to the single C3 failure recorded in the Claidex graph, pegcetacoplan-c3-delayed-graft-function-phase3-strategic-reprioritization, where a C3 inhibitor was withdrawn from delayed graft function after kidney transplantation for portfolio reasons before any participant was enrolled. The flag is filed at MILD for that reason. The one transferable point is tissue source. C3 is produced locally by stromal cells in injured tissue as well as by the liver, so a systemic C3 inhibitor and a local C3 measurement are not interchangeable readouts, and programmes that dose systemically while assaying plasma complement should expect a gap between target engagement and local pathway activity.

Abstract excerpt

Langerhans cells (LC) are antigen-presenting cells that form dense epidermal networks for immune surveillance. Upon antigen uptake, LCs are activated and subsequently orchestrate immune responses by migrating into the lymphatic system. However, the regulation of transcriptional programs during activation and the behavior of LCs in vivo during this transition remain poorly understood. Therefore, this study combines single-cell transcriptomic analysis with intravital imaging to reconstruct the activation trajectory of epidermal LCs. In particular, the study generates a high-resolution single-cell transcriptomic dataset comprising over 22,000 high-quality epidermal LCs under both homeostatic and injury conditions. Notably, a distinct intermediate activated state that precedes LC migration was identified and characterized at the level of signaling pathways and transcription factors. The integration of this dataset with external datasets from homeostatic and injured skin reveals wound-specific fibroblasts as the major source of C3, which is the central component of the complement cascade. Moreover, intravital imaging of C3-deficient mice and pegcetacoplan treatment demonstrates that C3 contributes to LC accumulation adjacent to wound sites. Collectively, the study findings identify an activated epidermal LC population and implicate complement signaling in the regulation of LC behavior during skin injury.

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Sep 3, 2026Pegcetacoplan in delayed graft function: a Phase 3 withdrawn before its first patientPegcetacoplanSponsorMRS 32

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.