KPL-404 and autoimmune diseases mediated by the CD40/CD154 interaction
KPL-404 is a human monoclonal antibody inhibitor of the CD40/CD154 (formerly referred to as CD40 ligand or CD40L) co-stimulatory interaction. It blocks the interaction between CD40 and CD154 by binding to CD40.
The interaction between CD40/CD154 is one of the most critical co-stimulatory immune checkpoints. It plays a crucial role in T-cell-dependent B-cell activation and differentiation, steps that are necessary for an antibody-mediated humoral response. It also has an impact on dendritic cells and macrophage activity.
The CD40/CD154 interaction has been implicated in many autoimmune conditions including:
- Rare diseases, such as ankylosing spondylitis, systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis
- More prevalent diseases, such as rheumatoid arthritis, psoriatic arthritis, and Graves’ disease
- Solid organ transplant graft rejection
KPL-404 clinical program
Kiniksa has completed a Phase 1 single-ascending dose study designed to investigate the safety and tolerability as well as the pharmacokinetic and pharmacodynamic properties of a single dose of KPL-404 administered intravenously (IV) or subcutaneously (SC) in healthy volunteers. KPL-404 was well tolerated, with no dose-limiting safety findings. The data supported testing of longer-term SC administration in patients with autoimmune disease:
- A single administration of 3 mg/kg and 10 mg/kg IV demonstrated full CD40 receptor occupancy (RO) through Day 29 and Day 71, respectively
- A single administration of 3 mg/kg and 10 mg/kg IV demonstrated complete suppression of the primary T-cell-dependent antibody response (TDAR) through Day 29 and suppressed TDAR to antigen rechallenge (at Day 29) through Day 43 and at least Day 57, respectively
- A single administration of 5 mg/kg SC showed full RO through Day 43 and complete suppression of the antigen response through at least Day 29, similar to the 3 mg/kg IV dose