Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1.

Purpose: Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-β (TGF-β) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)-pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-β is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs).

The ICE inhibitor pralnacasan prevents DSS-induced colitis in C57BL/6 mice and suppresses IP-10 mRNA but not TNF-alpha mRNA expression.

Previously we demonstrated an ameliorating effect of the interleukin-1beta converting enzyme (ICE) inhibitor pralnacasan on dextran sulfate sodium (DSS)-induced colitis. This study investigates the effects of pralnacasan on cytokine expression in DSS-induced colitis. Colitis was induced by oral administration of DSS.

The specific type-4 phosphodiesterase inhibitor mesopram alleviates experimental colitis in mice.

Mesopram, a specific inhibitor of type-4 phosphodiesterase, decreases the synthesis of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). In the present study, we investigated the effect of mesopram in dextran sulfate sodium (DSS)-induced murine colitis. In the preventive model, colitis was induced by DSS simultaneously with the application of mesopram in BALB/c mice.