Interference with Systemic Negative Feedback as a Potential Mechanism for Nonmonotonic Dose-Responses of Endocrine-Disrupting Chemicals

• DOI: 10.1093/toxsci/kfaf060
• Publication Date: 2025-05-03T05:19:19Z
• Authors: Zhenzhen Shi; Shuo Xiao; Qiang Zhang

Abstract The transforming growth factor-β (TGFβ) cytokine family, which comprises three pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer fibrosis. of TGFβ disease is well established efforts to develop therapies via inhibition the isoforms their receptors have been pursued for decades. Unfortunately, progress this pursuit has limited as complete signaling pathway using small molecule inhibitors receptor or following administration potent pan-TGFβ (inhibiting TGFβ1, TGFβ3) neutralizing monoclonal antibodies (mAb) associated with adverse toxicities cardiac valvulopathies, hemorrhage, anemia nonclinical toxicology species. Here we evaluated selective individual (TGFβ1 alone, TGFβ2 TGFβ3 alone) dual (TGFβ1,2 TGFβ2,3) mice and/or cynomolgus monkeys mAbs targeted against these isoforms. Our data show that TGFβ2,3 resulted several organs, cardiovascular toxicity. However, isoform-specific 2, 3 generally tolerated devoid studies. Importantly, RO7303509 (MTBT1466A), an anti-TGFβ3 inhibiting mAb currently Phase 1 clinical trials, was GLP mouse monkey studies RO7303509-related effects were non-adverse histopathologic findings teeth injection-site reactions. In conclusion, manner safe species could be explored therapeutic intervention.