Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated in mouse and cynomolgus monkey toxicology studies

Abstract

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

Keywords: TGFβ; cardiotoxicity; hemorrhage; toxiciology.