A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys.

Transforming growth factor beta (TGF(beta) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGF beta therapies for potential combination with cancer immunotherapy agents. Inhibition of TGF beta signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of TGF beta receptor and not considered to be a liability associated with pan-TGF beta neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGF beta neutralizing mAb (pan-TGF beta mAb; neutralizes TGF beta 1, 2, and 3) after 5 weekly intravenous doses of 10, 30, and 100 mg/kg, followed by a 4-week recovery period, in mice and cynomolgus monkeys. Mortality was observed due to acute bleeding and cardiovascular toxicity in mice at >= 30 mg/kg and prolonged menstruation in female monkeys at 100 mg/kg. Additional findings considered to be on-target exaggerated pharmacology included generalized bleeding and cardiovascular toxicity in mice and monkeys; histopathologic changes in the teeth, tongue, and skin in mice; and abnormal wound healing and microscopic pathology in the bone in monkeys. Importantly, our data indicate that the cardiovascular toxicities associated with the inhibition of TGF beta signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGF beta inhibiting mAb.