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

Abstract

Transforming growth factor β (TGFβ) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGFβ therapies for potential combination with cancer immunotherapy agents. Inhibition of TGFβ 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 TGFβ receptor and not considered to be a liability associated with pan-TGFβ neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGFβ neutralizing mAb (pan-TGFβ mAb; neutralizes TGFβ1, 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 TGFβ signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGFβ inhibiting mAb.

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

“…Galunisertib is a thoroughly studied small molecule, TGFβRI kinase inhibitor. Pre-clinical mouse models showed promising treatment effects but, at the same time, cardiac toxicity [137,138]. An intermittent treatment schedule, or so-called 'drug holiday' , was found to minimize toxicity in mice and humans [139,140].…”

Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization

“…However, later studies using a potent murine anti-TGF-β antibody, or genetic methods for reducing TGF-β signaling have not corroborated these findings, and have worsened, rather than improved disease in MFS mouse models (Cook et al, 2015b, Holm et al, 2011, Lindsay et al, 2012, Wei et al, 2017). Furthermore, administration of small molecule inhibitors of the TGF-β type I receptor, or a pan-TGF-β neutralizing antibody, have been associated with serious adverse cardiovascular toxicities, such as valve defects, similar to those found in MFS (Anderton et al, 2011, Stauber et al, 2014, Mitra et al, 2020). The finding that mutations in FBN1 that prevent binding of LTBPs might result in lower levels of TGF-β signaling, rather than excessive signaling, is not so surprising given the more recent understanding of how TGF-β is activated.…”

Nonclinical Development of SRK-181: An Anti-Latent TGFβ1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors

“…These toxicities include cardiovascular abnormalities, skin lesions, epithelial oral hyperplasia, and gingival bleeding. [15][16][17][18] Although many of these are either reversible or manageable, the cardiovascular lesions such as inflammation, hemorrhage or hyperplasia in the valves, aortic arch, and associated arteries of the heart are not reversible and therefore continue to be key safety concerns for TGFb inhibitors. [17][18][19] To date, the majority of TGFb inhibitors target 2 or all 3 TGFb isoforms (ie, pan-TGFb inhibition), and therefore it is unknown if the toxicity profile associated with these drugs can be attributed to a specific isoform.…”

“…[15][16][17][18] Although many of these are either reversible or manageable, the cardiovascular lesions such as inflammation, hemorrhage or hyperplasia in the valves, aortic arch, and associated arteries of the heart are not reversible and therefore continue to be key safety concerns for TGFb inhibitors. [17][18][19] To date, the majority of TGFb inhibitors target 2 or all 3 TGFb isoforms (ie, pan-TGFb inhibition), and therefore it is unknown if the toxicity profile associated with these drugs can be attributed to a specific isoform. 15,18 Recent analysis of RNA-seq data from The Cancer Genome Atlas dataset identified TGFb1 as the most prevalent TGFb isoform in a majority of solid tumor types in humans, which suggests that TGFb1 may be important in the disease state.…”