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A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys
Mayur S Mitra1, Karla Lancaster1, Adeyemi O Adedeji1
1Genentech Inc, South San Francisco, California 94080.
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.
Insights
Transforming growth factor beta (TGFβ) inhibition, crucial for cancer immunotherapy, caused significant bleeding and cardiovascular toxicities in preclinical models. These serious adverse events were observed with a neutralizing antibody, not just small molecule inhibitors.
Area of Science:
- Immunology
- Pharmacology
- Toxicology
Background:
- Transforming growth factor beta (TGFβ) signaling negatively impacts antitumor responses to PD-L1 blockade.
- This has spurred interest in anti-TGFβ therapies combined with cancer immunotherapies.
- TGFβ pathway inhibition in toxicology studies has shown severe toxicities like cardiac issues and anemia.
Purpose of the Study:
- To evaluate the toxicity profile of a potent pan-TGFβ neutralizing monoclonal antibody (mAb).
- To assess potential cardiovascular liabilities associated with pan-TGFβ mAb therapy.
- To compare toxicities of pan-TGFβ mAb with small molecule inhibitors of TGFβ signaling.
Main Methods:
- Administration of a pan-TGFβ mAb (neutralizing TGFβ1, 2, and 3) intravenously weekly for 5 weeks at 10, 30, and 100 mg/kg in mice and cynomolgus monkeys.
- Inclusion of a 4-week recovery period post-dosing.
- Monitoring for mortality, clinical signs, and conducting histopathological examinations.
Main Results:
- Mortality in mice at ≥ 30 mg/kg due to acute bleeding and cardiovascular toxicity.
- Prolonged menstruation in female monkeys at 100 mg/kg.
- Generalized bleeding and cardiovascular toxicity in both species, along with target-related histopathological changes in teeth, tongue, skin, and bone.
Conclusions:
- Cardiovascular toxicities linked to TGFβ inhibition are not exclusive to small molecule inhibitors.
- A potent pan-TGFβ neutralizing mAb elicits significant on-target toxicities, including bleeding and cardiovascular effects.
- These findings highlight potential safety concerns for combining TGFβ-targeted therapies with cancer immunotherapies.
