TGF-beta Monoclonal Antibody (C2BR1) (NHP-AB250)

This article describes a study to evaluate the toxicological effects in mice and cynomolgus monkeys of a potent pan-transforming growth factor beta (TGF-β) neutralizing monoclonal antibody. TGF-beta, therefore, belongs to one of the key factors governing different cellular processes and pathologies, for example, cancer, hence constituting a potential target for therapeutic intervention. However, the present study highlights substantial adverse effects related to cardiovascular toxicity as a response to TGF-beta signaling inhibition.

Administered via intravenous doses across a five-week period followed by a four-week recovery, the study reveals critical findings. For instance, the dosage of 30 mg/kg and more caused acute bleeding and cardiovascular toxicity which culminated in the death among the mice. Prolonged menstruation with severe anemia, and occasionally even death, occurred in cynomolgus monkeys at a high dose of 100 mg/kg. These toxicities encompass generalized bleeding, altered wound healing, and histopathologic changes in various organs, all pointing towards severe side effects emanating from inhibition of TGF-beta signaling.

Key experiment data has shown that both acute and prolonged exposure to monoclonal antibodies directly leads to significant disruption in normal physiological functions, with impacts ranging from bleeding and anemia to cardiovascular and wound-healing complications. The findings cast doubt on the standing assumption that cardiovascular toxicities were limited to small molecule inhibitors of TGF-beta, making it clear that monoclonal antibodies can be just as dangerous as the inhibitors of the molecule. This underscores the requirement for caution while therapeutically targeting TGF-beta, since it has wide-ranging physiological roles and has the potential for lethal side effects.

References

1. Mayur S Mitra, Karla Lancaster, Adeyemi O Adedeji, Gopinath S Palanisamy, Rutwij A Dave, Fiona Zhong, Matthew S Holdren, Shannon J Turley, Wei-Ching Liang, Yan Wu, Y Gloria Meng, Jean-Michel Vernes, Melissa M Schutten, A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys, Toxicological Sciences, Volume 175, Issue 1, May 2020, Pages 24–34,
2. Mayur S Mitra., et al. " A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys." Toxicological Sciences (2020) 24–34