Safety assessment of immunomodulatory biologics: The promise and challenges of regulatory T-cell modulation

Abstract

Regulatory T-cell (T reg ) modulation is developing as an important therapeutic opportunity for the treatment of a number of important diseases, including cancer, autoimmunity, infection, and organ transplant rejection. However, as demonstrated with IL-2 and TGN-1412, our understanding of the complex immunological interactions that occur with T reg modulation in both non-clinical models and in patients remains limited and appears highly contextual. This lack of understanding will challenge our ability to identify the patient population who might derive the highest benefit from T reg modulation and creates special challenges as we transition these therapeutics from non-clinical models into humans. Thus, in vivo testing in the most representative animal model systems, with careful progress in the clinic, will remain critical in developing therapeutics targeting T reg and understanding their clinical utility. Moreover, toxicology models can inform some of the potential liabilities associated with T reg modulation, but not all, suggesting a continued need to explore and validate predictive models.

Stem Cell Models for Drug Discovery and Toxicology Studies

“…The most notorious example of a drug deemed safe after animal trials but with devastating effects in humans is thalidomide, which had no effect on prenatal development in rodents but which caused severe developmental defects in human children whose mothers had taken it during pregnancy to relieve morning sickness . Another example is the 2006 clinical trial of the TGN1412 antibody to treat multiple sclerosis, rheumatoid arthritis, and leukemia . Although previous tests in various different animals including primates had shown no adverse effects, the drug caused catastrophic systemic organ failure in all six human volunteers who took it.…”