The number of highly targeted and efficacious small-molecule immunomodulators is rapidly increasing. Small-molecule compounds have several advantages over conventional immunotherapeutic agents, including their ease of production and their potential for oral administration. There is a potential niche for small-molecule immunomodulators to enhance the efficacy of existing immunotherapeutic and cytotoxic agents.
Although using animal models for the nonclinical safety assessment of small molecules offers fair concordance, human models with a complete and functional immune system are often required to assess concerns regarding immunomodulatory function, differences in metabolism profiles or off-target effects. The interrelationships of cytokine signaling and receptor biology are complex, highly integrated and at times paradoxical. Moreover, the loss of specificity at high doses may result in unforeseen consequences caused by the impact on complex downstream pathways, culminating in exaggerated and adverse responses. The species specificity of such responses may not be inherently familiar or anticipated.