IMiDs: a novel class of immunomodulators

IMiDs are structural and functional analogues of thalidomide that represent a promising new class of immunomodulators for treatment of a variety of inflammatory, autoimmune, and neoplastic diseases. The discovery of the antiangiogenic and T-cell co-stimulatory functions of IMiD compounds has led to the investigation of these agents for treatment of hematologic neoplasms such as multiple myeloma and myelodysplastic syndromes, as well as certain solid tumors. The second-generation IMiDs, such as lenalidomide and CC-4047, exhibited a greatly enhanced potency for immunomodulation and antiangiogenesis in nonclinical studies when compared with the parent compound, thalidomide. In clinical studies, the IMiDs appear to have reduced sedative and neurotoxicity effects, which are often associated with long-term thalidomide dosing. The precise mechanism of action of IMiDs in the treatment of specific diseases is not entirely clear and may differ for various diseases depending on their underlying pathobiologies. Although IMiDs have similar effects on inflammatory cytokine secretion, T-cell modulation, angiogenesis, and expression of adhesion molecules, each IMiD has a unique potency profile for these activities, which may ultimately indicate selective applicability of specific IMiDs for distinct diseases and conditions. Clinical trials of lenalidomide, the primary second-generation IMiD, have shown clinical benefits in both myelodysplastic syndrome and multiple myeloma and a better safety profile than that of thalidomide, with no evidence of teratogenicity. It is anticipated that lenalidomide and other IMiD compounds will become important alternatives to thalidomide because of their more potent anti-inflammatory and anticancer properties, as well as their improved side-effect profiles.