IL-2 is first captured by IL-2Rα (Kd 10e-8 M).The IL-2Rα-IL-2 binary complex leads to a very small conformational change in IL-2 that promotes association with IL-2Rβ.The ternary IL-2Rα-IL-2Rβ-IL-2 complex then recruits Ƴ through a weak interaction with IL-2 and a stronger interaction with IL-2Rβ to produce a stable quaternary high-affinity IL-2R (Kd 10e-11 M).
Using in vitro evolution, Levin AM and his co-workers eliminated IL-2's functional requirement for CD25 expression by engineering an IL-2 'superkine' (termed H9) with increased binding affinity for IL-2Rβ. Compared to IL-2(termed H2), H9 induced superior expansion of cytotoxic T cells, leading to improved anti-tumor responses in vivo, and elicited less expansion of T regulatory cells and reduced adverse effects. |