Insufficient (Sub-native) Helix
Interleukin-2 (IL2) is a protein with therapeutic value which has been discontinued from therapeutic use due to its various side-effects. IL2 is very aggregation-prone, and is formulated for injection as a soluble aggregate. We hypothesized that several of the side-effects of IL2 can be explained by its aggregation, and set out to obviate such aggregation through protein engineering, by building hypotheses about the mode of its aggregation (using its known structure) and then taking steps to prevent aggregation. We tried four different protein engineering-based approaches and failed completely in preventing IL2’s aggregation. However, we learned that aggregates of IL2 contain less helical content than the known helical content calculated from the crystal structure of the protein. We think, therefore, that soluble IL2 aggregates formulated with aggregation-reducing excipients are not directly active. Rather, dissociation of individual IL2 molecules from such aggregates allows chains to adopt native structure and bind to the IL2 receptor.
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