Immunocytokines with modulated selectivity
AssigneeEMD Lexigen Research Center Corp.
InventorStephen D. Gillies
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Abstract
The invention provides cytokine fusion proteins with an increased therapeutic index, and methods to increase the therapeutic index of such fusion proteins. The fusion proteins of the invention are able to bind to more than one type of cytokine receptor expressed on cells and also bind to more than one cell type. In addition, the fusion proteins of the invention exhibit a longer circulating half-life in a patient's body than the corresponding naturally occurring cytokine.
Claims48
A fusion protein comprising a non-IL-2 moiety fused to a mutant IL-2 moiety, wherein said fusion protein exhibits greater selectivity than a reference protein towards cells expressing a high affinity receptor, wherein said reference protein comprises the non-IL-2 moiety fused to a non-mutant IL-2 moiety, and
- wherein said selectivity is measured as a ratio of activation of cells expressing IL-2Rαβγ receptor relative to activation of cells expressing IL-2Rβγ receptor.
A fusion protein comprising an IL-2 moiety and a non-IL-2 moiety, said non-IL-2 moiety comprising a mutation that has a differential effect on said fusion protein's affinity for IL-2Rβγ receptor relative to said fusion protein's affinity for IL-2Rαβγ receptor.
A method for improving a therapeutic fusion protein, said fusion protein comprising two or more protein domains that bind to distinct receptors on cell surfaces, said method comprising:
- i. testing said fusion protein for activity in two or more in vitro assays, said assay being specific for said distinct receptors,
- ii. modifying said fusion protein by mutation or by chemical or biochemical modification
- iii. testing said modified fusion protein in said two or more assays,
- iv. identifying modified fusion proteins that are differentially affected in their activity in said assays relative to said non-modified fusion protein,
- v. testing said identified modified fusion proteins for activity in an animal.
Dependencies are inferred from the claim text.