Novel complementing receptor-ligand pairs and adoptive immunotherapy using the same
First Claim
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1. A method for identifying novel receptor-ligand binding pairs, comprising contacting a cell expressing a mutated receptor with a putative ligand and assaying for receptor-ligand binding and biological response and binding of higher affinity as compared to the corresponding wild-type receptor.
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Abstract
This invention provides a screen to identify novel therapeutic receptor-ligand pairs. In one embodiment, the receptor-ligand pairs identified by this method induce proliferation of tumor-infiltrating lymphocytes without systemic toxicity associated with the administration of wild-type cytokines. Diagnostic and therapeutic methods using the cytokine-receptor pairs identified by this screen also are provided.
13 Citations
40 Claims
- 1. A method for identifying novel receptor-ligand binding pairs, comprising contacting a cell expressing a mutated receptor with a putative ligand and assaying for receptor-ligand binding and biological response and binding of higher affinity as compared to the corresponding wild-type receptor.
- 10. A method of activating a receptor comprising administering to a subject an effective amount of a host cell expressing a polynucleotide encoding a mutated receptor and an effective amount of a ligand that selectively binds to the receptor wherein the receptor is activated by the binding of said ligand to said receptor.
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17. A method of inducing an immune response in a subject bearing a tumor comprising the steps of:
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administering to said tumor an effective amount of a polynucleotide encoding a mutated IL-2 receptor and activating said mutated IL-2 receptor by means of locoregionally administering a mutated ligand that selectively binds to the mutant receptor. - View Dependent Claims (18, 19)
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23. A method for selectively activating cytokine expression in a subject comprising the steps of:
- administering to said subject an effective amount of a host cell(s) expressing a polynucleotide encoding a mutated receptor and administering an effective amount of a ligand that selectively binds to said mutated receptor activating cytokine expression in said host cell(s).
- View Dependent Claims (38, 39, 40)
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27. A method for identifying mutant IL-2 receptor-ligand binding pairs, comprising:
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1) introducing a plurality of polynucleotides encoding for IL-2 receptor β
mutants into an IL-2 dependent cell that expresses a mutant IL-2, and2) selecting said cells that survive in the absence of IL-2, and 3) from said surviving cells, recovering the polynucleotides encoding for said IL-2 receptor β
mutants, wherein said mutant IL-2 and said recovered IL-2 receptor β
mutant bind each other and provide the biological response of the wild-type IL-2 ligand-receptor pair.
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28. A method for identifying mutant IL-2 receptor-ligand binding pairs, comprising:
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1) introducing a plurality of polynucleotides encoding for IL-2 mutants into an IL-2 dependent cell that expresses a mutant IL-2 receptor β
, and2) selecting said cells that survive in the absence of IL-2, and 3) from said surviving cells, recovering the polynucleotides encoding for said IL-2 receptor β
mutants, wherein said mutant IL-2 and said recovered IL-2 receptor β
mutant bind each other and provide the biological response of the wild-type IL-2 ligand-receptor pair.
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30. A method for identifying mutant IL-2 receptor-ligand binding pairs, comprising:
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1) providing cells comprising a reporter gene operatively linked to an upstream activating sequence recognized by a selected transcription factor, and expressing an IL-2 mutant fused to the DNA binding domain of said transcription factor and, 2) introducing a plurality of polynucleotides encoding for IL-2 receptor β
mutants fused to the activation domain of said transcription factors into said cell and,3) selecting the cells that then express said reporter gene, and 4) recovering the polynucleotides encoding for said IL-2 receptor β
mutant fusion proteins from said expressing cells,wherein said recovered IL-2 receptor β
mutant interacts with the mutant IL-2 ligand.
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31. A method for identifying mutant IL-2 receptor-ligand binding pairs, comprising:
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1) providing cells comprising a reporter gene operatively linked to an upstream activating sequence recognized by a selected transcription factor, (need something here?,) and expressing an IL-2 receptor β
mutant fused to the DNA binding domain of said transcription factor and,2) introducing a plurality of polynucleotides encoding for IL-2 mutants fused to the activation domain of said transcription factors into said cell and, 3) selecting the cells that then express said reporter gene, and 4) recovering the polynucleotides encoding for said IL-2 mutant fusion proteins from said expressing cells, wherein said recovered IL-2 receptor β
mutant interacts with the mutant IL-2 ligand.
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Specification