Protein therapeutics for treatment of senescent cells
AssigneeBioAtla, Inc.
InventorJay M. Short
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Abstract
Methods of generating conditionally active proteins that target senescent cells and which are conditionally active in an extracellular environment of a senescent cell. The methods include discovery methods using libraries of evolved proteins and assays employing physiological concentrations of components of bodily fluids. Also disclosed are conditionally active proteins for killing or removing senescent cells, pharmaceutical compositions employing these conditionally active proteins and methods for treatment of age-related diseases, conditions or disorders using same. The conditionally active proteins may be further evolved, conjugated to other molecules, masked, reduced in activity by attaching a cleavable moiety.
Claims33
A method of producing a conditionally active protein that binds to a target associated with a senescent cell from a parent protein that binds to the target associated with the senescent cell, said method comprising steps of:
- (i) evolving a DNA encoding the parent protein using one or more evolutionary techniques to create mutant DNAs;
- (ii) expressing the mutant DNAs to obtain mutant proteins;
- (iii) subjecting the mutant proteins to an assay under an extracellular condition of the senescent cell and an assay under a normal physiological condition;
- and
- (iv) selecting the conditionally active protein from the mutant proteins that exhibits at least one of:
- (a) a decrease in an activity in the assay under the normal physiological condition compared to the same activity of the parent protein in the same assay, and an increase in the activity in the assay under the extracellular condition of the senescent cell compared to the same activity of the conditionally active protein in the assay under the normal physiological condition;
- and
- (b) a decrease in the activity in the assay under the normal physiological condition compared to the same activity of the parent protein in the same assay and an increase in the activity in the assay under the extracellular condition of the senescent cell compared to the same activity of the parent protein in the assay under the extracellular condition of the senescent cell.
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