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US 9,994,841 B2Granted
Mirac proteins
AssigneeBioAtla, Inc.
InventorsJay M. Short, Hwai Wen Chang, Gerhard Frey
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Abstract
This disclosure relates to a method of generating conditionally active biologic proteins from wild type proteins, in particular therapeutic proteins, which are reversibly or irreversibly inactivated at the wild type normal physiological conditions. For example, evolved proteins are virtually inactive at body temperature, but are active at lower temperatures.
Claims32
A method of preparing a conditionally active polypeptide, the method comprising the steps of:
- i. evolving DNA which encodes a template polypeptide using one or more evolutionary techniques to create a first set of mutant DNAs;
- ii. expressing and assaying the first set of mutant DNAs to obtain at least one first mutant polypeptide which exhibits both:
- (a) a decrease in activity in an assay at a normal physiological condition that is within a normal range of the physiological condition at a site of administration of the first mutant polypeptide to a subject, or at a tissue or organ at a site of action of the first mutant polypeptide of a subject, when compared to the activity of the template polypeptide in the assay at the same normal physiological condition, and
- (b) an increase in activity in an assay under an aberrant condition that deviates from the normal range of the physiological condition at the site of administration of the first mutant polypeptide, or at the tissue or organ at the site of action of the first mutant polypeptide, when compared to the activity of the template polypeptide in the assay at the same aberrant condition;
- and
- iii. selecting a first conditionally active polypeptide from the at least one first mutant polypeptide which exhibits both:
- (a) the decrease in the activity in the assay at the normal physiological condition when compared to the activity of the template polypeptide in the assay at the same normal physiological condition, and
- (b) the increase in the activity in the assay under the aberrant condition when compared to the activity of the template polypeptide in the assay at the same aberrant condition;
- and
- wherein the normal physiological condition and aberrant condition are the same condition selected from the group consisting of temperature, pH, osmotic pressure, oxidation, osmolality, and electrolyte concentration.
7 more elements
Dependencies are inferred from the claim text.