US 11,718,844 B2
Mirac proteins
Jay M. Short, Jackson, CA (US); Hwai Wen Chang, San Marcos, CA (US); and Gerhard Frey, San Diego, CA (US)
Assigned to BIOATLA, INC., San Diego, CA (US)
Filed by BioAtla, Inc., San Diego, CA (US)
Filed on Sep. 8, 2017, as Appl. No. 15/699,543.
Application 14/196,950 is a division of application No. 13/523,509, filed on Jun. 14, 2012, granted, now 8,709,755, issued on Apr. 29, 2014.
Application 15/699,543 is a continuation of application No. 15/337,283, filed on Oct. 28, 2016, granted, now 9,994,841.
Application 15/337,283 is a continuation of application No. 14/196,950, filed on Mar. 4, 2014, granted, now 9,637,734, issued on May 2, 2017.
Application 13/523,509 is a continuation of application No. 13/255,676, granted, now 9,464,284, issued on Oct. 11, 2016, previously published as PCT/US2010/026611, filed on Mar. 9, 2010.
Claims priority of provisional application 61/209,489, filed on Mar. 9, 2009.
Prior Publication US 2017/0369867 A1, Dec. 28, 2017
This patent is subject to a terminal disclaimer.
Int. Cl. C12N 15/10 (2006.01); C07K 14/315 (2006.01); C12N 9/68 (2006.01); C12N 9/72 (2006.01); G01N 33/68 (2006.01); C07K 7/06 (2006.01); C07K 14/47 (2006.01); C07K 14/575 (2006.01); C12N 9/16 (2006.01); G01N 33/543 (2006.01); G01N 33/573 (2006.01); A61K 38/00 (2006.01)
CPC C12N 15/102 (2013.01) [C07K 7/06 (2013.01); C07K 14/3153 (2013.01); C07K 14/47 (2013.01); C07K 14/575 (2013.01); C07K 14/57545 (2013.01); C07K 14/57563 (2013.01); C12N 9/16 (2013.01); C12N 9/6435 (2013.01); C12N 9/6459 (2013.01); C12N 9/6462 (2013.01); C12N 15/1058 (2013.01); C12Y 304/21007 (2013.01); C12Y 304/21069 (2013.01); C12Y 304/21073 (2013.01); G01N 33/54306 (2013.01); G01N 33/573 (2013.01); G01N 33/6845 (2013.01); G01N 33/6854 (2013.01); A61K 38/00 (2013.01); C12Y 302/01035 (2013.01); C12Y 304/23015 (2013.01); C12Y 304/24029 (2013.01); Y02A 50/30 (2018.01)] 18 Claims
 
1. A method of preparing a conditionally active therapeutic antibody, the method comprising steps of:
(i) selecting a subject, a site of administration, a site of action and an antigen;
(ii) evolving a DNA which encodes a parent antibody that binds the antigen using one or more evolutionary techniques to create mutant DNAs;
(iii) expressing the mutant DNAs to obtain mutant antibodies including at least one said conditionally active therapeutic antibody;
(iv) subjecting the mutant antibodies to a screening assay under a value of a normal physiological condition that is within a normal range of the physiological condition at a site of administration of the mutant antibody and a screening assay under a value of an aberrant condition that deviates from a value of a physiological condition that is within a normal range at a normal tissue or a normal organ at the site of action;
(v) subjecting mutant antibodies determined to be active under the value of the aberrant condition in step iv to a second screening assay under the value of the normal physiological condition that is within the normal range of the physiological condition at the site of administration of the mutant antibody to determine if the activity under the value of the aberrant condition is reversible; and
(vi) selecting from the mutant antibodies the conditionally active therapeutic antibody which exhibits:
(a) an increased binding activity to the antigen in the assay at the value of the aberrant condition, compared to the binding activity of the same conditionally active antibody in the assay under the value of the normal physiological condition that is within the normal range of the physiological condition at the site of administration of the conditionally active antibody in the subject,
(b) a decreased binding activity to the antigen in the assay under the value of the normal physiological condition that is within the normal range of the physiological condition at the site of administration of the conditionally active antibody in the subject compared to the binding activity of the parent antibody in the same assay, and
(c) which is reversibly activated at the aberrant condition,
wherein the normal physiological condition and the aberrant condition are both a same condition selected from temperature, pH, osmotic pressure, oxidative stress, osmolality, and electrolyte concentration.