	US 12,252,531 B2
	Methods of screening for high-affinity, isoform-selective TGFβ1 inhibitors
Abhishek Datta, Boston, MA (US); Allan Capili, Somerville, MA (US); Thomas Schurpf, Cambridge, MA (US); Constance Martin, Arlington, MA (US); Kevin B. Dagbay, Brighton, MA (US); Christopher Chapron, Watertown, MA (US); Stefan Wawersik, Westborough, MA (US); Christopher Littlefield, Marblehead, MA (US); Gregory J. Carven, Maynard, MA (US); Alan Buckler, Arlington, MA (US); Susan Lin, Boston, MA (US); Justin W. Jackson, Cambridge, MA (US); Caitlin Stein, Lebanon, NH (US); Andrew Avery, Lebanon, NH (US); Anthony Cooper, White River Junction, VT (US); and Matthew Salotto, Hanover, NH (US)
Assigned to Scholar Rock, Inc., Cambridge, MA (US)
Appl. No. 17/258,771
Filed by Scholar Rock, Inc., Cambridge, MA (US)
PCT Filed Jul. 11, 2019, PCT No. PCT/US2019/041373 § 371(c)(1), (2) Date Jan. 8, 2021, PCT Pub. No. WO2020/014460, PCT Pub. Date Jan. 16, 2020.
Claims priority of provisional application 62/827,552, filed on Apr. 1, 2019.
Claims priority of provisional application 62/810,263, filed on Feb. 25, 2019.
Claims priority of provisional application 62/758,180, filed on Nov. 9, 2018.
Claims priority of provisional application 62/737,534, filed on Sep. 27, 2018.
Claims priority of provisional application 62/718,196, filed on Aug. 13, 2018.
Claims priority of provisional application 62/696,752, filed on Jul. 11, 2018.
Prior Publication US 2021/0122814 A1, Apr. 29, 2021
Int. Cl. G01N 33/74 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); C07K 16/22 (2006.01)

CPC C07K 16/22 (2013.01) [A61K 45/06 (2013.01); A61P 35/00 (2018.01)]

5 Claims

1. A method for screening an isoform-selective TGFβ1 inhibitor suitable for therapeutic use, the method comprising:

i) providing an antibody that specifically binds each of: human LTBP1-proTGFβ1, human LTBP3-proTGFβ1, human GARP-proTGFβ1 and human LRRC33-proTGFβ1 complexes with a K_D≤1 nM,

ii) carrying out an in vivo efficacy study in a preclinical animal model, wherein the preclinical animal model is a syngeneic tumor model that recapitulates a human condition, wherein the antibody is administered to the preclinical animal model at a dosage of about 10 mg/kg/week or less in combination with an immune checkpoint inhibitor, wherein the in vivo efficacy study comprises measurement of tumor volume in the animal model, and selecting the antibody as achieving efficacy when the tumor volume is less than 25% of endpoint tumor volume in the preclinical animal model;

iii) carrying out a cardiovascular toxicology study in a preclinical model that is sensitive to pharmacological inhibition of TGFβ, to determine a maximally tolerated and/or minimum toxic amount of the antibody, wherein the cardiovascular toxicity comprises a cardiac lesion, a valvulopathy, hyperplasia in aortic valve, right AV valve or left AV valve, inflammation in aortic valve, left AV valve or ascending aorta, hemorrhage in ascending aorta, aortic valve or left AV valve, and/or connective tissue degeneration in ascending aorta; wherein the antibody is administered to the animal model at a dosage of about 10 mg/kg/week or less; and selecting the antibody as lacking cardiovascular toxicity when the maximally tolerated amount or minimum toxic amount is achieved with administration of the antibody at a dosage of greater than 10 mg/kg/week;

(iv) selecting the antibody as a therapeutic candidate if the antibody is selected as achieving efficacy in step (ii), and if the antibody is selected as lacking cardiovascular toxicity in step (iii).