HIGH-AFFINITY, ISOFORM-SELECTIVE TGFß1 INHIBITORS AND USE THEREOF

1 .- 14 . (canceled)

15 . 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 1-30 mg/kg/week in combination with an immune checkpoint inhibitor; and

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 toxicology study in a preclinical model that is sensitive to pharmacological inhibition of TGFβ, to determine a maximally tolerated amount of the antibody,

wherein the toxicology study comprises evaluation of cardiovascular toxicity comprising 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; and

wherein the antibody is administered to the animal model at a dosage of at least 30-100 mg/kg/week for at least 4 weeks;

and selecting the antibody as not causing cardiovascular toxicity when the maximally tolerated amount is greater than 30 mg/kg/week; and

(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).

16 . The method of claim 15 , wherein the antibody is selected as not causing cardiovascular toxicity when the maximally tolerated amount is greater than 100 mg/kg/week.

17 . The method of claim 15 , wherein the endpoint tumor volume is 2,000 mm 3 .

18 . The method of claim 15 , wherein the antibody is selected as a therapeutic candidate if the maximally tolerated amount or minimum toxic amount of the antibody determined in step (iii) compared to the dosage of antibody required to achieve efficacy in step (ii) has a therapeutic window of at least three-fold.

19 . The method of claim 15 , wherein the antibody is selected as a therapeutic candidate if the maximally tolerated amount or minimum toxic amount of the antibody determined in step (iii) compared to the dosage of antibody required to achieve efficacy in step (ii) has a therapeutic window of at least six-fold.

20 . The method of claim 15 , wherein the syngeneic tumor model that recapitulates a human condition comprises overexpression of a TGFβ1 gene or TGFβ1 protein.

21 . The method of claim 15 , wherein the syngeneic tumor model that recapitulates a human condition comprises resistance to a checkpoint blockade therapy.

22 . The method of claim 15 , wherein the syngeneic tumor model that recapitulates a human condition comprises a Cloudman S91 model, an MBT-2 model, or an EMT-6 tumor model.

23 . The method of claim 15 , wherein the in vivo efficacy study performed in the preclinical model further comprises one or more of immunohistochemical analyses, measurement of tumor growth, regression of tumor volume, regression of tumor growth, incidence of regression responses, or magnitude of regression responses.