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Antibody conjugates of immune-modulatory compounds and uses thereof

A technology of immune regulation and conjugates, applied in the direction of antibodies, immunoglobulins, anti-growth factor immunoglobulins, etc., which can solve the problems of lack of treatment for fibrotic diseases

Pending Publication Date: 2020-03-17
SILVERBACK THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current therapies for the treatment of fibrotic diseases are lacking or have shortcomings

Method used

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  • Antibody conjugates of immune-modulatory compounds and uses thereof
  • Antibody conjugates of immune-modulatory compounds and uses thereof
  • Antibody conjugates of immune-modulatory compounds and uses thereof

Examples

Experimental program
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preparation example Construction

[0073] In certain embodiments, the compounds disclosed herein have 2 Some or all of the H atoms substituted 1 H atom. Synthetic methods of deuterium-containing compounds are known in the art, and include the following synthetic methods only as non-limiting examples.

[0074] Deuterium substituted compounds were synthesized using various methods such as those described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0075] Deuterated starting materials are readily available and subjected to the synthetic methods described herein to provide synthesis of deuterium-containing compounds. A large n...

Embodiment 1

[0625] Synthesis of immunomodulatory compounds, linker payloads and conjugates

[0626] Linkers with immunomodulatory compounds such as PI3K inhibitors, calcineurin inhibitors, mTOR inhibitors, BTK inhibitors, JAK inhibitors, CRAC inhibitors, PARP1 antagonists, PPARg agonists, Kv1.3 antagonists, KCa3. 1 Antagonist, PP2A agonist, IRAK4 inhibitor, MYD88 inhibitor, BCL-2 antagonist, A2ar agonist, TLR7 antagonist, c-KIT kinase inhibitor, KCA3.1 agonist, TGFβR1 inhibitor, TGFβR2 inhibitor , ACC antagonist, ASK1 antagonist, GLI1 inhibitor, TNKS antagonist or TNIK antagonist link. Linker to Immunomodulatory Compound A linker-immunomodulatory compound (LP) was prepared. Subsequently, LP is conjugated to the antibody construct. Such as antibodies to form antibody constructs immunomodulatory compound conjugates or conjugates.

[0627] Inhibitors of TGFβR2

Embodiment 11

[0628] Example 1.1 Synthesis of (S)-N1-(4-(5-amino-6-((4-morpholinopyridin-3-yl)carbamoyl)pyrazin-2-yl)benzyl)-2- (6-(4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-cyclohexane-1-carboxamido)hexanoylamino)- N5-(2-(3-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl )pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethyl)glutaramide (compound 1-1 )

[0629]

[0630] Step A: Preparation of Int 1B-1

[0631]

[0632] HATU (3.54 g, 9.36 mmol) was added to a solution of 1.64 g (7.5 mmol) 3-amino-6-bromopyrazine-2-carboxylic acid in 25 mL DMF. The reaction was stirred for 5 minutes, then 2.5 mL (22.5 mmol) of N-methylmorpholine and 1.68 g (9.36 mmol) of 4-morpholinopyridin-3-amine were added. The reaction mixture was stirred for 16 h, then washed with 10 mL of saturated NH 4 The Cl solution followed by 10 mL of water was quenched. The mixture was extracted 3 times with EtOAc; the combined organics were washed with brine, then wash...

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Abstract

Antibody conjugates of immune-modulatory compounds and pharmaceutical compositions for use in the treatment of disease, such as fibrotic diseases, autoimmune, or autoinflammatory diseases, are disclosed herein. The disclosed conjugates are useful, among other things, in treating fibrotic diseases, autoimmune diseases, or autoinflammatory diseases, such as by modulating TGFbetaR1, TGFbetaR2, TNKS,TNIK, or mTOR.

Description

[0001] priority [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 516,638, filed June 7, 2017, the disclosure of which is incorporated herein by reference in its entirety. Background technique [0003] Autoimmune and autoinflammatory diseases can result from abnormal responses of the immune system to normal parts of the body. In autoimmune diseases, the adaptive immune system can attack the body's own tissues. For example, one hallmark of autoimmune disease may be the production of autoantibodies against antigens in the patient's normal tissues. Persistent inflammation may be another symptom of autoimmune disease and may play a role in the pathogenesis of common autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis. Treatments for autoimmune diseases typically focus on reducing immune system activity, but many patients do not respond to current ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K47/68C07K16/28
CPCC07K16/22C07K16/2863C07K16/32A61K2039/505A61K47/6803A61K47/6845A61K47/6849A61K47/6851A61P19/04A61P35/00C07K16/30
Inventor 彼得·阿姆斯特朗·汤普森巴德尔丁·埃德里斯克雷格·艾伦·科伯恩彼得·罗伯特·鲍姆瓦莱丽·奥德加德
Owner SILVERBACK THERAPEUTICS INC
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