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Antibody−Drug Conjugates for the Treatment of Inflammation Gerard Rosse* Structure Guided Chemistry, Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States Adjunct Associate Professor, Department of Pharmacology and Physiology, College of Medicine, Drexel University, New College Building, 245 North 15th Street, Philadelphia, Pennsylvania 19102, United States Title:
Antibody−Drug Conjugates for the Treatment of Inflammation
Patent/Patent Application Number:
WO 2017/062271 A2
Publication date:
April 13, 2017
Priority Application:
US 2015−62237668
Priority date:
October 6, 2015
Inventors:
Brandish, P. E.; Garbaccio, R. M.; Kern, J.; Liang, L.; Shah, S.; Zaller, D.; Beck, A.; Gately, D.; Knudsen, N.; Manibusan, A.; Wang, J.; Sun, Y.
Assignee Company:
Merck Sharp & Dohme Corp., USA; Ambrx, Inc.
Disease Area:
Inflammatory Diseases or Disorders
Summary:
The present application claims a series of antibody−drug conjugates (ADCs) for the treatment of inflammatory diseases. The ADC is composed of an antibody targeting a CD74 or CD163 protein attached to an anti-inflammatory therapeutic agent via a phosphate-based linker. Several phosphate-based linkers are claimed and described to have a differentiated and tunable stability for intracellular delivery of the therapeutic agent. The anti-inflammatory therapeutic agent comprises a glucocorticoid receptor agonist, cortisol, cortisone acetate, beclometasone, prednisone, prednisolone, methylprednisolone, betamethasone, trimcinolone, budesonide, dexamethasone, fluticasone, or mometasone.
Biological Target:
N/A
The ACDs described in this application are potentially useful in the treatment of a wide range of inflammatory diseases such as Alzheimer’s disease, osteoarthritis, rheumatoid arthritis, asthma, atherosclerosis, Crohn’s disease, dermatitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), Parkinson’s disease, or ulcerative colitis. Important Compound Classes:
Definitions:
V is selected from O and S; W is selected from O, N, and 0. D is an anti-inflammatory agent. T is selected from NR, CR2, 0, or S.
Received: September 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00377 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters Key Structures:
Patent Highlight
Examples of drug linkers
Antibody−drug conjugates
Biological Assay:
The drug-linker conjugates were evaluated in a series of experiments to determine solubility in aqueous solutions and in vitro stability in blood and rat lysosomal lysates. The ADC 12-1 was prepared from an antimouse CD25 antibody, and the drug linker 1-4 (dexamethasone with a diphosphate linker) was evaluated in a series of experiments to determine stability in DBA 1 mice serum, in vivo pharmacokinetic stability in DBA 1 mice, and aggregation. The in vitro activity and targeted delivery of several ADCs were assessed in HUT-78 an SUDHL-6 cells (CD74 positive T and B lymphoma cell lines, respectively) as well as 786-0 cells (a CD74 negative renal carcinoma cell line).
B
DOI: 10.1021/acsmedchemlett.7b00377 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Pharmacological Data:
Results of in vitro activity and targeted delivery studies
Synthesis:
Synthesis, purification, and analysis of 15 ADCs are described. The anti-inflammatory agent-linker conjugates are attached to the antibody using click (2 + 3) chemistry.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The author declares no competing financial interest.
C
DOI: 10.1021/acsmedchemlett.7b00377 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
