IP Library › Granted Patent US 12,473,355
Granted Patent B2
US 12,473,355 · App. 18/502,188 · Granted Nov 18, 2025

Gremlin-1 crystal structure and inhibitory antibody

Inventors: Neesha Dedi (Slough, GB); Breda Twomey (Slough, GB); Michael John Wright (Slough, GB); Gareth Charles Glyndwr Davies (Slough, GB); David James Mcmillan (Slough, GB)
Assignee: UCB BIOPHARMA SRL
C07K16/22A61P9/12C07K14/51G01N33/6854A61K2039/505C07B2200/13C07K2317/21C07K2317/34C07K2317/55C07K2317/565C07K2317/76
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Quick Facts
Patent No.
US 12,473,355
App. No.
18/502,188
Granted
Nov 18, 2025
Kind
B2
Abstract

This invention relates to crystals of the human Gremlin-1 protein, and the human Gremlin-1 protein in complex with an inhibitory antibody. The invention also relates to the structure of human Gremlin-1 (on its own, or in complex with the antibody) and uses of these structures in screening for agents which modulate Gremlin-1 activity. The invention further provides antibodies which bind an allosteric inhibitory site on Gremlin-1, together with pharmaceutical compositions and medical uses of such antibodies and agents identified by the screening methods.

Claims (17)

1 . A method of treating pulmonary arterial hypertension comprising administering a therapeutically effective amount of a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9 or SEQ ID NOs: 3/5/6/7/8/9 or a therapeutically effective amount of a pharmaceutical composition thereof to a patient in need thereof.

2 . The method of claim 1 , wherein said monoclonal anti-Gremlin-1 antibody comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9.

3 . The method of claim 1 , wherein said monoclonal anti-Gremlin-1 antibody comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 3/5/6/7/8/9.

4 . The method of claim 1 , wherein said method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9 to a patient in need thereof.

5 . The method of claim 1 , wherein said method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 3/5/6/7/8/9 to a patient in need thereof.

6 . The method of claim 1 , wherein said monoclonal anti-Gremlin-1 antibody is a human antibody and comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9.

7 . The method of claim 1 , wherein said monoclonal anti-Gremlin-1 antibody is a human antibody and comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 3/5/6/7/8/9.

8 . The method of claim 1 , wherein said method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9 to a patient in need thereof, wherein said monoclonal anti-Gremlin-1 antibody is a human antibody.

9 . The method of claim 1 , wherein said method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 3/5/6/7/8/9 to a patient in need thereof, wherein said monoclonal anti-Gremlin-1 antibody is a human antibody.

10 . The method of claim 1 , wherein said monoclonal anti-Gremlin-1 antibody is a humanized antibody and comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9.

11 . The method of claim 1 , wherein said monoclonal anti-Gremlin-1 antibody is a humanized antibody and comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 3/5/6/7/8/9.

12 . The method of claim 1 , wherein said method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9 to a patient in need thereof, wherein said monoclonal anti-Gremlin-1 antibody is a humanized antibody.

13 . The method of claim 1 , wherein said method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 3/5/6/7/8/9 to a patient in need thereof, wherein said monoclonal anti-Gremlin-1 antibody is a humanized antibody.

14 . The method of claim 1 , wherein said monoclonal anti-Gremlin-1 antibody is a chimeric antibody and comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9.

15 . The method of claim 1 , wherein said monoclonal anti-Gremlin-1 antibody is a chimeric antibody and comprises a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 3/5/6/7/8/9.

16 . The method of claim 1 , wherein said method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 4/5/6/7/8/9 to a patient in need thereof, wherein said monoclonal anti-Gremlin-1 antibody is a chimeric antibody.

17 . The method of claim 1 , wherein said method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a monoclonal anti-Gremlin-1 antibody comprising a HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 sequence combination of SEQ ID NOs: 3/5/6/7/8/9 to a patient in need thereof, wherein said monoclonal anti-Gremlin-1 antibody is a chimeric antibody.

Assignments (7)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2023
From: CELLTECH R&D LIMITED
To: UCB BIOPHARMA SPRL
Reel/Frame 065504/0598 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2023
From: CELLTECH R&D LIMITED
To: UCB BIOPHARMA SPRL
Reel/Frame 065504/0610 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2023
From: CELLTECH R&D LIMITED
To: UCB BIOPHARMA SPRL
Reel/Frame 065504/0627 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2023
From: CELLTECH R&D LIMITED
To: UCB BIOPHARMA SPRL
Reel/Frame 065504/0644 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2023
From: CELLTECH R&D LIMITED
To: UCB BIOPHARMA SPRL
Reel/Frame 065504/0654 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2023
From: DEDI, NEESHA; TWOMEY, BREDA; WRIGHT, MICHAEL JOHN; DAVIES, GARETH CHARLES GLYNDWR; MCMILLAN, DAVID JAMES
To: CELLTECH R&D LIMITED
Reel/Frame 065528/0187 →
CHANGE OF NAME Recorded Nov 9, 2023
From: UCB BIOPHARMA SPRL
To: UCB BIOPHARMA SRL
Reel/Frame 065531/0265 →
Priority Claims (1)
GB 1621635 · Dec 19, 2016 · national
Continuity (3)
Division 17172109 · Feb 10, 2021
Division 16470996
Related Publication 20240076365A1 · Mar 7, 2024
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Yin, Y. et al. “Overexpression of Gremlin promotes non-small cell lung cancer progression” [cited by applicant]
Yu, Y. Y. et al. “Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair” [cited by applicant]
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Lederman, S. et al. “A Single Amino Acid Substitution in a Common African Allele of the CD4 Molecule Ablates Binding of the Monoclonal Antibody, OKT4” [cited by applicant]
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Panka, D. J. et al. “Variable region framework differences result in decreased or increased affinity of variant anti-digoxin antibodies” [cited by applicant]
Amit, A. G. et al. “Three-Dimensional Structure of an Antigen-Antibody Complex at 2.8 Å Resolution” [cited by applicant]
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Torre, L.A. et al. “Global Cancer in Women: Burden and Trends” [cited by applicant]
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Mittal, S. et al. “The breast tumour microenvironment—role in cancer development, progression and response to therapy” [cited by applicant]
Merino, R. et al. “The BMP antagonist Gremlin regulates outgrowth, chondrogenesis and programmed cell death in the developing limb” [cited by applicant]
Schuetz, C. S. et al. “Progression-Specific Genes Identified by Expression Profiling of Matched Ductal Carcinomas In situ and Invasive Breast Tumors, Combining Laser Capture Microdissection and Oligonucleotide Microarra… [cited by applicant]
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Muñoz, J. et al. “The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers” [cited by applicant]
Moser, A. R. et al. “The Min (Multiple Intestinal Neoplasia) Mutation: Its Effect on Gut Epithelial Cell Differentiation and Interaction with a Modifier System” [cited by applicant]
Shibata, H. et al. “Rapid Colorectal Adenoma Formation Initiated by Conditional Targeting of the Apc Gene” [cited by applicant]
El Marjou, F. et al. “Tissue-Specific and Inducible Cre-Mediated Recombination in the Gut Epithelium” [cited by applicant]
Rudling, R. et al. “A simple device to rapidly prepare whole mounts of murine intestine” [cited by applicant]
Sato, T. et al. “Long-Term Expansion of Epithelial Organoids From Human Colon, Adenoma, Adenocarcinoma, and Barrett's Epithelium” [cited by applicant]
Knappik, A. et al. “Fully Synthetic Human Combinatorial Antibody Libraries (HuCAL) Based on Modular Consensus Frameworks and CDRs Randomized with Trinucleotides” [cited by applicant]
Park, S.-A. et al. “Gremlin-1 augments the oestrogen-related receptor α signalling through EGFR activation: implications for the progression of breast cancer” [cited by applicant]
O'Reilly, S. et al. “Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Pro… [cited by applicant]
Sato, M. et al. “Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance” [cited by applicant]
Uchiyama, H. et al. “Adhesion of Human Myeloma-Derived Cell Lines to Bone Marrow Stromal Cells Stimulates Interleukin-6 Secretion” [cited by applicant]
Van Vlodrop, I. J. H. et al. “Prognostic Significance of Gremlin1 (GREM1) Promoter CpG Island Hypermethylation in Clear Cell Renal Cell Carcinoma” [cited by applicant]
Yu, Y. et al. “Overexpression of Gremlin 1 by sonic hedgehog signaling promotes pancreatic cancer progression” [cited by applicant]
Clark, K. C. et al. “Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo” [cited by applicant]
Cao, A. et al. “Beta-thalassemia” [cited by applicant]
Dabrowski, M. et al. “Diffuse Idiopathic Skeletal Hyperostosis of Cervical Spine with Dysphagia-Molecular and Clinical Aspects” [cited by applicant]