LGR4 Specific Monoclonal Antibodies and Their Use

­Researchers at UTHealth have isolated and characterized monoclonal antibodies as well as antibody fragments that specifically binding to LGR4, a 7TM receptor that is highly expressed in major types of solid tumors, including but not limited to colorectal cancer, non-small cell lung cancer, and ovarian cancer. These LGR4 specific monoclonal antibodies have the potential applications for cancer therapeutics, diagnosis and detection.

Background

Leucine-rich repeat-containing, G-protein coupled receptor 4 (LGR4) consists of a large extracellular domain with 17 leucine-rich repeats and a seven-transmembrane (7TM) domain typical of the rhodopsin family of G protein-coupled receptors. It has been demonstrated that LGR4, along with its closely related homologs LGR5 and LGR6, function as receptors of the R-spondin group of stem cell factors that potentiate Wnt signaling. Hyper expression of R-spondins drives tumor formation primarily through binding to LGR4 and inhibiting E3 ubiquitin ligase activity. Aberrant RSPO-LGR4 signaling has been demonstrated to promote cancer cell growth and metastasis in major cancer types, including breast, colon, hematological, lung, and ovarian cancer. Targeting LGR4 may provide a novel approach to the treatment of tumors driven by RSPO-LGR4 signaling.

Technology Highlights

Scientists at UTHealth have identified antibodies as well as antibody fragments that specifically binding to LGR4. Affinity analysis of these LGR4 binding affinity using mammalian cell lines expressing human LGR4 revealed high binding affinity with a Kd of about 0.7 nM. In addition, a specificity cross check analysis showed that none of the LGR4 specific monoclonal antibodies bound to LGR5 or LGR6, closely related homolog receptors.  Anti-LGR4 antibody drug conjugates show robust antitumor activity in vitro and in vivo without obvious toxicity.

Potential Benefits/Applications

• The LGR4 specific monoclonal antibodies can bind to LGR4 and internalize into the lysosome, thus can be potentially used as part of an antibody-drug conjugate for cancer therapeutics.
• The LGR4 specific monoclonal antibodies can be used to detect cancer in a patient through the specific detection of increased LGR4 levels.
• The LGR4 specific monoclonal antibodies can specifically detect LGR4 and has been validated as research tools for immunohistochemistry and western blotting applications​​​​​​​
• • • Anti-LGR4-Antibody-7E7
    • Anti-LGR4 Antibody-5A3

Intellectual Property Status

• Issued U.S. Utility Patent 16/062,386
• Available for licensing; exclusive or non-exclusive depending on field of use

Stage of Development

• Pre-clinical

Associated Publications

• Analysis of LGR4 Receptor Distribution in Human and Mouse Tissues
• Differential activities and mechanisms of the four R-spondins in potentiating Wnt/β-catenin signaling

About the Lead Creator/Inventor

Dr. Qingyun (Jim) Liu, Ph.D.

Professor and Director, Center for Translational Cancer Research, Brown Foundation Institute of Molecular Medicine;

Leads a research team primarily focused on the identification and characterization of targeted drug candidates in the area of cancer and immunology.

UTHealth Ref. No.: 2015-0049