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LGR5

Official Full Name
leucine rich repeat containing G protein-coupled receptor 5
Organism
Homo sapiens
GeneID
8549
Background
The protein encoded by this gene is a leucine-rich repeat-containing receptor (LGR) and member of the G protein-coupled, 7-transmembrane receptor (GPCR) superfamily. The encoded protein is a receptor for R-spondins and is involved in the canonical Wnt signaling pathway. This protein plays a role in the formation and maintenance of adult intestinal stem cells during postembryonic development. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]
Synonyms
FEX; HG38; GPR49; GPR67; GRP49;
Bio Chemical Class
GPCR rhodopsin
Protein Sequence
MDTSRLGVLLSLPVLLQLATGGSSPRSGVLLRGCPTHCHCEPDGRMLLRVDCSDLGLSELPSNLSVFTSYLDLSMNNISQLLPNPLPSLRFLEELRLAGNALTYIPKGAFTGLYSLKVLMLQNNQLRHVPTEALQNLRSLQSLRLDANHISYVPPSCFSGLHSLRHLWLDDNALTEIPVQAFRSLSALQAMTLALNKIHHIPDYAFGNLSSLVVLHLHNNRIHSLGKKCFDGLHSLETLDLNYNNLDEFPTAIRTLSNLKELGFHSNNIRSIPEKAFVGNPSLITIHFYDNPIQFVGRSAFQHLPELRTLTLNGASQITEFPDLTGTANLESLTLTGAQISSLPQTVCNQLPNLQVLDLSYNLLEDLPSFSVCQKLQKIDLRHNEIYEIKVDTFQQLLSLRSLNLAWNKIAIIHPNAFSTLPSLIKLDLSSNLLSSFPITGLHGLTHLKLTGNHALQSLISSENFPELKVIEMPYAYQCCAFGVCENAYKISNQWNKGDNSSMDDLHKKDAGMFQAQDERDLEDFLLDFEEDLKALHSVQCSPSPGPFKPCEHLLDGWLIRIGVWTIAVLALTCNALVTSTVFRSPLYISPIKLLIGVIAAVNMLTGVSSAVLAGVDAFTFGSFARHGAWWENGVGCHVIGFLSIFASESSVFLLTLAALERGFSVKYSAKFETKAPFSSLKVIILLCALLALTMAAVPLLGGSKYGASPLCLPLPFGEPSTMGYMVALILLNSLCFLMMTIAYTKLYCNLDKGDLENIWDCSMVKHIALLLFTNCILNCPVAFLSFSSLINLTFISPEVIKFILLVVVPLPACLNPLLYILFNPHFKEDLVSLRKQTYVWTRSKHPSLMSINSDDVEKQSCDSTQALVTFTSSSITYDLPPSSVPSPAYPVTESCHLSSVAFVPCL
Open
Disease
Colorectal cancer, Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
3 +
Discontinued Drug
0

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Detailed Information

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a target gene of the oncogenic Wnt signaling pathway in colorectal cancer (CRC) cells. LGR5 is overexpressed in a range of human malignancies, including but not limited to CRC, hepatocellular carcinoma (HCC), gastric cancer, ovarian cancer, breast cancer, glioblastoma, and certain B-cell malignancies. In colorectal cancer cells, LGR5 expression is essential for proliferation, migration, chemosensitivity, colony formation, and in vivo engraftment capacity. The high expression of LGR5 in tumor cells is critical for tumor cell proliferation, underscoring its potential as a therapeutic target. Although LGR5-targeted antibodies have significant potential for clinical application in immunotherapy, the lack of robustly validated and suitable antibodies has hindered the development of such therapies.

On August 21, 2024, researchers published a study titled "Novel immunotherapeutics against LGR5 to target multiple cancer types" in EMBO Molecular Medicine, reporting the development of highly specific monoclonal α-LGR5 antibodies that can be employed across a broad range of experimental and therapeutic applications. The study described the development of α-LGR5 as a therapeutic antibody, its functional validation for targeting LGR5+ CRC and pre-B-ALL cells via antibody-drug conjugates (ADCs), and its ability to direct cytotoxic immune-mediated cancer cell killing via BiTE and CAR formats. The robust preclinical efficacy of α-LGR5 in all three therapeutic modalities was demonstrated in a mouse model of human pre-B-ALL, thereby supporting the continued development of α-LGR5-based immunotherapies targeting all LGR5-expressing cancer types.

Generation and Validation of Anti-LGR5 Antibodies

LGR5 antibodies were generated by immunizing mice with the N-terminal 101 amino acids of the extracellular domain of human LGR5. Four LGR5-positive clones were isolated, which reacted exclusively with human and cynomolgus monkey LGR5, but not with murine LGR4, murine LGR5, or closely related human LGR4 and LGR6. Western blot analysis revealed that all four α-LGR5 clones specifically bound to antigen fragment 1 of LGR5, and epitope mapping identified the N-terminal 15 amino acids of LGR5 as the binding site, showing high-affinity interactions. Binding of the antibody to LGR5 did not interfere with the R-spondin1 ligand binding, nor did it impair LGR5's role in augmenting Wnt pathway activity, either for α-LGR5 or any previously reported LGR5 antibodies. α-LGR5 was able to specifically recognize overexpressed hLGR5 and cLGR5 in fixed cells by Western blot and immunofluorescence, and in live cells by flow cytometry, while showing no cross-reactivity with other LGR family members.

LGR5 sustains Wnt/β-catenin signaling by binding RSPO, which blocks RNF43/ZNRF3 activity and promotes Wnt receptor stabilization.Figure 1. Mechanism of LGR5 in Wnt/β-catenin signaling. (Morgan RG, et al., 2018)

Survey of LGR5 Expression in Healthy Tissues and Cancers

The study revealed that LGR5 is highly expressed in several cancers, particularly within a discrete group including colorectal cancer, hepatocellular carcinoma, and acute lymphoblastic leukemia (ALL). A significant expression window was observed between CRC, HCC, certain ALL cases, and healthy tissues. In most healthy tissues, LGR5 expression was extremely low or undetectable, presenting an opportunity to develop LGR5-targeted therapies with minimal impact on normal cells. The use of specific and well-validated antibodies, such as α-LGR5, was highlighted as a valuable diagnostic tool.

α-LGR5 Specifically Detects LGR5 Protein in Human Cancer Cell Lines

α-LGR5 antibodies were utilized to detect cellular expression of LGR5 in three human pre-B-ALL cell lines. It was found that LGR5 was predominantly localized to intracellular punctate structures, with major expression in internal vesicles and small transient plasma membrane pools. Immunofluorescence detection of LGR5 in LoVo colon cancer cells showed that expression was mainly intracellular, with little to no LGR5 detectable at the cell surface, suggesting that endogenous LGR5 primarily undergoes internalization. Endogenously expressed LGR5 was rapidly internalized from the plasma membrane via endocytosis, recycled back to the membrane, and targeted to lysosomal vesicles, and α-LGR5 was efficiently internalized into LGR5-overexpressing cell lines.

Validation of LGR5-based Antibody-Drug Conjugates (ADCs)

The high expression levels of LGR5 in specific malignancies, the rapid internalization kinetics of α-LGR5, and LGR5's lysosomal trafficking all provided a compelling rationale for using α-LGR5-based ADCs to target cancer cells. α-LGR5-ADCs demonstrated potent cytotoxicity against LGR5-positive cancer cells in vitro and exhibited significant antitumor effects in vivo in a human NALM6 pre-B-ALL mouse model, effectively suppressing tumor growth.

In Vitro and In Vivo Efficacy of LGR5-based BiTEs

Using the α-LGR5 scFv fragment, researchers engineered a humanized BiTE by fusing the α-LGR5 scFv to an α-CD3ε scFv, generating CL-BiTE. This construct showed high specificity and potent activation of human CD4+ and CD8+ T cells, effectively inducing cancer cell killing in vitro. In vivo, CL-BiTE co-injected with PBMCs into NALM6 tumor-bearing mice resulted in significant tumor growth inhibition, with approximately a two-fold reduction in tumor burden after treatment.

LGR5-targeted Cellular Therapy Effectively Targets NALM6 Cells

Based on the α-LGR5 scFv, LGR5-CAR-T cells were developed. These LGR5 scFv-CAR-T cells exhibited specific and robust cytotoxicity against tumor cells in vitro and showed excellent therapeutic efficacy in vivo. Treatment with LGR5 scFv-CAR-T cells significantly reduced tumor cell numbers in the bone marrow of treated animals, leading to a four-fold reduction in pre-B-ALL tumor burden compared to controls. The high specificity and potent antitumor activity of the LGR5 scFv-CAR system demonstrated its potential to effectively target multiple types of LGR5-positive cancers.

Conclusion

LGR5 represents a versatile therapeutic target that can be leveraged in ADC, BiTE, and CAR-T cell modalities to attack cancer cells. Although variations in in vivo efficacy were observed among the three strategies when targeting pre-B-ALL tumors, these complementary therapeutic approaches offer substantial flexibility to meet the diverse pharmacodynamic requirements across different LGR5-positive cancer types. The findings suggest that LGR5 is not only a useful research tool and biomarker but also provides a multifunctional building block for the development of highly effective immunotherapeutic combinations targeting a wide range of LGR5-expressing tumors.

References

  1. Razavi-Amoli SK, Omrani-Nava V, Heydari K, et al. LGR5 As a Potential Therapeutic Target for Breast Cancer: A Systematic Review and Meta-analysis. Curr Stem Cell Res Ther. 2023;18(5):690-698.
  2. Morgan RG, Mortensson E, Williams AC. Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic? Br J Cancer. 2018;118(11):1410-1418.
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