Antibodydrug conjugates (ADCs) are monoclonal antibodies (mAbs) that are covalently linked to cell-killing drugs and have emerged as a major modality in anti-cancer treatment. This approach combines high specificity of mAbs against their antigen targets with highly potent cytotoxic drugs, resulting in armed mAbs that deliver the payload (drug) to tumor cells with enriched levels of the antibody target. As antibody engineering and linker-payload optimization are becoming mature, the discovery and development of new ADCs is increasingly dependent on the identification and validation of new targets that are suitable to this approach. LGR4 (leucine-rich repeat containing, G protein-coupled receptor 4) is a seven transmembrane domain receptor that is highly upregulated expression in the majority of solid tumors, including colorectal, lung, and ovarian cancers. LGR4 functions as a receptor of the R-spondin group of stem cell factors to potentiate Wnt signaling. Remarkably, LGR4 is rapidly internalized into intracellular vesicles in a constitutive fashion. The highly upregulated expression of LGR4 in tumor cells and its robust internalization make it a potential target of the ADC approach for the treatment of major types of solid tumors. We have generated and characterized a panel of highly potent and specific mAbs against native LGR4. Preliminary data showed that LGR4 mAbs conjugated with a potent cytotoxin were able to inhibit the growth of several cancer cell lines with high LGR4 expression in vitro and tumor xenografts in vivo. Here we propose to determine the potency, efficacy, and therapeutic window of anti-LGR4 ADCs in xenograft models of patient-derived tumors to establish proof-of-principle for the use of LGR4-targeded ADCs for the treatment of LGR4-high tumors. These results and conclusions may, for the first time, validate LGR4 as a novel target for the development of ADC-based therapeutics that has the potential to treat a large population of cancer patients.
Public Health Relevance Statement: Public Health Relevance Statement: Project title: Investigation of antibody-drug conjugates of a novel target Contact P.I. Jie Cui Statement: Cancer remains a leading cause of death in the world. The proposed study aims to establish proof-of-principle in preclinical models for the use of drug conjugates of monoclonal antibodies against a novel membrane receptor that is highly upregulated in substantial fractions of all major types of solid tumors. The work may lead to the discovery and development of a novel class of therapeutics for the treatment of cancer patients.
Project Terms: Adverse effects; Affinity; Antibodies; antibody conjugate; antibody engineering; Antibody-drug conjugates; Antigen Targeting; Antineoplastic Agents; Automobile Driving; base; Binding; Biotechnology; cancer cell; Cancer cell line; Cancer Patient; cancer therapy; Cause of Death; cell killing; Cell Line; Clinic; Clinical; Colorectal; Colorectal Cancer; cytotoxic; Cytotoxic agent; cytotoxicity; Cytotoxin; Data; design; Development; drug development; Drug Kinetics; Drug usage; Endocytosis; Epithelial; Gene Expression; Gene Fusion; Generations; Goals; GPR4 gene; Growth; Hand; Human; improved; In Vitro; in vivo; Incubators; Inhibition of Cancer Cell Growth; Investigation; Investments; Laboratories; Lead; Legal patent; Leucine-Rich Repeat; Ligands; Link; Lung Adenocarcinoma; Lysosomes; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant Neoplasms; Mediating; Medical center; Membrane; Methods; Modality; Modeling; Monoclonal Antibodies; neoplastic cell; novel; Oncogenic; Patients; Pharmaceutical Preparations; Phase; Population; Pre-Clinical Model; Preparation; public health relevance; receptor; Recurrence; Research; Role; Secure; Series; Signal Transduction; Solid Neoplasm; Specificity; stable cell line; Stem Cell Factor; System; Testing; Texas; Therapeutic; therapeutic development; therapy development; Time; Toxicology; Transmembrane Domain; tumor; tumor growth; tumor xenograft; Tumor-Derived; Universities; Validation; Vesicle; WNT Signaling Pathway; Work; Xenograft Model
