WNTRIX INC — Department of Health and Human Services STTR Phase I: NCI

Description

PROJECT SUMMARY Antibody drug 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 LGR leucine rich repeat containing G protein coupled receptor is a seven transmembrane domain receptor that is highly upregulated expression in the majority of solid tumors including colorectal lung and ovarian cancers LGR functions as a receptor of the R spondin group of stem cell factors to potentiate Wnt signaling Remarkably LGR is rapidly internalized into intracellular vesicles in a constitutive fashion The highly upregulated expression of LGR 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 LGR Preliminary data showed that LGR mAbs conjugated with a potent cytotoxin were able to inhibit the growth of several cancer cell lines with high LGR expression in vitro and tumor xenografts in vivo Here we propose to determine the potency efficacy and therapeutic window of anti LGR ADCs in xenograft models of patient derived tumors to establish proof of principle for the use of LGR targeded ADCs for the treatment of LGR high tumors These results and conclusions may for the first time validate LGR 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 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