Periodic Reporting for period 1 - CONQR (Translation and Commercialization of a QSOX1-inhibitory Antibody Targeting the Tumor Microenvironment in Breast Cancer)
Reporting period: 2018-12-01 to 2020-05-31
We have developed inhibitory antibodies against Quiescin sulfhydryl oxidase 1 (QSOX1), a secreted enzyme that functions in assembly of extracellular matrix (ECM). QSOX1 is over-produced in adenocarcinomas and in tumor stroma, and the enzyme may play a role in ECM remodeling in cancer. We demonstrated that administration of QSOX1 inhibitory antibodies in mouse cancer models-- with a focus on a triple negative breast cancer (TNBC)-- decreases tumor growth and metastasis. Moreover, tumors of treated animals show impaired ECM organization. QSOX1 inhibitory antibody administration does not cause any noticeable negative effects on animal health, and, remarkably, treatment with antibody together with chemotherapy appears to partially alleviate the side effects of the chemotherapy. These promising observations motivate further steps toward commercialization for future use of QSOX1 inhibitory antibodies in human TNBC patients.
Of the various options for commercialization considered, we selected a partnership with a focused pharmaceutical company specializing in targeting the tumor microenvironment. There are a number of reasons for this choice. After exploring the fate of a few other microenvironment-directed drug candidates that reached clinical trials but did not show a benefit in phase III studies, we decided that it is very important to fully characterize the mechanism of QSOX1 inhibitors and improve our understanding of the best indications for use before releasing control of the drug development project. The planned partnership with a focused company will provide funding for continuing research in the laboratory as well as logistics for the necessary outsourcing of experiments that cannot be done in-house. We are currently negotiating with a company that specializes in development of microenvironment-targeted precision drugs for cancer.
While exploring and identifying optimal entry points into the drug market, we made further progress in strengthening our pre-clinical package. We showed that QSOX1 inhibitory antibodies were also beneficial in a murine melanoma model, suggesting that the antibodies may be widely applicable. We chose, however, to focus on TNBC for further pre-clinical analysis in our laboratory, as this indication will be a suitable entry point into clinical trials, and the experimental systems have certain technical advantages. In addition to demonstrating efficacy in slowing tumor growth and metastasis, we also determined that administration of QSOX1 inhibitory antibody has no apparent detrimental effects on overall well-being of mice, nor does it interfere with important normal functions of QSOX1 in the body. Specifically, by studying QSOX1 knockout mice, we learned that QSOX1 in goblet cells of the gastrointestinal tract is involved in generating the protective mucus lining of the gut epithelium, making QSOX1 knockout mice more sensitive to induced colitis. However, as QSOX1 inhibitory antibodies do not target intracellular QSOX1, they do not cause the same sensitivity. Together with in vivo experiments validating the efficacy of QSOX1 inhibitory antibodies as disease therapeutics and confirming their safety, we also progressed in the protein biochemical engineering required to produce a humanized antibody variant suitable for clinical use.
Of the various options for commercialization considered, we selected a partnership with a focused pharmaceutical company specializing in targeting the tumor microenvironment. There are a number of reasons for this choice. After exploring the fate of a few other microenvironment-directed drug candidates that reached clinical trials but did not show a benefit in phase III studies, we decided that it is very important to fully characterize the mechanism of QSOX1 inhibitors and improve our understanding of the best indications for use before releasing control of the drug development project. The planned partnership with a focused company will provide funding for continuing research in the laboratory as well as logistics for the necessary outsourcing of experiments that cannot be done in-house. We are currently negotiating with a company that specializes in development of microenvironment-targeted precision drugs for cancer.
While exploring and identifying optimal entry points into the drug market, we made further progress in strengthening our pre-clinical package. We showed that QSOX1 inhibitory antibodies were also beneficial in a murine melanoma model, suggesting that the antibodies may be widely applicable. We chose, however, to focus on TNBC for further pre-clinical analysis in our laboratory, as this indication will be a suitable entry point into clinical trials, and the experimental systems have certain technical advantages. In addition to demonstrating efficacy in slowing tumor growth and metastasis, we also determined that administration of QSOX1 inhibitory antibody has no apparent detrimental effects on overall well-being of mice, nor does it interfere with important normal functions of QSOX1 in the body. Specifically, by studying QSOX1 knockout mice, we learned that QSOX1 in goblet cells of the gastrointestinal tract is involved in generating the protective mucus lining of the gut epithelium, making QSOX1 knockout mice more sensitive to induced colitis. However, as QSOX1 inhibitory antibodies do not target intracellular QSOX1, they do not cause the same sensitivity. Together with in vivo experiments validating the efficacy of QSOX1 inhibitory antibodies as disease therapeutics and confirming their safety, we also progressed in the protein biochemical engineering required to produce a humanized antibody variant suitable for clinical use.