JOC-x: Chemotherapy conjugates that open tumor tight junctions to treat cancer

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Principal Investigator: DARRICK Albert CARTER
Organization: PAI LIFE SCIENCES, INC.
Fiscal Year: 2019
Award: $720,945
Funding agency: National Cancer Institute

PROJECT SUMMARY
A central mechanism of tumor drug resistance is the maintenance of tight junctions between
malignant cells preventing penetration of molecules into the tumor microenvironment. We have
generated junction openers (“JO”) that are small proteins that bind to desmoglein 2 (DSG2), a
junction protein that is overexpressed in many cancers. Intravenous injection of JO increases
tumor penetration and efficacy of many types of cancer therapy. Our studies have shown that the
effective doses of chemotherapy can be reduced when the drugs are combined with JO. JO
accumulates in tumor tissue as much as 100-fold above normal tissues making it a targeting
mechanism to tumors. We have also published that application of JO has not been associated
with toxicities in hDSG2 transgenic mice and that the co-administration of JO and chemotherapy
was well tolerated in non-human primates.
In phase 1 we were able to show that: (1) we can make JOC-x conjugates for a number of cancer
treatment and imaging applications; and (2) that the JOC-x constructs retain their activity in tumor
models. We now are motivated to build on the promising data generated in phase 1 and move
these conjugates towards clinical testing by: (1) Preparing JOC-x for cGMP compliant production
by process development, scaling, and writing manufacturing batch records; (2) Producing JOC-x
conjugates with distinct functionalities to demonstrate utility and flexibility of the platform; and (3)
Testing these JOC-x conjugates in animal models
At the conclusion of the research proposed here we will have produced a conjugatable tumor tight
junction opening candidate that can be used in a number of embodiments. Each of the products
could become stand-alone therapeutics and be developed towards clinical testing.

Terms: <Agonist><Animal Model><Animal Models and Related Studies><Back><Binding><Binding Proteins><Biological><Caelyx><Cancer Model><Cancer Treatment><CancerModel><Cancers><Carcinoma><Chromatography><Clinical><Clinical Evaluation><Clinical Testing><Clinical Treatment Moab><Coupled><Cyclic GMP><Cysteine><DOX SL><DOXSL><Data><Development><Dorsum><Dose><Doxilen><Doxorubicin HCl Liposome><Doxorubicin Hydrochloride Liposome><Drug resistance><Drugs><Ensure><Epithelial><Epithelial cancer><Epithelium><Epithelium Part><Evacet><Fermentation><Guanosine Cyclic Monophosphate><Half-Cystine><Heterograft><Heterologous Transplantation><Human><Image><Immune><Immune Targeting><Immunes><Immunologically Directed Therapy><Immunotherapy><Intravenous><L-Cysteine><L-Serine><Ligand Binding Protein><Ligand Binding Protein Gene><LipoDox><Liposomal Doxorubicin Hydrochloride><Maintenance><Malignant Cell><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Medication><Methodology><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Myocet><Normal Tissue><Normal tissue morphology><Occluding Junctions><Oncolytic viruses><Ovary Cancer><Particle Size><Patients><Pegylated Liposomal Doxorubicin><Penetration><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Phase I Study><Plant Embryos><Plant Zygotes><Poly I-C><Polyinosinic-Polycytidylic Acid><Polymers><Process><Production><Protein Binding><Proteins><Publishing><Recombinant Proteins><Records><Reproducibility><Research><S-Liposomal Doxorubicin><Seeds><Serine><Signal Pathway><Site><Stealth Liposomal Doxorubicin><Sterically Stabilized Liposome><T cell based therapeutics><T cell based therapy><T cell therapy><TLR3><TLR3 gene><Testing><Therapeutic><Therapeutic Effect><Tight Junctions><Toll-Like Receptor 3><Toxic effect><Toxicities><Transgenic Mice><Treatment Efficacy><Tumor Tissue><Work><Writing><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><Zonula Occludens><adoptive T cell transfer><adoptive T-cell therapy><anti-cancer therapy><anticancer therapy><bound protein><cGMP><cancer cell><cancer imaging><cancer microenvironment><cancer therapy><cancer type><chemotherapy><clinical test><desmoglein 2><desmoglein II><desmosomal glycoprotein 2><developmental><doxil><drug resistant><drug/agent><epithelial carcinoma><epithelial to mesenchymal transition><flexibility><flexible><global health><imaging><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><in vivo><in vivo evaluation><in vivo testing><intervention efficacy><intravenous injection><lipid nanoparticle><mAbs><malignancy><model of animal><model organism><neoplasm/cancer><non-human primate><nonhuman primate><oncologic imaging><oncology imaging><ovarian cancer><overexpress><overexpression><phase 1 study><poly IC><prevent><preventing><research clinical testing><resistance to Drug><resistant to Drug><scale up><seed><therapeutic efficacy><therapeutically effective><therapy efficacy><tumor><tumor imaging><tumor microenvironment><xeno-transplant><xeno-transplantation>