Development and Optimization of A Conjugable Junction-Opener Adenoviral Protein as A Co-Therapeutic Against Solid Tumors Jiho Kim1,2, Sean Gray2, Andre Lieber3, Darrick Carter1,2,3 1Pathobiology, Department of Global Health, University of Washington, Seattle WA; 2PAI Life Sciences, Seattle WA; 3Division of Medical Genetics, School of Medicine, University of Washington, Seattle WA
Although much progress has been made in cancer treatment with the advent of immunotherapy, there remain many issues when treating solid tumors - especially the physical barriers which cancers erect as a defense from therapeutics and the penetration of immune cells. Previous research indicates that the accessibility and penetrability of the tumor interior is an important factor for the success of various modes of therapy, including immunotherapy. Adenoviral proteins, which naturally bind human cell surface proteins of importance in cell attachment and cell-cell junctions, can be engineered as promising co-therapeutics. We have developed an adenovirus subtype 3 knob protein, named “Junction Opener” (JO). JO can bind and cause cleavage of DSG2, a key protein which in cancers forms tight junctions, barring entry of immune cells and drugs into the solid tumor. Transient openings of these junctions result in increased penetration of particles into the tumor, and improved survival in animal models in combination with conventional chemotherapy. JO has been found to accumulate at tumor sites due to dsg2 overexpression and increased accessibility of DSG2 in the disorganized junctions found in cancers. To capitalize on JO's localization to tumors, a conjugable form of JO was generated by removing all internal natural cysteines in the protein and introducing a cysteinyl residue at its terminus to allow targeted sulfhydryl-mediated conjugation to other molecules such as radioisotopes, drugs, or immune agonists. This conjugatable form, JOC, does not differ significantly from JO in in vitro DSG2 binding and cleaving activity. Several candidate molecules were tested as conjugates to JOC including DOTA for isotope chelation and biotin for streptavidin linking with no significant compromise in activity. Co-administration of JOC and other therapies - including CAR-T cells, oncolytic viruses, and other chemotherapeutics is being investigated in in vivo solid tumor (breast, ovarian) models. JOC promises many uses in therapy or imaging, leveraging multiple conjugated moieties.
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