Abstract 1934 MIRVing Towards a Clearer Future

Platinum-resistant ovarian cancer (PROC) has many forms of treatment, the current most aggressive and effective treatment is Mirvetuximab Soravtansine (MIRV). MIRV is a biomarker-driven antibody-drug conjugate composed of the antibody Mirvetuximab linked with a non-cleavable linker to the cancer drug soravtansine, targeting folate receptor alpha (FRα). While MIRV is the most effective treatment to date, one of the most common side effects is ocular events and even blindness. Ocular events occur in nearly 60 percent of patients, and The Mayo Clinic considers blindness a "common side effect." Off-target effects of MIRV's payload molecule that have toxic effects on the cells within the epithelial layer of the cornea. We hypothesize that increasing the binding affinity between the antibody and the conjugate would mitigate the issue of off-target effects that lead to ocular events and blindness. To increase binding affinity it is necessary to use sulfur bonds on the amino group 239 to link the conjugate to the antibody, instead of the currently used oxygen-nitrogen bonds on the amino groups of 231 to 238, as this new bond could help stabilize the ADC. The amino group of 239 is cystine, which uses sulfur to bond, allowing us to utilize a sulfur binding site, as the catenation power of a disulfide bond leads to high bond enthalpy, leading to greater affinity when compared to the current binding method. As both the antibody and the conjugate naturally use sulfur bonds there is no need to change either the antibody or the conjugate. Since the structure does not need to be changed, only a sulfur to sulfur catalyst must be added when scientists are combining the two molecules in order to support a sulfur to sulfur bond rather than a oxygen-nitrogen bond. This increased affinity helps to mitigate the off-target effect of MIRV and helps eradicate ocular events as a result of the drug.