Antibody Drug Conjugate Designs to Enhance the Therapeutic Window for Brain Tumors - PROJECT DESCRIPTION/ABSTRACT Glioblastoma, IDH-wildtype (GBM) is the most common and most lethal primary brain cancer. Despite tremendous research efforts, the last FDA drug approval for newly diagnosed GBM was temozolomide in 2005, and these tumors invariably recur with a median survival of only 16 months. Thus, there is a tremendous unmet medical need to develop effective therapies for this disease. Antibody drug conjugates (ADCs) are a rapidly growing class of molecularly targeted therapeutics with impressive clinical activity in various solid malignancies. ADCs capitalize on tumor-specific monoclonal antibodies to deliver highly potent toxins into tumor cells, while limiting exposure to normal tissues. Given this potential for selective tumor therapy, we have been investigating the potential of ADCs in GBM for over five years. GBM express a number of tumor antigens for which ADCs have been developed including Epidermal Growth Factor Receptor (EGFR) and B7 family of immune-regulatory checkpoint protein (B7H3). In partnership with AbbVie, members of our team evaluated three EGFR-targeted ADCs in a panel of GBM patient-derived xenografts (PDXs). These studies demonstrated that i) most EGFR-amplified GBM grown as heterotopic tumors are profoundly sensitive to these ADCs, ii) restricted delivery across the blood-tumor barrier after systemic dosing limits the efficacy of the same ADCs in most orthotopic PDXs, iii) direct infusion of ADCs into brain tumors using convection enhanced delivery (CED) can be highly efficacious, and iv) neuronal toxicity of ADCs delivered into the brain is highly dependent on stability of the linker. These key findings provide the overall rationale for this R01 that is focused on engineering ADCs specifically designed to enhance the therapeutic window for treatment of GBM and other cancers within the central nervous system. Importantly, the work proposed is only possible with the collective expertise of our key team members: Dr. Kyoji Tsuchikama (MPI) is a medicinal chemist and leader in ADC engineering, Dr. Jann Sarkaria (MPI) is an expert in translational development of novel therapeutic strategies for GBM, and Dr. William Elmquist (Co-I) is a world-leader in the pharmacokinetics of drug distribution in the central nervous system. With this team, we will address key challenges in the development of ADCs as a therapy for GBM in three specific Aims. Aim 1: Develop novel linker chemistries to improve stability of ADCs in the brain Aim 2: Evaluate the potential to limit neuronal toxicity through optimized toxin selection Aim 3: Evaluate novel ADC therapeutic strategies to address tumor heterogeneity
