Investigating the Mechanism of Internalization of the M610-IGF2 Complex

Background

Neuroblastoma is a pediatric cancer of the autonomic nervous system and is signified by its diversity. Tumors that express the high-risk phenotype are treated with intensive multimodality therapy but survival rates remain around 40%. The over-expression of insulin-like growth factor 2 (IGF2) is present in many neuroblastomas and is associated with a poor prognosis. We have developed a fully human IgG with a high affinity for IGF2 called m610 in collaboration with Dr. Dimiter Dmitrov's laboratory. The antibody was then converted into an Antibody-Drug Conjugate (ADC) with potent pyrrolobenzodiazepine (PBD) dimer payloads. In our preliminary studies, a number of findings indicated that treatment with an IGF2-targeting antibody-drug conjugate (ADC) was highly cytotoxic in vivo.

Project Goal

My project will focus on investigating the mechanism of internalization of the m610-IGF2 complex by IGF1R and if the m610-ADC is being internalized via this mechanism. I predict that m610-PBD is binding to IGF2 which remains in an intact protein complex with other IGF binding proteins (IGFBPs) and together are internalized upon binding to IGF1R on neuroblastoma cell surfaces in vivo. If this is the case, then this will lead us to a better understanding of the pathways utilized in the internalization of IGF2 and could allow more targeted therapies for children with neuroblastoma.