Objective

Antibody-drug conjugates have the potential to deliver specific cancer therapeutics to suitable targets ideally exhibiting little or no expression on normal cells yet with upregulated expression on cancerous tissue.  Here we describe an ADC program targeting the aberrant expression of ALK, a receptor tyrosine kinase expressed in neuroblastoma which is associated with poor prognosis in young patients.  ALK gene rearrangements resulting in the expression of dysregulated cytoplasmic ALK fusion proteins promote tumorigenesis in many tumour types.  ALK tyrosine kinase inhibitors have been employed for the treatment of ALK-rearranged tumours and often achieve marked regression, however, drug-resistance can limit use. While the oncogenic activity of ALK-fusion proteins has attracted much attention, the physiological function of full length, wild type ALK remains ambiguous. ALK expression is highly restricted to neuronal tissue during neonatal development and is largely undetectable in adults.  ALK has been recognised as a neuroblastoma tumour antigen associated with the failure of developing neural crest tissue to completely differentiate and hence represents a novel ADC target.  We will describe the selection and characterisation of ALK monoclonal antibodies and their conjugation to cytotoxic payloads to generate a potential ALK-ADC therapeutic effective in killing neuroblastoma cell lines in vitro.