ABY-029, an anti-epidermal growth factor receptor (EGFR) Affibody molecule labeled with IRDye 800CW, has been used in three Phase 0 microdosing clinical trials for fluorescence guided surgery. In May of 2019, the clinical trials were put on hold because the ABY-029 produced under Good Manufacturing Practices (GMP) for human administration had come to the end of term in which the drug product was known to be stable. Stability testing was halted due to limitations in supply of a suitable reference standard and a required test product being discontinued from commercial sale. In order to complete the remaining patients in the three clinical trials, new stability tests were developed and the GMP batch of ABY- 029 drug product tested under the new protocols. The GMP batch of ABY-029 passed all stability tests under the new protocols and the Federal Drug Administration (FDA) has given permission to complete the remaining patients with stability testing of ABY-029 performed for each patient. The tests developed and used to test ABY-029 drug product stability are described here.
Near-infrared (NIR) fluorescence combined with targeting epidermal growth factor receptor (EGFR) overexpression for surgical guidance in many cancers is gaining momentum. ABY-029 is an anti-EGFR Affibody molecule conjugated to IRDye 800CW that is FDA approved as an exploratory Investigational New Drug (eIND 122681). ABY-029 has a short plasma half-life (~15-20 minutes), which allows for administration of the imaging agent and excision surgery to occur on the same day unlike fluorescent antibodies. This fast tissue clearance may provide the means necessary to achieve clinically relevant tumor-to-normal tissue contrast levels using microdosing administration schemes. Pre-clinical studies have indicated that tumor-to-normal tissue contrast peaks between 4-8 hours depending on EGFR expression. Additionally, the No Observable Adverse Effect Level (NOAEL) was determined in pre-clinical toxicity studies to be 1,000X the microdose, or 30 micromole, whereas mild adverse events are common in antibody imaging studies. A number of promising first-in-human clinical Phase 0 trial microdose evaluation of ABY-029 have been initiated for recurrent glioma, soft-tissue sarcoma, and head and neck cancers (NCT0290925, NCT03154411, and NCT03282461, respectively). Here, we provide an update on our experience using ABY-029 for surgical resection at microdose levels and describe tissue contrast and correlation of ABY-029 fluorescence to EGFR tissue expression. Current progress indicates that moderate TBRs (~3-5) are observable at the microdose administration level but increased administration doses (3X and 6X microdoses) are being investigated. In addition, ex vivo tissue fluorescence is highly correlated to EGFR staining in both intensity and spatial localization.