Nonclinical safety evaluation and pharmacokinetics of Ab612, a novel anti-L1CAM (CD171) therapeutic antibody candidate against solid cancer.

L1 cell adhesion molecule (L1CAM, CD171) is a transmembrane glycoprotein important for nervous system development. Conversely, L1CAM is overexpressed in many human solid tumors with poor prognosis. Nonclinical safety evaluation and pharmacokinetics (PK) of Ab612, a human anti-L1CAM monoclonal antibody (mAb), were conducted to support a first-in-human (FIH) clinical trial for the treatment of L1CAM overexpressing tumors. A tissue cross-reactivity (TCR) assessment showed that Ab612 exhibited staining in various tissues from mouse, rat, canine, cynomolgus monkey, and human, including those associated with peripheral nerves, myenteric plexus, spinal nerve roots, and certain cell types, such as mononuclear cells (lymphocytes), cardiac Purkinje fibers, and epithelial cell in the lung and kidney. These findings were consistent with the reported expression of the L1CAM by these cell types. Dose range-finding (DRF) studies were conducted in rats and cynomolgus monkeys at doses up to 500 and 400 mg/kg, respectively, by intravenous (IV) administration once weekly for 2 weeks. Results showed no treatment-related adverse findings, and the maximum tolerated dose (MTD) was the highest dose tested. Four-week repeat-dose toxicity studies were conducted in rats and cynomolgus monkeys at doses up to MTD, by IV administration once weekly for 4 weeks with a 28-day recovery period. Results showed no treatment-related adverse findings, and the no-observed-adverse-effect-level (NOAEL) was the highest dose tested. Single dose PK studies in rats and cynomolgus monkeys with doses of 5-100 and 5-50 mg/kg, respectively, confirmed the PK in the expected range for mAbs. These preclinical data indicate no safety concerns and provide adequate safety margins for the planned dose levels in the FIH trial.