CD22 is a cell-surface adhesion molecule on most B-cell NHL, so it is a promising target for immunotherapy. HB22.7 is an anti-CD22 mAb that binds the two NH2-terminal immunoglobulin domains and specifically blocks the interaction of CD22 with its ligand. CD22-blocking mAbs induce apoptosis in neoplastic B-cells and are functionally distinguishable from other anti-CD22 mAbs. This study assessed the optimal dose, route, schedule, and the targeted CD22 epitope. Raji NHL-bearing nude mice were studied. A non-blocking anti-CD22 mAb (HB22.27) was used as a control. HB22.27 had minimal effect, whereas HB22.7 improved survival and shrank tumors substantially. HB22.7 doses greater than 1.4 mg/week did not further increase efficacy (or toxicity). Tumors less than 200 mm3 had a higher response rate than did larger tumors. Various schedules of HB22.7 administration were tested; one dose every other week was more effective than more or less frequent dosing. Pharmacokinetic studies revealed that the half-life of HB22.7 was 28 days; this correlated with the time needed to re-populate cell-surface CD22 after treatment with HB22.7. Immuno-PET showed that NHL was rapidly and specifically targeted by copper-64-labeled-HB22.7. This study provided data as to an optimal dose, route, schedule and interval between doses of HB22.7.