CD22 is a cell-surface molecule on most B-cells and B-cell non-Hodgkin’s lymphoma (NHL). A panel of anti-CD22 monoclonal antibodies (mAb) were developed and characterized. Some anti-CD22 mAb bind CD22 but do not stimulate intracellular signaling. However, HB22.7 is an anti-CD22 mAb that binds a unique CD22-epitope, blocks ligand binding, and its binding initiates an intracellular signaling cascade. Sodium orthovanadate (NaV) is a non-specific phosphatase inhibitor whose effect on CD22-mediated signaling in NHL cells was tested with and without HB22.7. Compared to other B-cell receptors, the SHP-1 tyrosine phosphatase is disproportionately associated with the cytoplasmic domain of CD22; NaV inhibits SHP-1. The SHP-1/CD22 interaction presents an opportunity to manipulate CD22-mediated signaling and thus has implications for NHL therapy. Methods: Cultured human NHL cell lines were assessed by trypan blue exclusion for efficacy of treatment with varying concentrations of NaV and HB22.7. Flow cytometry was used to assess how pre-incubation of NHL-cells with NaV before treatment with HB22.7 effected the internalization of CD22 and its cell-surface concentration. Intracellular staining for phospho-p38 and activation of SAP kinase were assessed by flow cytometry. Finally, nude mice bearing Raji (human NHL) xenografts were treated with HB22.7 with and without repeated administrations of oral NaV. Tumor volume, response rate and survival were assessed over the 84-day study period. Results: NaV (1– 100 μM) caused a dose dependent killing of Ramos NHL cells in vitro. When HB22.7 (10 or 30 μg) was given along with NaV cell death was augmented. Flow cytometry of three NHL cell lines (DOHH-2, Karpas, and Ramos) demonstrated that pre-treatment with NaV resulted in less internalization, and more persistence of CD22 on the cell-surface after ligation with HB22.7 than did cells not pretreated with NaV. P38 is a known mediator of CD22 signals. When Ramos cells were pre-treated with NaV a substantial enhancement of phospho-p38 was detected when CD22 was ligated with HB22.7 as compared to either agent alone. Similarly, pretreatment of Ramos cells with NaV resulted in a substantial increase in HB22.7-mediated phosphorylation of SAP kinase as compared to the controls. Pretreatment with NaV did not affect IgM-mediated signals. Studies in nude mice bearing Raji NHL xenografts showed that the in vitro data had applicability to this murine model. Control (untreated) mice and those treated thrice weekly with NaV (150 μg) showed relentless tumor growth and no pattern of response. Mice treated with HB22.7 (2.1 mg, intravenously; 4 doses) had slowing tumor growth by day 21, then regression; there was a 50% complete response rate. Mice treated with the same doses of both NaV and HB22.7 had a more rapid anti-NHL response, less tumor growth, 80% complete responses and the best survival rate. No toxicity could be detected in mice due to NaV treatment. Conclusion: NaV can increase the expression and/or persistence of cell-surface CD22, effect signaling stimulated by HB22.7, and alter or enhance intracellular signaling pathways in ways beneficial to NHL cell killing without observed toxicity in the mouse model. Further experiments will refine the use of these agents in pre-clinical studies of NHL therapy.