Treatment of non-Hodgkin's lymphoma xenografts with the HB22.7 anti-CD22 monoclonal antibody and phosphatase inhibitors improves efficacy.
OBJECTIVE
To examine the role of phosphatase inhibition on anti-CD22, HB22.7-mediated lymphomacidal effects.


METHODS
CD22 is a cell-surface molecule expressed on most B cell lymphomas (NHL). HB22.7 is an anti-CD22 monoclonal antibody that binds a unique CD22-epitope, blocks ligand binding, initiates signaling, and has demonstrated lymphomacidal activity. The SHP-1 tyrosine phosphatase is associated with the cytoplasmic domain of CD22. Sodium orthovanadate (NaV) is a phosphatase inhibitor. The SHP-1-CD22 interaction presents an opportunity to manipulate CD22-mediated signaling effects. In vitro cell culture assays and in vivo human NHL xenograft studies were used to assess the effects of phosphatase inhibition.


RESULTS
NaV caused dose dependent killing of NHL cells in vitro; when HB22.7 was given with NaV, antibody-mediated cell death was augmented. Flow cytometry showed that NaV-pretreatment resulted in less CD22 internalization after ligation with HB22.7 than did control cells. Studies in mice bearing Raji NHL xenografts showed that the combination of NaV and HB22.7 shrank NHL tumors more rapidly, had a higher complete response rate (80%), and produced the best survival compared to controls; no toxicity was detected. Studies using Raji cells stably transfected with SHP-1DN confirmed that these observations were due to SHP-1 inhibition.


CONCLUSIONS
The relatively specific association of SHP-1 with CD22 suggests that CD22-specific signal augmentation by phosphatase inhibitors can improve the clinical outcome of anti-CD22 based immunotherapy.
O'Donnell
Robert T
RT
Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Cancer Center, 4501 X Street, Suite 3016, Sacramento, CA 95817, USA.
Pearson
David
D
McKnight
Hayes C
HC
Ma
Ya Peng
YP
Tuscano
Joseph M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D051918:Sialic Acid Binding Ig-like Lectin 2; D014638:Vanadates; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6