Targeting 11q23 positive acute leukemia cells with high molecular weight-melanoma associated antigen-specific monoclonal antibodies |
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Authors: | Allison?S?Drake Michael?T?Brady Xin?Hui?Wang Sheila?J?N?Sait Justin?C?Earp Sampa?Ghoshal Soldano?Ferrone Eunice?S?Wang Meir?Wetzler |
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Institution: | Allison S. Drake, Michael T. Brady, Xin Hui Wang, Sheila J. N. Sait, Justin C. Earp, Sampa Ghoshal (Gupta), Soldano Ferrone, Eunice S. Wang and Meir Wetzler |
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Abstract: | Background Acute leukemia with 11q23 aberrations is associated with a poor outcome with therapy. The lack of efficacy of conventional
therapy has stimulated interest in developing novel strategies. Recent studies have shown that 11q23-positive acute leukemia
cells express the high molecular weight-melanoma associated antigen (HMW-MAA). This tumor antigen represents a useful target
to control growth of human melanoma tumors in patients and in severe combined immunodeficient (SCID) mice, utilizing antibody-based
immunotherapy. This effect appears to be mediated by inhibition of the HMW-MAA function such as triggering of the focal adhesion
kinase/proline-rich tyrosine kinase 2 (Pyk2) pathways. Therefore, in this study we tested whether HMW-MAA-specific monoclonal
antibodies (mAb) could inhibit growth of 11q23-positive leukemia cells in SCID mice.
Methods HMW-MAA-specific mAb were tested for their ability to inhibit the in vitro proliferation of an 11q23-positive acute myeloid
leukemia (AML) cell line and blasts from four patients with 11q23 aberrations and their in vivo growth in subcutaneous and
disseminated xenograft models.
Results The HMW-MAA-specific mAb did not affect in vitro proliferation although they down-regulated phosphorylated (P) Pyk2 expression.
Furthermore, the mAb enhanced the in vitro anti-proliferative effect of cytarabine. In vivo the mAb inhibited the growth of
leukemic cells in a dose-dependent fashion. However, the difference did not reach statistical significance. No effect was
detected on P-Pyk2 expression. Furthermore, HMW-MAA-specific mAb in combination with cytarabine did not improve tumor inhibition.
Lastly, the combination of two mAb which recognize distinct HMW-MAA determinants had no detectable effect on survival in a
disseminated xenograft model.
Conclusions HMW-MAA-specific mAb down-regulated P-Pyk2 expression and enhanced the anti-proliferative effect of cytarabine in vitro, but
had no detectable effect on survival or growth of leukemia cells in vivo. Whether the HMW-MAA-specific mAb can be used as
carriers of toxins or chemotherapeutic agents against 11q23-acute leukemia remains to be determined. |
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Keywords: | Acute leukemia 11q23 HMW-MAA Immunotherapy |
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