Targeting 11q23 positive acute leukemia cells with high molecular weight-melanoma associated antigen-specific monoclonal antibodies.

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.

• Authors: Allison S Drake, Michael T Brady, Xin Hui Wang, Sheila J N Sait, Justin C Earp, Sampa Ghoshal Gupta, Soldano Ferrone, Eunice S Wang, Meir Wetzler
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 58 Issue 3 Pg. 415-27 (Mar 2009) ISSN: 1432-0851 [Electronic] Germany
• PMID: 18677475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• HMW-MAA

Topics

• Animals
• Antibodies, Monoclonal (metabolism)
• Antigens, Neoplasm (metabolism)
• Cell Survival
• Chromosomes, Human, Pair 11
• Female
• Humans
• Immunotherapy (methods)
• Leukemia (genetics, metabolism)
• Melanoma (metabolism)
• Mice
• Mice, SCID
• Molecular Weight
• Neoplasm Transplantation