Targeting 11q23 positive acute leukemia cells with high molecular weight-melanoma associated antigen-specific monoclonal antibodies.
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.
Drake
Allison S
AS
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Brady
Michael T
MT
Wang
Xin Hui
XH
Sait
Sheila J N
SJ
Earp
Justin C
JC
Ghoshal Gupta
Sampa
S
Ferrone
Soldano
S
Wang
Eunice S
ES
Wetzler
Meir
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002470:Cell Survival; D002880:Chromosomes, Human, Pair 11; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D000099216:Chondroitin Sulfate Proteoglycan 4
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000099216:Chondroitin Sulfate Proteoglycan 4