Anti-EphA2 antibodies decrease EphA2 protein levels in murine CT26 colorectal and human MDA-231 breast tumors but do not inhibit tumor growth.
The EphA2 receptor tyrosine kinase has been shown to be over-expressed in cancer and a monoclonal antibody (mAb) that activates and down-modulates EphA2 was reported to inhibit the growth of human breast and lung tumor xenografts in nude mice. Reduction of EphA2 levels by treatment with anti-EphA2 siRNA also inhibited tumor growth, suggesting that the anti-tumor effects of these agents are mediated by decreasing the levels of EphA2. As these studies employed human tumor xenograft models in nude mice with reagents whose cross reactivity with murine EphA2 is unknown, we generated a mAb (Ab20) that preferentially binds, activates, and induces the degradation of murine EphA2. Treatment of established murine CT26 colorectal tumors with Ab20 reduced EphA2 protein levels to approximately 12% of control tumor levels, yet had no effect on tumor growth. CT26 tumor cell colonization of the lung was also not affected by Ab20 administration despite having barely detectable levels of EphA2. We also generated and tested a potent agonistic mAb against human EphA2 (1G9-H7). No inhibition of humanMDA-231 breast tumor xenograft growth was observed despite evidence for >85% reduction of EphA2 protein levels in the tumors. These results suggest that molecular characteristics of the tumors in addition to EphA2 over-expression may be important for predicting responsiveness to EphA2-directed therapies.
Corporate Research Oncology, Berlex Biosciences, Richmond, CA 94804, USA.
David
D
Kiewlich
Jianhuan
J
Zhang
Cynthia
C
Gross
Wei
W
Xia
Brent
B
Larsen
Ronald R
RR
Cobb
Sandra
S
Biroc
Jian-Ming
JM
Gu
Takashi
T
Sato
David R
DR
Light
Tara
T
Heitner
Joerg
J
Willuda
David
D
Vogel
Felipe
F
Monteclaro
Andrzej
A
Citkowicz
Steve R
SR
Roffler
Deborah A
DA
Zajchowski
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000628:therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D036104:Receptor, EphA2 / Q000737:chemistry* / Q000276:immunology
D000911:Antibodies, Monoclonal; D036104:Receptor, EphA2