Effect of a fully human anti-CD70 antibody on apoptosis and dephosphorylation of MAPK proteins in chronic lymphocytic leukemia

[Guest guest]

Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting

Edition).

Vol 26, No 15S (May 20 Supplement), 2008: 3073

Effect of a fully human anti-CD70 antibody on apoptosis and dephosphorylation of

MAPK proteins in chronic lymphocytic leukemia

C. A. Llanos, J. A. Terrett, L. Cohen, T. J. Kipps and J. E. Castro

University of California San Diego s Cancer Center, CLL Research

Consortium, La Jolla, CA; Medarex Pharmaceuticals, Princeton, NJ

3073

Background: CD70 is a member of the tumor necrosis factor receptor family and

receptor for CD27, which is expressed on activated T cells. Both CD70 and CD27

are expressed in chronic lymphocytic leukemia (CLL). Ligation of CD70 on normal

B or CLL cells may play a role in activation, suggesting co-expression of CD27

and CD70 might have pathophysiologic significance. MAbs specific for CD70 can

induce apoptosis of CD70+ carcinoma cells in vitro and in vivo in xenograft

models. As such, we investigated whether a novel fully human anti-CD70 antibody

(h-anti-CD70) could induce apoptosis of CLL cells. Methods: Blood mononuclear

cells from 12 patients with CLL and healthy volunteers were evaluated for

expression of CD70 by flow cytometry. Also, CLL cells were treated with h-anti-

CD70 (10-300 µg/ml) and evaluated after 24 hours culture by flow cytometry and

immunoblot analysis. Results: CLL cells of each examined case expressed levels

of CD70 that were significantly higher that noted on normal blood B cells. The

levels of CD70 on CLL cells from patients with high risk vs. low risk CLL (IgVH

mutation status or ZAP-70 level of expression) were comparable. CLL cells

treated with h-anti-CD70 underwent apoptosis at rates that were significantly

greater than that observed in control cultures. The CLL cells from each of the

12 cases studied underwent apoptosis when treated with h-anti-CD70. This was

associated with apparent dephosphorylation of MAPK proteins that typically are

phosphorylated in CLL cells and that have been associated with cellular

activation. Conclusions: CLL cells express high levels of CD70 independent of

whether they have features of high-risk disease. Ligation of CD70 with

h-anti-CD70 induced specific apoptosis of CLL cells in all samples tested.

Decreased viability was associated with loss of phosphorylated MAPK kinases. Our

findings suggest that CD70 is a relevant target in CLL for therapeutic

development and support the rationale for the use of h-anti-CD70 in future

clinical trials.