Abstract C62: 5A2, a new IL-3Ra (CD123) monoclonal antibody for the treatment of AML.

Acute myeloblast leukemia (AML) is a classic stem cell disease driven by leukemic stem cells (LSCs). LSCs in general are resistant to the existing therapies and the current treatment prognosis are rather poor. Targeting AML-LSCs has thus been suggested as a new potential approach to improve the current treatment. IL-3 receptor -chain (IL-3R, or CD123) has been shown over-expressed on leukemic blasts, progenitors and LSCs. CD123 signaling contributes to leukemic development. CD123 may thus represent a suitable target for monoclonal antibody based treatment approaches against AML. We immunized mice with purified IL3RA ECD/Fc fusion protein and the IL3RA expressing plasmid respectively. From the immunized mice we generated 3 and 8 hybridoma cell lines that secreted monoclonal antibodies recognize to IL3RA ECD/Fc and CD123 expressed on TF-1 (a CD123 expressing AML cell line) and 8G9 (a CD123 stable-expressing CHO established by us). In particular, among the 11 positive cell lines, one of the antibodies, 5A2, was confirmed with antagonist property to block the binding of IL-3/IL3RA. We demonstrated that 5A2 dose-dependently suppresses the IL-3 induced proliferation of TF-1 cells. In addition, 5A2 can also efficiently internalize into TF-1 cells. These observations suggest that 5A2 can be a potential candidate for development as an antibody based therapy against AML. At present, we are in process of further characterizing 5A2 (including determination of K d , epitope, cross-species reactivity, inhibition of ex vivo proliferation of patient leukemic cells, along with in vivo efficacy in a suitable animal model, etc. ). We are also initiating humanization of 5A2 to identify clinical candidate. We plan to also report and discuss the progresses on some of these studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C62.