A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia

作者：He Simon Z^*; Busfield Samantha; Ritchie David S; Hertzberg Mark S; Durrant Simon; Lewis Ian D; Marlton Paula; McLachlan Andrew J; Kerridge Ian; Bradstock Kenneth F; Kennedy Glen; Boyd Andrew W; Yeadon Trina M; Lopez Angel F; Ramshaw Hayley S; Iland Harry; Bamford Simone; Barnden Megan; DeWitte Mark; Basser Russell; Roberts Andrew W

来源：Leukemia and Lymphoma, 2015, 56(5): 1406-1415.

DOI：10.3109/10428194.2014.956316

• Acute myeloid leukemia (AML)
• interleukin-3 (IL-3) receptor-alpha (CD123)
• leukemic stem cell (LSC)
• immunotherapy

Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-alpha (CD123). CSL360 is a recombinant, chimeric immunoglobulin G(1) (IgG(1)), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses >= 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.

• 出版日期2015-5
• 单位河北医科大学