Abstract LB-305: Soluble CD23 levels increase following lumiliximab dosing in relapsed chronic lymphocytic leukemia patients

Abstract

Abstract Lumiliximab is an anti-CD23 monoclonal antibody under investigation for the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL). Lumiliximab binds specifically to human CD23, a glycoprotein expressed on the majority of CLL B cells. CD23 is a trimeric molecule with both membrane-bound (mCD23) and soluble (sCD23) forms. mCD23 is a 45 kD glycoprotein expressed on B cells, monocytes/macrophages, eosinophils, platelets, and dendritic cells, with increased levels observed on chronic lymphocytic leukemia (CLL) cells. Soluble CD23 is produced by the cleavage of mCD23 by endogenous proteases into various fragments, with the 25 kD fragment found in normal human serum at concentrations around 2 ng/ml. Increased levels of sCD23 are found in the serum of patients with several disease states including CLL. Data from a Phase 1 lumiliximab monotherapy trial in relapsed CLL showed that levels of sCD23 rapidly increased in the serum of some patients after dosing with lumiliximab. To confirm this phenomenon, serum sCD23 levels and their relationship with treatment response were evaluated in a Phase 1/2 study of lumiliximab in combination with fludarabine, cyclophosphamide, rituximab (FCR) in patients with relapsed CLL. The pharmacokinetic (PK) profiles of both lumiliximab and rituximab were also compared to sCD23 profiles. Methods: Thirty-one patients with relapsed CLL were enrolled to receive up to 6 cycles treatment with lumiliximab plus FCR. Lumiliximab PK, Rituxan PK and sCD23 levels were each measured in 31 patients using validated enzyme-linked immunosorbant assays. PK data was analyzed with WinNonlin. Results and Conclusions: Our analysis shows that sCD23 increases from the ng/ml range to the ug/ml range immediately after each dosing with lumiliximab/FCR, then declines throughout the remainder of the treatment cycle. The levels of sCD23 increase again with subsequent lumiliximab/FCR doses, until the there are little to no B-CLL cells remaining in the circulation. The pattern of increase parallels the PK profile of lumiliximab. The intensity of sCD23 increase varied from patient to patient, and did not appear to correlate with treatment outcome. These data demonstrate that although lumiliximab/FCR dosing increases serum levels of sCD23, there is no apparent impact on patient response. This will be evaluated further in upcoming clinical trials. The mechanism of sCD23 release is also currently being investigated.