Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200

Abstract

Purpose: Samalizumab is a novel recombinant humanized monoclonal antibody that targets CD200, an immunoregulatory cell surface member of the immunoglobulin superfamily that dampens excessive immune responses and maintains self-tolerance. This first-in-human study investigated the therapeutic use of samalizumab as a CD200 immune checkpoint inhibitor in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM).

Experimental design: Twenty-three patients with advanced CLL and 3 patients with MM were enrolled in an open-label phase 1 study (NCT00648739). Patients were assigned sequentially to one of 7 dose level cohorts (50 to 600 mg/m2) in a 3 + 3 study design, receiving a single dose of samalizumab intravenously once every 28 days. Primary endpoints were safety, identification of the maximum tolerated dose (MTD), and pharmacokinetics. Secondary endpoints were samalizumab binding to CD200, pharmacodynamic effects on circulating tumor cells and leukocyte subsets, and clinical responses.

Results: Twenty-one patients received > 1 treatment cycle. Adverse events (AEs) were generally mild to moderate in severity. Samalizumab produced dose-dependent decreases in CD200 expression on CLL cells and decreased frequencies of circulating CD200 + CD4+ T cells that were sustained at higher doses. The MTD was not reached. Decreased tumor burden was observed in 14 CLL patients. One CLL patient achieved a durable partial response and 16 patients had stable disease. All MM patients had disease progression.

Conclusions: Samalizumab had a good safety profile and treatment was associated with reduced tumor burden in a majority of patients with advanced CLL. These preliminary positive results support further development of samalizumab as an immune checkpoint inhibitor.

Trial registration: ClinicalTrials.gov, NCT00648739 registered April 1, 2008.

Keywords: CD200; CLL; Immune checkpoint inhibitor; Multiple myeloma; Samalizumab.

Conflict of interest statement

Academic authors have nothing to disclose. MW, SJF, TU, AK, LL, CLB, and XP are employed by Alexion Pharmaceuticals, Inc.

Figures

Fig. 1

Each panel displays data for a single patient (indicated at the top of each graph) at baseline (Day 0) and after samalizumab dosing at the indicated time points. For simplicity, no more than the first 4 dosing cycles are shown. a. Percent change from baseline in CLL CD200 expression (mean channel fluorescence (MFI)) in CLL patients. b. Percent change from baseline in CD200+ CD4+ T cells (%) in CLL and MM patients

Fig. 2

Each vertical bar represents the maximum change obtained for a single patient, identified by the six digit code at the bottom of the graph, that had a baseline CT scan and at least one subsequent scan. The horizontal dotted line at 50% represents a cut-off above which lymph node enlargement represents progressive disease whereas the horizontal dotted line at − 30% represent a cut-off below which lymph node regression represents clinically significant improvement. Patient 107–602 (500 mg/m2 cohort) did not have a post-dose CT scan and was not evaluable