designed the research, analyzed and interpreted the data, and published the manuscript; K.C.C., D.M.S., T.A.W., and J.E.J. rheumatoid arthritis,14 multiple sclerosis,15 ulcerative colitis,16 refractory celiac disease,17C18 type 1 diabetes,19 and diseases associated with the retrovirus HTLV-1.20 To address such putative IL-15Cmediated disorders, agents that inhibit IL-15 activity have been developed. These include soluble IL-15R, a dominant-negative IL-15 molecule, and antibodies specific for IL-15 or IL-2/IL-15R.21,22 The approach used in the present study involved a humanized Ab, Hu-Mik1, which is specific for IL-2/IL-15R.23C25 This Ab prevents presentation of IL-15, thus inhibiting IL-15Cmediated effects. 13 Hu-Mik1 has also been shown to extend cardiac allograft survival in cynomolgus monkeys.26 We previously translated these observations into a phase 1 clinical trial in individuals with T-cell large granular lymphocytic (T-LGL) leukemia with associated hematocytopenias23 using the murine mAb Mu-Mik1.23 The present study evaluated the safety, pharmacokinetics, and ability to saturate the IL-2/IL-15R and the immunogenicity of the humanized mAb Hu-Mik1 in individuals with monoclonal T-LGL with hematocytopenias. The majority of individuals with T-LGL have a clinically indolent program.27 However, a significant fraction is known to develop neutropenia, anemia, symptomatic splenomegaly, recurrent bacterial infections, and autoimmune disorders including rheumatoid arthritis.27 Several have studies suggested that IL-15 might play a role in the pathogenesis of T-LGL leukemia, including a network model of survival signaling in LGL.28,29 In addition, increased serum-soluble IL-15R levels were shown previously in patients with T-LGL leukemia.30 These studies offered the scientific basis for evaluating IL-2/IL-15R (CD122) blockade with Hu-Mik1 in patients with T-LGL leukemia and hematocytopenias.13,31 Previously, we conducted a phase 1 clinical trial that involved IL-15 blockade in T-LGL leukemia using the murine Mik1 mAb,23 but no efficacy was observed. Several factors may underlie this lack of effectiveness. One factor is that the period of blockade of IL-2/IL-15 receptors may have been insufficient because the murine mAb experienced a very short in vivo survival. Furthermore, in contrast to Hu-Mik1, murine Mik1 does not fix complement nor manifest Ab-dependent cellular cytotoxicity with human being mononuclear cells.24 To address these issues of pharmacokinetics and Rabbit Polyclonal to SRY function, a humanized form of Mik1 was generated.24 These characteristics of Hu-Mik1, but not the murine form, COG 133 were associated with COG 133 higher effectiveness in prolonging cardiac allograft survival inside a cynomolgus monkey model.26 A reason for performing initial studies of Hu-Mik1 in individuals with T-LGL leukemia rather than in individuals with autoimmune disorders was that the T-LGL group provides an excellent opportunity to accomplish classic phase 1 goals to define toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics because T-LGL leukemia, a very indolent stable disorder, does not usually require urgent treatment with chemotherapy. Furthermore, T-LGL leukemia cells communicate high levels of IL-2/IL-15R, the prospective of Hu-Mik1. Methods Hu-Mik1 (anti-CD122) Tsudo et al defined 3 unique mAbs, including Hu-Mik1, that interacted with IL-2/IL-15R -chain.31 Humanization of Hu-Mik1 is layed out in supplemental Methods (available on the web page; see the Supplemental Materials link at the top of the online article).24 Patient population and treatment plan Eligibility requirements were as follows: histologically confirmed T-LGL leukemia; an absolute C3+CD8+CD4?CD57+ T-LGL cell count 1000/L; 50% of T cells must communicate CD122 (IL-2R/IL-15R); hematocytopenia defined as an absolute granulocyte count of 1000/L, platelet count 100 000/L, or hemoglobin 10 g/dL, or a requirement of transfusion of 3 or more units of blood in the last 6 months for LGL-related anemia; age 18 years and circulating mononuclear cells comprising a monoclonal T-cell human population as shown by PCR analysis of the TCR -c rearrangement. Individuals were came into at 3 sequential dose levels of Hu-Mik1. Groups of 3 individuals each received 0.5, 1.0, or 1.5 mg/kg as a single IV dose. Adverse COG 133 events were assessed using the National Tumor Institute Common Toxicity COG 133 Criteria Version 3.0. The study was authorized by the National Tumor Institute institutional review table and by the Food and Drug Administration, was conducted in accordance with the Declaration of Helsinki protocol, and all individuals gave written knowledgeable consent. See Table 1 for any description of the individuals. Nine individuals having a mean age of 65 years (range, 49-82), 7 males and 2 females, 8 whites and 1 Hispanic were treated. One individual experienced rheumatoid arthritis and an additional 5 individuals experienced detectable serum rheumatoid element (range, 32-540 /mL). Seven individuals were anemic (hemoglobin 10 g/L) and 2 experienced thrombocytopenia. Leukocyte counts ranged from 3000-17 000 COG 133 (geometric imply, 9213/L), the geometric imply absolute lymphocyte count was 8650/L (range, 2109-16 016/L), the neutrophil counts ranged from 57-996/L (geometric imply, 593/L). The number of leukemic cells characterized as CD4?CD8+CD122+ ranged.