Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease.

The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an ¹¹¹In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channel-blocking IC50 value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.

A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin's lymphoma.

PURPOSE: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. EXPERIMENTAL DESIGN: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). RESULTS: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. CONCLUSIONS: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.

Combination immunotherapy of B-cell non-Hodgkin's lymphoma with rituximab and interleukin-2: a preclinical and phase I study.

PURPOSE: Cytokine-induced modulation of innate immunity is being explored to enhance the activity of monoclonal antibodies. Severe combined immunodeficient (SCID) mice engrafted with peripheral blood leukocytes (PBLs) from Epstein Barr virus-seropositive donors develop human B-cell non-Hodgkin's lymphomas [B-NHLs (hu-PBL-SCID mouse model)]. We used this hu-PBL-SCID mouse model to study the synergism between interleukin (IL)-2 and rituximab. We also conducted a phase I trial of IL-2 and rituximab in relapsed B-NHL to study whether expansion of natural killer (NK) cells and enhanced cellular cytotoxicity could be safely accomplished in vivo. EXPERIMENTAL DESIGN: Hu-PBL-SCID mice were treated with various schedules of rituximab and IL-2, with survival as the end point. Patients with relapsed B-NHL received rituximab (375 mg/m2 weekly x 4) followed by daily low-dose IL-2 (1 MIU/m2/day x 4 weeks) with pulses of intermediate-dose IL-2 (3-15 MIU/m2). Toxicity, NK cell numbers, and cellular cytotoxicity were measured. RESULTS: In the hu-PBL-SCID mouse, the combination of rituximab and IL-2 showed greater activity against B-NHL than either agent alone. Treatment was most effective when IL-2 was given before rituximab. Twelve patients with heavily pretreated B-NHL entered the phase I trial. Toxicity was manageable, and responses were observed. NK cell expansion and enhanced cellular cytotoxicity against a B-cell lymphoma target were observed but did not correlate with response. CONCLUSIONS: The combination of IL-2 and rituximab is synergistic against B-NHL in the hu-PBL-SCID model. In the phase I trial, a sequential combination of rituximab and IL-2 was well tolerated and achieved biological end points. Responses were observed.

The national lesbian family study: 4. Interviews with the 10-year-old children.

This 4th report from a longitudinal study of U.S. lesbian families presents data from 78 families in which the children were conceived by donor insemination. Results indicate that the prevalence of physical and sexual abuse in these children was lower than national norms. In social and psychological development, the children were comparable to children raised in heterosexual families. Children of unknown donors were indistinguishable from those with known donors in psychological adjustment. In total, 57% of the children were completely out to their peers, and 43% had experienced homophobia. The children demonstrated a sophisticated understanding of diversity and tolerance.

Durable hematologic complete response and suppression of HTLV-1 viral load following alemtuzumab in zidovudine/IFN-{alpha}-refractory adult T-cell leukemia.

Adult T-cell leukemia (ATL) is a highly chemoresistant and usually fatal T-cell malignancy due to the human T-cell lymphotropic virus-1 (HTLV-1). After chemotherapy failure, antiretrovirals and interferon-alpha (IFN-alpha) produce brief responses followed by progression and death. More effective agents and new approaches to detect and treat minimal residual disease are needed. ATL cells express CD52, the target of the antibody alemtuzumab, which is active in a preclinical model of ATL and is cytotoxic for p53-deficient cells. A patient with refractory chronic ATL in transformation achieved longer than a 1-year complete hematologic response following 12 weeks of outpatient subcutaneous alemtuzumab. Persistent suppression of HTLV-1 viral load, even at recovery of T cells, after alemtuzumab and efficient in vitro complement-mediated cytotoxicity of primary ATL cells with mutated TP53 were observed. The unprecedented response and the profound suppression of HTLV-1 viral load observed in this patient suggest that further clinical investigation of alemtuzumab in ATL is warranted.