Zevalin (ibritumomab tiuxetan; IDEC Pharmaceuticals Corporation, San Diego, CA, USA) was approved by the United States Food and Drug Administration on February 19, 2002, following 9 years of clinical development. Six clinical studies supported the Zevalin Biologics License Application. The Zevalin regimen is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), and for those with follicular NHL refractory to Rituxan (rituximab, MabThera; IDEC Pharmaceuticals Corporation, San Diego, CA and Genentech, South San Francisco, CA). In the year following FDA approval, approximately 1300 patients were treated in clinical trials or with the commercially available product.

257 Rationale The costimulatory molecule, CD80 (B7-1), is well known for its role in the regulation of T-cell function.1 Recent evidence suggests that CD80 also plays a role in the regulation and activation of normal and malignant B cells.2,3 CD80 is expressed on a variety of B-cell lymphomas, including follicular, diffuse, small noncleaved, mantle cell, small lymphocytic, and other subtypes.4,5 Crosslinking of CD80 with anti-CD80 antibodies on lymphoma cells has been shown to inhibit cell proliferation and to upregulate proapoptotic molecules.2 Taken together, these observations constitute rationale for the development of an anti-CD80 therapy for B-cell lymphoma. Galiximab (IDEC-114) is a Primatized® anti-CD80, immunoglobulin G1 lambda monoclonal antibody with human constant regions and primate (cynomolgus macaque) variable regions.6 Galiximab blocks binding of CD80 with CD28 but not with CTLA-4. Preclinical studies explored the potential of galiximab as a targeted therapy for lymphoma, as a single agent, or in combination with rituximab, an anti-CD20 monoclonal antibody.7 CD80 expression was confirmed on several lymphoma cell lines and on biopsy specimens from patients with low-grade, intermediate-grade, and high-grade lymphoma, using immunohistochemistry and flow cytometry. CD80 expression on 12 biopsy specimens of follicular small-cleaved lowgrade non-Hodgkin’s lymphoma (NHL) is shown in Table 1. The mechanism of action of galiximab was investigated using in vitro assays. These studies demonstrated that both galiximab and rituximab lysed cells via antibody-dependent cellular cytotoxicity mechanisms (Figure 1). Animal studies explored the in vivo effects of galiximab. In a model of severe combined immunodeficient mice implanted with human lymphoma xenografts, mice treated with galiximab had a significantly longer disease-free survival (DFS) compared to untreated control mice. Similarly, mice treated with galiximab and rituximab had significantly longer DFS compared to mice treated with rituximab alone. In addition, no adverse reactions were observed in primate toxicology studies in which animals received up to 30 mg/kg (≈ 1200 mg/m2) for 5 months (ie, weekly for 5 weeks and then monthly for 5 months). In humans with moderate to severe plaque psoriasis, approximately 300 patients received up to 15 mg/kg (≈ 600 mg/m2) galiximab in single-dose8 and multiple-dose9 clinical trials. Galiximab was infused over 1 hour in an outpatient setting. The 1M. D. Anderson Cancer Center, Houston,TX 2IDEC Pharmaceuticals Corporation, San Diego, CA

Mildly thrombocytopenic patients with relapsed or refractory low-grade non-Hodgkin lymphoma (NHL) have an increased risk of chemotherapy-induced myelosuppression following treatment. The safety and efficacy of radioimmunotherapy with a reduced dose of (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]; maximum 32 mCi [1.2 GBq]) was evaluated in 30 patients with mild thrombocytopenia (100-149 x 10(9) platelets/L) who had advanced, relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. The ibritumomab tiuxetan regimen included an infusion of rituximab (250 mg/m(2)) and injection of (111)In ibritumomab tiuxetan (5 mCi [185 MBq]) for dosimetry evaluation, followed 1 week later with rituximab (250 mg/m(2)) and (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]). Patients (median age, 61 years; 90% stage III/IV at study entry; 83% follicular lymphoma; and 67% with bone marrow involvement) had a median of 2 prior therapy regimens (range, 1-9). Estimated radiation-absorbed doses were well below the study-defined maximum allowable for all 30 patients. With the use of the International Workshop criteria for NHL response assessment, the overall response rate was 83% (37% complete response, 6.7% complete response unconfirmed, and 40% partial response). Kaplan-Meier estimated median time to progression (TTP) was 9.4 months (range, 1.7-24.6). In responders, Kaplan-Meier estimated median TTP was 12.6 months (range, 4.9-24.6), with 35% of data censored. Toxicity was primarily hematologic, transient, and reversible. The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 33%, 13%, and 3%, respectively. Reduced-dose ibritumomab tiuxetan is safe and well tolerated and has significant clinical activity in this patient population.

Pathologic T-cell activation is implicated in psoriasis progression. CD80, a costimulatory molecule involved in T-cell activation, likely plays a key role. IDEC-114, an IgG(1) anti-CD80 antibody, was evaluated for safety, pharmacokinetics, and preliminary clinical activity in this open-label, single-dose, dose-escalating study in patients with moderate to severe chronic plaque psoriasis. Twenty-four patients received IDEC-114 (0.05 mg/kg, 0.25 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, or 15 mg/kg). Psoriasis Area and Severity Index, Physician's Global Psoriasis Assessment, and Psoriasis Severity Scale scores improved in the highest-dose groups. Average plaque thickness and plaque CD3+ and CD8+ T-cell counts decreased in the 10 mg/kg dose group. Adverse events were primarily mild, transient, constitutional symptoms; the most common related events were mild asthenia (29% of patients), chills (25%), and headache (21%). The serum half-life of IDEC-114 was approximately 13 days. A single dose of IDEC-114 appears to be safe and well tolerated and has promising clinical activity in psoriasis.

purpose: Our objectives were to assess whether plasma neuropeptide Y (NPY) levels are elevated in patients with congestive heart failure (CHF) and whether or not NPY levels can serve as a reliable indicator of sympathetic activity in CHF.