Radioimmunotherapy (RIT) with ␣-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of ␣-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target ␣-emitters with IntroductionNon-Hodgkin lymphoma (NHL) is the sixth most common type of cancer, with over 74 000 new cases diagnosed annually in the United States. 1 Following conventional treatment with chemotherapy or radiation therapy, patients with advanced stage indolent NHL inevitably relapse, with death occurring a median of 5 years after recurrence. 2 The introduction of rituximab, a monoclonal antibody against CD20, has led to improved survival in patients with NHL. [3][4][5] Despite the encouraging clinical results with anti-CD20 antibodies, however, the majority of patients with indolent NHL who respond to immunochemotherapy eventually relapse with recurrent lymphoma. 6,7 Recently, radioimmunotherapy (RIT) has emerged as a promising treatment option for lymphoma. RIT with iodine-131( 131 I) tositumomab or yttrium-90 ( 90 Y) ibritumomab tiuxetan as a single agent has yielded excellent overall response rates of 50% -80%, with complete response rates of 20% -40% in patients with relapsed or refractory indolent NHL. [8][9][10][11][12][13] Even more notable response rates have been observed when RIT is used as front-line treatment in patients with indolent NHL. 14 In a recent large phase 3 trial, the addition of 90 Y-ibritumomab tiuxetan in first remission after chemotherapy significantly improved response rates and remission durations in patients with advancedstage follicular lymphoma, 15 presumably by killing residual tumor cells that survived the induction chemotherapy. 16 Based on this data, 90 Y-ibritumomab tiuxetan has been approved by the FDA for first line consolidation therapy in follicular lymphoma. However, the ␤-emitting radionuclides used in current RIT schemes may not be ideal for irradiating microscopic tumors and isolated tumor cells present in the setting of minimal residual disease (MRD). It is estimated that the fraction of energy deposited in a tumor measuring 200 m in diameter is only 1.5% and 17% for 90 Y-labeled and 131 I-labeled antibodies (Abs), respectively. 17,18 The remainder of the ␤ energy is deposited in surrounding normal tissues, resulting in dose-limiting toxicities. Furthermore, the relatively low decay energies of ␤-particles result in suboptimal killing of tumor cells, ultimately contributing to relapse in the majority of treated patients. In contrast, ␣-emitting radionuclides impart high-linear-energytransfer radiation along densely ionized, linear tracks over relatively short distances (40 to 90 m or few cell diameters), which are highly effective in cell-killing. Alpha-particle...

Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and DOTA-biotin labeled with ␤-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. ␣-emitting radionuclides exhibit high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to ␤-emitting radionuclides for patients with acute myeloid leukemia. Accordingly, we have used 213 IntroductionFor more than a decade, antibodies (Abs) conjugated to a radionuclide emitting particulate radiation have been used in the management of leukemia in an effort to deliver targeted doses of radiation to bone marrow, spleen, and other sites of disease while sparing normal organs. This radioimmunotherapy (RIT) approach has been used to achieve significant remissions in patients with acute myeloid leukemia (AML), particularly when used at high doses of radioactivity in conjunction with myeloablation. 1-10 One of the major limitations of this approach, however, has been the pharmacokinetic properties of the Ab protein. Abs accrete slowly in solid tumors and are eliminated slowly from the circulation. Use of radiolabeled Abs, therefore, results in prolonged exposure in radiosensitive tissues, particularly marrow, because of the extended time within the circulation. In addition, the extended time required for tumor localization of the Ab may result in loss of tumoricidal potency of the radionuclide because of ongoing isotopic decay. To address this shortcoming, the pretargeted (P)RIT system has been developed. This system differs from conventional RIT in that it uncouples the targeting agent from the radioisotope, which is administered in a separate step after facilitated clearance of non-tumor-bound targeting agent. 11 Because the radioisotope can be delivered on a small molecule (Ͻ 1 kDa) that is rapidly excreted through the kidneys, normal organ exposure to circulating radiation is effectively reduced by this approach. It has been demonstrated that PRIT technology can further amplify the amount of radiation delivered to CD45 ϩ tissues and, at the same time, diminish the radiation dose to nontargeted cells. [12][13][14][15] A variety of radionuclides have been investigated for RIT of leukemias, where the types of emissions used have primarily focused on the use of ␤-particles ( 131 I, 90 Y, and 188 Re). Over the past several years, interest has developed in targeting ␣-emitters to leukemia cells for RIT. 8,16 As opposed to the relative nonspecific cytotoxicity of ␤-emitting constructs because of the crossfire effect, ␣-particle decay of radionuclides, such as 213 Bi, 211 At, and 225 Ac, results in high-energy (6-8 MeV) delivery over a very short distance (50-80 m). The short path length may provide a therapeutic advantage for targeting leukemic cells in the marrow and thus prevent the exposure of many normal hematopoietic stem cells to nonspecific irradiation. Therefore, the novel approach of PRIT combined with very shor...

BackgroundSystemic lupus erythematosus (SLE) is a multifactorial disorder characterized by the presence of autoantibodies. We and others have implicated free radical mediated peroxidative damage in the pathogenesis of SLE. Since harmful free radical products are formed during this oxidative process, including 4-hydroxy 2-nonenol (4-HNE) and malondialdehyde (MDA), we hypothesized that specific HNE-protein adducts would be present in SLE red blood cell (RBC) membranes. Catalase is located on chromosome 11p13 where linkage analysis has revealed a marker in the same region of the genome among families with thrombocytopenia, a clinical manifestation associated with severe lupus in SLE affected pedigrees. Moreover, SLE afflicts African-Americans three times more frequently than their European-American counterparts. Hence we investigated the effects of a genetic polymorphism of catalase on risk and severity of SLE in 48 pedigrees with African American ancestry.MethodsTryptic digestion followed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) analysis was used to identify the protein modified by HNE, following Coomassie staining to visualize the bands on the acrylamide gels. Genotyping analysis for the C → T, -262 bp polymorphism in the promoter region of catalase was performed by PCR-RFLP and direct PCR-sequencing. We used a "pedigree disequilibrium test" for the family based association analysis, implemented in the PDT program to analyze the genotyping results.ResultsWe found two proteins to be HNE-modified, migrating around 80 and 50 kD respectively. Tryptic digestion followed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) analysis of the Coomassie stained 80 kD band revealed that the target of HNE modification was catalase, a protein shown to associate with RBC membrane proteins. All the test statistics carried out on the genotyping analysis for the C → T, -262 bp polymorphism in the promoter region of catalase were non-significant (p > 0.05) in our data, which suggested that this SNP is not associated with SLE.ConclusionOur results indicate that catalase is one of the proteins modified due to oxidative stress. However, catalase may not be a susceptibility gene for SLE. Nonetheless, catalase is oxidatively modified among SLE patients. This suggests a possible role between oxidative modification of catalase and its affects on enzymatic activity in SLE. An oxidatively modified catalase could be one of the reasons for lower enzymatic activity among SLE subjects, which in turn could favor the accumulation of deleterious hydrogen peroxide. Furthermore, HNE-products are potential neoantigens and could be involved in the pathogenesis of SLE. Decrease in catalase activity could affect the oxidant-antioxidant balance. Chronic disturbance of this balance in patients with SLE may work favorably for the premature onset of atherogenesis with severe vascular effect.