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PubMed2006

Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study.

OBJECTIVE: To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving > or =1 traditional nonbiologic and/or biologic disease-modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study. METHODS: This was a 1-year, multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo. RESULTS: The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7-12.5%). CONCLUSION: Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.

Abatacept↗
PubMed2006

CTLA-4IG suppresses reactive oxygen species by preventing synovial adherent cell-induced inactivation of Rap1, a Ras family GTPASE mediator of oxidative stress in rheumatoid arthritis T cells.

OBJECTIVE: Oxidative stress contributes to the inflammatory properties of rheumatoid arthritis (RA) synovial T lymphocytes. This study was undertaken to investigate the mechanisms leading to production of reactive oxygen species (ROS) and oxidative stress in RA synovial T lymphocytes. METHODS: ROS production in T lymphocytes from the peripheral blood (PB) of healthy donors and from the PB and synovial fluid (SF) of RA patients was measured by ROS-dependent fluorescence of 6-carboxy-2',7'-dichlorofluorescein. Rap1 GTPase activation was assessed by activation-specific probe precipitation. Proliferation of RA PB and SF T lymphocytes was assayed by 3H-thymidine incorporation. In some experiments, RA PB T cells were preincubated with autologous SF or with PB or SF adherent cells. Experiments were performed in the absence or presence of transwell membranes or CTLA-4Ig fusion proteins. Short- and long-term stimulations of healthy donor PB T lymphocytes were performed with inflammatory cytokines, in the absence or presence of activating anti-CD28 antibodies. RESULTS: T lymphocyte ROS production and Rap1 inactivation were mediated by cell-cell contact with RA synovial adherent cells, and this correlated with T cell mitogenic hyporesponsiveness. CTLA4-Ig blockade of synovial adherent cell signaling to CD28 T cells reversed the inhibition of Rap1 activity and prevented induction of ROS. Introduction of active RapV12 into T cells also prevented induction of ROS production. Coincubation of T cells with stimulating anti-CD28 antibodies and inflammatory cytokines synergistically increased T cell ROS production. CONCLUSION: Cell-cell contact between T cells and RA synovial adherent cells mediates Rap1 inactivation and subsequent ROS production in T lymphocytes following exposure to inflammatory cytokines. This process can be blocked by CTLA4-Ig fusion protein.

Abatacept↗
PubMedDate not supplied

Influence of linker unit on performance of palladium(II) coproporphyrin labelling reagent and its bioconjugates.

In this paper we describe the preparation of a series of new phosphorescent labelling reagents, based on monosubstituted palladium(II) coproporphyrin-I and the isothiocyanato reactive group. The labelling reagents differ with respect to the chemical composition of the linker unit that combines the reactive group and the porphyrin chromophore. Altogether, seven different labelling reagents are prepared. The new labelling reagents are conjugated with monoclonal mouse IgG to yield label conjugates with variable degrees of conjugation. The effect is studied of linker unit on: (a) the conjugation reaction kinetics; (b) the biological activity of the resulting IgG conjugates; and (c) the efficiency of phosphorescence emission. The results show that an increase in the length of the linker unit has a positive effect on both the reactivity of the label and the biological activity of the resulting conjugates. In addition, the results indicate that the labels with the most hydrophilic linker units exhibit the highest phosphorescence emission efficiencies.

Animals↗
PubMed2004

Efficient strategies for the conjugation of oligonucleotides to antibodies enabling highly sensitive protein detection.

Three methods for the conjugation of oligonucleotides to antibodies and the subsequent application of these conjugates to protein detection at attomole levels in immunoassays are described. The methods are based on chemical modification of both antibody and oligonucleotide. Aldehydes were introduced onto antibodies by modification of primary amines or oxidation of carbohydrate residues. Aldehyde- or hydrazine-modified oligonucleotides were prepared either during phosphoramidite synthesis or by post-synthesis derivatization. Conjugation between the modified oligonucleotide and antibody resulted in the formation of a hydrazone bond that proved to be stable over long periods of time under physiological conditions. The binding activity of each antibody-oligonucleotide conjugate was determined to be comparable to the corresponding unmodified antibody using a standard sandwich ELISA. Each oligonucleotide contained a unique DNA sequence flanked by universal primers at both ends and was assigned to a specific antibody. Highly sensitive immunoassays were performed by immobilizing analyte for each conjugate onto a solid support with cognate capture antibodies. Binding of the antibody-oligonucleotide conjugate to the immobilized analyte allowed for amplification of the attached DNA. Products of amplification were visualized using gel electrophoresis, thus denoting the presence of bound analyte. The preferred conjugation method was used to generate a set of antibody-oligonucleotide conjugates suitable for high-sensitivity protein detection.

Antibodies↗
PubMed2002

Radionuclide-antibody conjugates for single-cell cytotoxicity.

BACKGROUND: Radioimmunotherapy has primarily utilized high-energy beta-particles, which are intended to kill macroscopic tumor masses. Such conjugates do not kill single cells or micrometastases efficiently. For killing single cells, it may be preferable to use radiation with a much shorter path length, such as alpha-particles or Auger or conversion electrons. METHODS: This selective review focuses on the use of radiolabeled antibody (Ab) conjugates to achieve single-cell kill. The advantages and disadvantages of particular types of radionuclides, the significance of intracellular localization of the Ab, and the potential clinical application of this approach are discussed. Potentially useful radionuclides are listed. RESULTS: Auger and conversion electrons can kill cells effectively, with at least 6 logs of cell kill. Abs on the cell surface are only slightly less potent than Abs internalized into the cytoplasm, and this is consistent with theoretical considerations. alpha-Particles kill single cells very effectively, but the short half-lives of the available alpha-particle emitters are probably a disadvantage. High-energy beta-particles can also kill single cells if they bind in sufficient amounts, but their disadvantage appears to be greater nonspecific toxicity. CONCLUSIONS: Single-cell kill can be obtained with radionuclide-Ab conjugates. The selection of the optimal radionuclide may depend on the details of the clinical situation, such as the size and accessibility of the tumor burden, and the particular Ab to be used. Direct comparisons of various radionuclides are required in order to identify the optimal approach. However, for single-cell kill, as required for therapy of micrometastases, the use of Auger and conversion electron emitters appears to have substantial advantages. While current methods limit the applicability of this approach to Abs having a high level of binding, it may be applicable to lower-density antigens if higher specific activities or more potent radionuclides can be used. Tumor cure may require a mixture of radionuclides intended to kill both single cells and large tumor masses.

Alpha Particles↗
PubMed2002

Biokinetics of yttrium-90--labeled huBrE-3 monoclonal antibody.

BACKGROUND: This study reports summary biokinetics for 17 patients treated with huBrE-3 antibody labeled with indium-111 ((111)In) and yttrium-90 ((90)Y) in a Phase I dose escalation trial. METHODS: Patients were infused with huBrE-3 antibody conjugated to 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyl-diethylenetriamine pentaacetic acid (MX-DTPA). The huBrE-3 was labeled with increasing amounts of (90)Y radioactivity according to the following activity regimen: 10 mCi/m(2), 20 mCi/m(2), 33 mCi/m(2), 50 mCi/m(2), and 70 mCi/m(2). In addition to the (90)Y activity, 3--5 mCi of (111)In was labeled to huBrE-3 to serve as an imaging agent. In characterizing the biokinetics of huBrE-3, serial urine and blood samples were acquired. Additionally, whole-body imaging using a scintillation camera was performed at four time points postinfusion. RESULTS: Cumulative urine data yielded a plot of total-body biologic excretion that was relatively flat. Total body regions of interest derived from nuclear medicine scintigrams decreased according to a monoexponential function with a slope slightly greater than the rate of physical decay. When physical decay was combined with the urine biologic excretion rate, the calculated rate of activity decrease was indistinguishable from the scintigraphic rate of decrease in total-body activity. CONCLUSIONS: The authors concluded from these observations that the radioactivity remains essentially inside the patient, that biologic excretion of activity from the total body is not appreciable, and that the path for biologic excretion of activity that does occur is via the urine. The half-time associated with the beta (slow) phase for extraction from the blood averages 40.5 hours. Since large amounts of radioactivity do not appear in the urine, and total-body activity is decreased approximately according to physical decay (64.1 hours), activity must pool elsewhere after leaving the blood. The logical place is the skeleton, with possible selective binding to the bone marrow. Bone marrow biopsies from 4 of 7 patients who consented to serial biopsies were supportive of this conclusion.

Antibodies, Monoclonal↗
PubMed2002

Volume reduction versus radiation dose for tumors in previously untreated lymphoma patients who received iodine-131 tositumomab therapy. Conjugate views compared with a hybrid method.

BACKGROUND: A Phase II study of previously untreated patients with malignant low grade follicular lymphoma given a combination of unlabeled tositumomab and tositumomab labeled with iodine-131 has recently been completed. The responses of these patients have been characterized, and for some of them tumor dosimetry during therapy has been estimated not only by pretherapy tracer conjugate views but also by a hybrid method. METHODS: Available patients were studied if they had had a pelvic or abdominal tumor evaluation by single photon emission computed tomography (SPECT) and achieved a partial response. A tumor outlined on the iodine-131 conjugate-view images was called a composite tumor. Its volume estimate came from multiple, not necessarily contiguous, regions of interest (ROI) on the pretherapy computed tomography (CT) scan. Its radiation dose was estimated from the weeklong series of pretherapy images and standard Medical Internal Radiation Dose methods. Computed tomography ROI were also grouped into smaller, contiguous volumes that defined individual tumors. Their radiation doses were estimated by the hybrid method. This method employed the activity measured for each individual tumor by a single intratherapy SPECT scan, as well as the tumor's volume, to individually normalize the composite time-activity curve as appropriate. The individual normalization factors then converted the composite radiation dose to radiation doses for individual tumors. Reduction in tumor volume was calculated for both composite and individual tumors at 12 weeks posttherapy. RESULTS: For 14 composite tumors in 10 patients, the median pretherapy volume was 170 cm(3). Application of a sigmoidal curve function to the plot of volume reduction versus radiation absorbed dose resulted in degeneration of the curve into a straight line with a negative slope. There was no statistical significance in the relationship (P = 0.73). For 43 individual tumors, the median pretherapy tumor volume was 26 cm(3). The plot of volume reduction versus dose was fairly well fit by a sigmoidal curve, and the relationship approached statistical significance (P = 0.06). The representation assigned 56% of the shrinkage to the effects of unlabeled tositumomab. For the subset of individual tumors with a pretherapy volume less than 10 cm(3) from 6 patients (n = 15), the relationship was significant (P = 0.03). The sigmoidal representation assigned only 12% of the shrinkage to unlabeled tositumomab, as contrasted with 72% for tumors with pretherapy volume greater than 10 cm(3). CONCLUSIONS: For patients who attained a partial response, analysis of individual tumors by a hybrid dosimetric method led to a dependence between volume reduction at 12 weeks and radiation dose that tended to be significant. The same was not true with dosimetry of composite tumors based on pretherapy conjugate views alone. It appeared that volume reductions from both unlabeled antibody and radiation dose were important in tositumomab therapy of lymphoma patients, with unlabeled antibody relatively more important for larger tumors.

Antibodies, Monoclonal↗
PubMed2002

Model prediction of treatment planning for dose-fractionated radioimmunotherapy.

BACKGROUND: Clinical trials of radioimmunotherapy (RIT) often use dose fractionation to reduce marrow toxicity. The dosing scheme can be optimized if marrow and tumor cell kinetics following radiation exposure are known. METHODS: A mathematic model of tumor clonogenic cell kinetics was combined with a previously reported marrow cell kinetics model that included marrow stromal cells, progenitor cells, megakaryocytes, and platelets. Reported values for murine tumor and marrow cellular turnover rates and radiosensitivity were used in the model calculation. RESULTS: Given a tolerated level of thrombocytopenia, there is a fractionation scheme in which total radioactive dose administration can be maximized. Isoeffect doses that had different numbers of fractions and total radioactivity, but induced identical platelet nadirs of 20%, were determined. Assuming identical tumor uptake for all dose fractions, six tumor types were examined: early-responding tumors, late-responding tumors, and tumors that lacked a late-responding effect, with either constant or accelerated doubling time. For most tumor types, better tumor control (tumor growth delay and nadir of survival fraction) was predicted for a dosing scheme in which total radioactive dose was maximized. For late-responding tumors with accelerated doubling time, tumor growth delay increased, but the nadir of survival fraction became shallower as the number of fractions increased. CONCLUSIONS: A mathematic model has been developed that allows prediction of the nadir and duration of thrombocytopenia as well as tumor clonogenic cell response to various RIT doses and fractionation schemes. Given a maximum tolerated level of thrombocytopenia, the model can be used to determine a dosing scheme for optimal tumor response.

Abnormalities, Radiation-Induced↗
PubMed2002

Single tumor cell uptake and dosimetry of technetium-99m Fab' or minute anti-CD22 in low-grade B-cell lymphoma.

BACKGROUND: A patient with follicular lymphoma was investigated with 0.5 mg Fab' or minute anti-CD22 labeled with 1100 MBq technetium-99m ((99m)Tc). A computed tomography scan performed a week later revealed regression. This unexpected response prompted an investigation of single cell dosimetry of low-energy electron emitters. METHODS: Another patient with low-grade, unclassifiable B-cell lymphoma with a low expression of CD22 was injected with (99m)Tc anti-CD22. Blood samples were drawn 30 minutes, 4 hours, and 24 hours after injection. Lymphoma cells (CD19+) and T cells (CD3+), which served as control cells, were separated using a flow cytometer. The radioactivity of the two cell populations was measured in an NaI(Tl) well-type detector. The mean uptake per cell and absorbed dose were calculated. The CD22 expression of the patient's cells and of a B-cell lymphoma cell line (Raji) were assessed by flow cytometry for the extrapolation of the absorbed dose from the patient's cells to a cell line with higher CD22 expression. RESULTS: The average number of (99m)Tc atoms per CD19+ and CD3+ cell 4 hours postinjection were 5.4 and 0.054, respectively. Depending on the assumed ratio between antibody and CD22 molecules (1:2 or 1:1), the CD22 expression on the patient's cells and Raji cells varied from 2800 to 5700 and from 37,000 to 74,000 per cell, respectively. The average absorbed dose per cell ranged from 4 x 10(-7) to 0.1 grays (Gy). CONCLUSIONS: It seems feasible to assess the mean single tumor cell uptake of (99m)Tc targeted by Fab' or minute anti-CD22 in a patient's lymphoma using sorted cell populations, thereby allowing single cell dosimetry. Extrapolation of the absorbed dose from (99m)Tc to cells with higher CD22 expression was made and under certain conditions absorbed doses of 0.1 Gy were obtained, indicating the potential relevance of low-energy electron emitters to therapy.

Antigens, CD↗
PubMed2002

Application of extracorporeal immunoadsorption to reduce circulating blood radioactivity after intraperitoneal administration of indium-111-HMFG1-biotin.

BACKGROUND: Extracorporeal immunoadsorption (ECAT) is a method of reducing activity in radiosensitive organs by removing excess monoclonal antibodies (MAbs) from the blood. Previously, the authors experimentally evaluated ECAT based on the avidin-biotin concept after intravenous administration of radioimmunoconjugates. The aim of the current study was to determine whether ECAT could be used to reduce activity after intraperitoneal (i.p.) administration of indium-111((111)In)-HMFG1-biotin in rats, and to compare the pharmacokinetics of (111)In-HMFG1 with or without attached biotin after i.p. injection. METHODS: HMFG1, a murine immunoglobulin G(1) MAb that recognizes an epitope on the polymorphic epithelial mucin (PEM) antigen, was labeled with (111)In and then biotinylated. ECAT was explored from unseparated blood using an avidin-agarose adsorption column. Thirty rats were used as controls and 13 underwent ECAT. The whole-body (WB), blood, and organ activity were monitored. RESULTS: The binding capacity of (111)In-HMFG1-biotin to avidin was high. Biotinylation did not enhance the excretion of HMFG1. When ECAT was employed, the WB and blood radioactivity were reduced by 35-40% (P < 0.05) and 75--86% (P < 0.01), respectively. After the completion of ECAT, the activity uptake in organs was significantly decreased. CONCLUSIONS: ECAT was successfully applied after i.p. injection of the (111)In-HMFG-biotin MAb to reduce the radioactivity in the WB, blood, and radiosensitive organs. Due to redistribution of the radiolabeled MAbs during and after the completion of ECAT, the adsorption may have been prolonged or repeated. Biotinylation did not significantly change the biodistribution of the (111)In-HMFG1 in rats after intraperitoneal injection.

Animals↗
PubMed2002

The combination of external beam radiotherapy and experimental radioimmunotargeting with a monoclonal anticytokeratin antibody.

BACKGROUND: Doses to tumors of up to 80 grays (Gy) have been postulated to eradicate solid experimental tumors with radiommunotargeting, but this value has proved difficult to reach. Combining two treatment modalities, external beam radiotherapy and radioimmunotargeting, could potentially give rise to a number of advantages. METHODS: The purpose of this study was to detect potential benefits with different treatment timing strategies when combining external beam radiotherapy and radioimmunotargeting, with the anticytokeratin monoclonal antibody (MAb) TS1 injected into a nude mouse model carrying subcutaneous human HeLa Hep 2-cell tumors. Cytokeratins are present in necrotic regions within tumors, thereby providing a potential increase in binding sites for TS1 if combined with external beam radiotherapy. External beam radiotherapy was given before, after, and simultaneously with injection of radiolabeled MAb. RESULTS: The highest yields in terms of total accumulated dose (Gy), percentage of injected activity per gram of tumor tissue, and accumulated dose per injected activity (Gy/MBq) were seen in the group receiving external beam radiotherapy prior to MAb-injection. CONCLUSIONS: Enhanced effects may be achievable by combining external beam radiotherapy with experimental radioimmunotargeting using the monoclonal anticytokeratin antibody TS1, if the radiotherapy is given prior to MAb injection.

Animals↗
PubMed2002

High-dose myeloablative radioimmunotherapy of mantle cell non-Hodgkin lymphoma with the iodine-131-labeled chimeric anti-CD20 antibody C2B8 and autologous stem cell support. Results of a pilot study.

BACKGROUND: CD20 has been used successfully as a target molecule for conventional low-dose, as well as high-dose, myeloablative radioimmunotherapy (RIT) of B-cell non-Hodgkin lymphoma (NHL). Mantle cell lymphoma (MCL) is an especially aggressive, prognostically unfavorable subtype of B-cell NHL, associated with an overall 5-year survival rate of less than 20%. Recent evidence has failed to show convincing therapeutic efficacy of conventional, nonmyeloablative RIT in patients with MCL. The aim of this pilot study was to investigate whether high-dose, myeloablative RIT with the iodine-131 ((131)I)-labeled chimeric anti-CD20 antibody C2B8 (rituximab, obtained as Mabthera from Roche Pharma, Reinach, Switzerland) is therapeutically effective in MCL patients. METHODS: A total of seven patients with chemorefractory or relapsed MCL were studied in this pilot trial. All had relapsed after high-dose chemotherapy with autologous stem cell transplantation (four of them combined with 12 grays (Gy) total-body irradiation). A diagnostic-dosimetric study was performed with approximately 10 mCi of (131)I-labeled C2B8 at a protein dose of 2.5 mg per kg body weight, in order to assess its biodistribution and dosimetry. If splenic pooling was observed, as is typically the case in patients with splenomegaly, the protein dose was doubled in additional studies until a "favorable" biodistribution was obtained. Therapy was performed with myeloablative doses of 261-495 mCi of (131)I-labeled C2B8 at the previously optimized protein dose, aiming at lung doses less-than-or-equal 27 Gy. Homologous stem cell support was provided. Clinical follow-up was obtained at 3-month intervals for up to 38 months (median observation time, 25 months). Overall, in six patients the 2.5 mg/kg protein dose was used, whereas in one patient with splenomegaly, 10 mg/kg was necessary to overcome the splenic antigenic sink. RESULTS: Blood cell nadirs were reached at 2-3 weeks after therapy infusion, but all patients reengrafted at 7-10 days after stem cell reinfusion. Nonhematologic toxicity was restricted to mild-to-moderate nausea, fever, transient bilirubin, or liver enzyme elevations. One patient with preexisting alcoholic cirrhosis experienced a deterioration of liver function. Despite thyroid blocking, 5 of 7 patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. Six patients experienced a complete and one a good partial remission. Five patients were still in CR at the time this article was written, and six are still alive for more than 3 years; one patient relapsed locally at 3 months and one systemically at 26 months after RIT. CONCLUSIONS: High-dose myeloablative radioimmunotherapy with (131)I-labeled anti-CD20 antibodies seems to be associated with a high response rate and moderate toxicity in patients with MCL. Further follow-up to monitor the long-term outcome as well as systematic prospective clinical studies are indicated.

Adult↗
PubMed2002

Radioimmunotherapy of small-volume disease of metastatic colorectal cancer.

BACKGROUND: Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small-volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine-131 ((131)I)-labeled humanized anti-carcinoembryonic antigen (anti-CEA) antibody (MAb) hMN-14 in small-volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this (131)I-labeled humanized anti-CEA antibody in colorectal cancer patients with small-volume disease or in an adjuvant setting. METHODS: Thirty colorectal cancer patients, with small-volume metastatic disease (n = 21; all lesions less-than-or-equal 3.0 cm, and chemorefractory to 5-fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4-6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of (131)I-hMN-14 immunoglobulin G at a 60 mCi/m(2) dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow-up was obtained at 3-month intervals for as long as 36 months. RESULTS: At a mean blood-based red marrow dose of 1.8 +/- 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60-mCi/m(2) dose level at 8-16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection. CONCLUSIONS: These data suggest that RIT is a safe and effective form of therapy for small-volume colorectal cancer and has potential as treatment for colorectal cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko- and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated.

Antibodies, Monoclonal↗
PubMed2003

Lineage specific treatment of adult patients with acute lymphoblastic leukemia in first remission with anti-B4-blocked ricin or high-dose cytarabine: Cancer and Leukemia Group B Study 9311.

BACKGROUND: Anti-B4-blocked ricin is an immunotoxin comprised of an anti-CD19 murine monoclonal antibody (B4) conjugated to blocked ricin, which has cytotoxic activity in patients with lymphoid malignancies. METHODS: Adults with untreated acute lymphoblastic leukemia (ALL) were treated with a previously developed and tested chemotherapeutic regimen. Patients with CD19 positive ALL were given anti-B4-blocked ricin as 2 7-day continuous infusions 1 week apart. Patients with CD19 negative ALL received high-dose cytarabine. Serial polymerase chain reaction (PCR) assays of BCR-ABL, immunoglobulin heavy chain (IGH), and T-cell receptor (TCR) genes were used to measure the impact of lineage specific intensification treatment on minimal residual disease. RESULTS: Eighty-two adults were enrolled, and 78 were eligible. The median age was 34 years (range, 17-81 years). Sixty-six patients (85%) achieved complete remission. Forty-six patients received the anti-B4-blocked ricin, which generally was well tolerated; 80% were able to receive both courses. The most common toxicity was asymptomatic transient elevation of liver function tests in 72% of patients. Lymphopenia occurred in 46% of patients. Two patients developed antibodies to the anti-B4-blocked ricin. Molecular monitoring before and after the experimental course of intensification did not show a consistent change in the number of leukemia cells remaining, and the immediate posttreatment PCR studies did not correlate with remission duration. CONCLUSIONS: Intensification therapy with anti-B4-blocked ricin is feasible for patients with CD19 positive ALL, although there is little evidence of an additional clinical benefit from the anti-B4-blocked ricin. Cancer 2003;97:1471-80.

Adolescent↗
PubMedDate not supplied

Current knowledge of Japanese type 1 diabetic syndrome.

The Japanese have one of the lowest incidence of childhood type 1 diabetes in the world, but the incidence of this disease is clearly increasing within the Japanese population, as reported in several European countries. Latent autoimmune diabetes mellitus in adult (LADA) patients are also likely to have a lower incidence compared to Caucasians. Among the non-autoimmune (type 1B) diabetes in Japanese adults, there exists a novel subtype of type 1 diabetes characterized by extremely rapid onset and pancreatic exocrine inflammation. HLA and non-HLA gene associations to type 1 diabetes may vary depending on ethnic origin. Highly susceptible HLA haplotypes of type 1 diabetes observed in Caucasian patients are not found in Japanese patients, while protective HLA haplotypes are similar. Association studies of non-HLA genes have identified several candidate genes that influence the heterogeneity of disease phenotypes as well as disease susceptibility to type 1 diabetes. The INS-VNTR gene or polymorphisms of MICA gene are associated with susceptibility, whereas a certain allele of MICA gene and IL-10 gene polymorphism are associated with clinical heterogeneity of the disease. An expression of multiple autoantibodies to a biochemically determined autoantigen confers a high risk for progression to type 1 diabetes. The combined evaluation of multiple autoantibodies is more sensitive than is ICA testing for the diagnosis of type 1 diabetes. A high titer of GAD autoantibody has the predictive value of future insulin deficiency in patients with LADA. For accurate predictive strategies of future insulin deficiency, combinational multiple autoantibodies analysis or genetic determination should be considered for effective immune intervention.

Abatacept↗
PubMed1994

Expression and function of the costimulatory molecule B7 on murine Langerhans cells: evidence for an alternative CTLA-4 ligand.

We have previously shown, through transfection experiments, that the murine B7 (mB7) molecule, a ligand for the CD28 and CTLA-4 receptors, is a sufficient costimulatory signal for the antigen-specific and major histocompatibility complex (MHC)-restricted activation of murine CD4+ T lymphocytes. In addition to mB7, another ligand with affinity for CTLA-4 has been described on spleen cells. Here we report our studies on the expression and function of these molecules on murine Langerhans cells (LC). Both anti-mB7 monoclonal antibody (mAb) 16-10A1 and human CTLA4Ig (hCTLA4Ig), a chimeric fusion protein consisting of the extracellular domain of human CLTA-4 and the constant domain of human IgG1, detected antigen(s) on cultured but not freshly isolated LC. Preincubation of cultured LC with anti-mB7 mAb did not significantly affect binding of hCTLA4Ig to these cells. This result demonstrate the existence of at least one other ligand for the CLTA-4 receptor on cultured LC. Functional studies revealed that the costimulatory activity of LC was inhibited better by hCTLA4Ig than by the anti-mB7 mAb. This differential effect was seen in the case of both alloreactive and antigen-specific, syngeneic T cell responses. These findings suggest that the non-mB7-ligand for CTLA-4 is functional and participates in the induction of immune responses by LC. Importantly, even synergistic combinations of anti-mB7 mAb and hCTLA4Ig did not inhibit completely the activity of LC. These findings therefore raise the possibility that LC express other costimulatory ligands besides mB7 and related family members.

Abatacept↗
PubMed1994

Activation of CD4+ T cells by delivery of the B7 costimulatory signal on bystander antigen-presenting cells (trans-costimulation).

Increasing evidence in both murine and human systems suggests that the interaction of the T cell surface antigens CD28/CTLA4 with their ligand B7 on the antigen-presenting cells (APC) is the critical costimulatory pathway involved in the induction of maximal T cell activation and the prevention of induction of anergy. It has also been demonstrated that efficient induction of clonal expansion of normal CD4+ T cells requires the delivery of the T cell receptor (TCR) ligand and costimulation by the same APC. We demonstrate here that normal murine CD4+ T cells can be efficiently activated by soluble anti-CD3 cross-linked by fixed macrophages and by a costimulatory signal delivered by a bystander APC, B7-transfected L cells. The major factor which determined the ability of an APC to provide costimulation in "trans" was the level of cell surface B7 expression. The requirement for B7 costimulation appears to be at initial stage of TCR engagement since optimal T cell activation was only observed when TCR triggering and B7 costimulatory activity were delivered at same time by different APC. Induction of maximal proliferation of both naive CD45RBhi and memory CD45RBlo CD4+ T cells was B7 dependent and both populations of cells responded equally well to the B7 costimulation delivered in "trans". Furthermore, trans-costimulation provided by B7 transfected L cells efficiently prevented the induction of anergy in normal murine CD4+ T cells induced by anti-CD3 cross-linked by fixed-resting macrophages. Addition of exogenous interleukin-2 (IL-2) and IL-7 to the primary culture in the absence of B7-transfected L cells or addition of IL-2 to the culture containing the B7 transfectant and CTLA4Ig completely prevented the induction of hyporesponsiveness. These findings raise the possibility that in certain pathological states, CD4+ T cells in vivo may be activated by costimulation delivered by bystander APC.

Abatacept↗