Browsing by keyword "Immunoconjugates"
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Adding a clearing agent to pretargeting does not lower the tumor accumulation of the effector as predictedClearing agents are often used in pretargeting despite the potential for decreased tumor accumulation of the effector. However, according to the authors' semiempirical model, a clearing agent should not necessarily decrease tumor accumulation. In this study, the authors have added a clearing step to their model-morpholino phosphorodiamidate oligomer (MORF)/complement MORF (cMORF) pretargeting system-to confirm this prediction. The CC49 antibody was conjugated with both biotin and an 18 mer MORF. The influence of avidin on antibody clearance was first evaluated in normal mice in which each animal received 30 mug of MORF-CC49-biotin, 0-70 mug of avidin 1 day later, and 1.2 mug of (9)(9)(m)Tc-cMORF 3 hours later, with sacrifice at 3 hours. Thereafter, a pretargeting study in mice bearing an LS174T tumor was performed at a 34 mug avidin dosage. In normal mice, the blood level of (9)(9)(m)Tc-cMORF fell by 60% at an avidin dosage of 10 mug or higher. In tumored mice, avidin produced a similar reduction in blood but had no influence on tumor level, which remained at 6.30% ID/g as predicted. In conclusion, in addition to the expected reduced effector levels in blood and normal tissues, a reduction in tumor accumulation was avoided when adding a clearing agent as predicted.
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Item response theory methods can improve the measurement of physical function by combining the modified health assessment questionnaire and the SF-36 physical function scaleOBJECTIVE: To compare the measurement properties of the Modified Health Assessment Questionnaire [MHAQ], the SF-36((R)) Health Survey 10 item Physical Functioning scale [PF10], and scores from an item response theory (IRT) based scale combining the two measures. STUDY DESIGN: Rheumatoid arthritis (RA) patients (n = 339) enrolled in a multi-center, randomized, double-blind, placebo-controlled trial completed the MHAQ and the SF-36 pre- and post-treatment. Psychometric analyses used confirmatory factor analysis and IRT models. Analyses of variance were used to assess sensitivity to changes in disease severity (defined by the American College of Rheumatism (ACR)) using change scores in MHAQ, PF10, and IRT scales. Analyses of covariance were used to assess treatment responsiveness. RESULTS: For the entire score range, the 95% confidence interval around individual patient scores was smaller for the combined (total) IRT based scale than for other measures. The MHAQ and PF10 were about 70% and 50% as efficient as the total IRT score of physical functioning in discriminating among ACR groups, respectively. The MHAQ and PF10 were also less efficient than the total IRT score in discriminating among treatment groups. CONCLUSIONS: Combining scales from the two short forms yields a more powerful tool with greater sensitivity to treatment response.
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Successful radiotherapy of tumor in pretargeted mice by 188Re-radiolabeled phosphorodiamidate morpholino oligomer, a synthetic DNA analoguePURPOSE: Pretargeting has been attracting increasing attention as a drug delivery approach. We recently proposed Watson-Crick pairing of phosphorodiamidate morpholino oligomers (MORF) for the recognition system in tumor pretargeting. MORF pretargeting involves the initial i.v. injection of a MORF-conjugated antitumor antibody and the subsequent i.v. injection of the radiolabeled complement. Our laboratory has reported on MORF pretargeting for diagnosis using (99m)Tc as radiolabel. We now report on the use of MORF pretargeting for radiotherapy in a mouse tumor model using (188)Re as the therapeutic radiolabel. EXPERIMENTAL DESIGN: An initial tracer study was done to estimate radiation dose, and was followed by the radiotherapy study at 400 muCi per mouse with three control groups (untreated, MORF antibody alone, and (188)Re complementary MORF alone). RESULTS: Tracer study indicated rapid tumor localization of (188)Re and rapid clearance from normal tissues with a tumor area under the curve (AUC) about four times that of kidney and blood (the normal organs with highest radioactivity). Tumor growth in the study group ceased 1 day after radioactivity injection, whereas tumors continued to grow at the same rate among the three control groups. At sacrifice on day 5, the average net tumor weight in the study group was significantly lower at 0.68 +/- 0.29 g compared with the three control groups (1.24 +/- 0.31 g, 1.25 +/- 0.39 g, and 1.35 +/- 0.41 g; Ps < 0.05), confirming the therapeutic benefit observed by tumor size measurement. CONCLUSIONS: MORF pretargeting has now been shown to be a promising approach for tumor radiotherapy as well as diagnosis.
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Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of lifeOBJECTIVE: This study examined the effect of abatacept, a costimulation modulator, on the health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA). METHODS: Three hundred thirty-nine patients with RA on a background of methotrexate (MTX), who participated in a multicenter, double-blind, placebo-controlled trial, were randomized to abatacept 2 mg/kg, abatacept 10 mg/kg, or placebo. HRQOL was assessed at pretreatment, and at 3, 6, and 12 months posttreatment using the SF-36 Health Survey (SF-36). Changes in SF-36 scores from baseline to 12 months were compared across treatment and placebo groups to examine HRQOL benefits of abatacept. A link between American College of Rheumatology improvement and changes in SF-36 scores was established to demonstrate the association between HRQOL outcomes and clinical response. RESULTS: After 12 months of treatment, patients randomized to abatacept 10 mg/kg showed significantly better HRQOL outcomes overall versus patients randomized to placebo (MANOVA F = 4.71, p < 0.001) or to abatacept 2 mg/kg (MANOVA F = 1.97, p = 0.05). Differences in SF-36 change scores between abatacept 10 mg/kg and placebo groups reached statistical significance on all 8 domain scales, the 2 summary measures, and the SF-36 utility index (SF-6D). Differences in SF-36 change scores between abatacept 10 mg/kg and abatacept 2 mg/kg reached statistical significance on 5 of the 8 domain scales, the physical summary measure, and the SF-6D. Improvement in HRQOL was highly related to clinical response. CONCLUSION: Abatacept 10 mg/kg plus MTX demonstrated a stronger HRQOL response than placebo plus MTX. The abatacept 2 mg/kg arm showed a very weak and transient response.