The authors developed quantitative radioimmunoassays to allow direct measurement of total human I... more The authors developed quantitative radioimmunoassays to allow direct measurement of total human IgG and individual IgG subclasses among antibodies bound to cell surfaces. The assays use four mouse monoclonal radioiodinated antibodies, one that reacts equally well with all four human IgG subclasses and three that are specific for human IgG subclasses 1, 2, or 3. The assays were used to analyze IgG subclass composition in 21 high-titer anti-D samples from Rh-negative volunteers immunized for Rh immunoglobulin production. Anti-D activity was restricted primarily to the IgG1 and IgG3 subclasses. Eleven of 21 sera demonstrated red cell antibodies with a marked predominance of IgG1 (87 +/- 3.6% of total IgG antibody, +/- SEM) and low levels of IgG3 (1.4 +/- 0.73%). In the remaining 10 sera, IgG3 made up a greater proportion of total IgG antibody (32 +/- 3.8%), although IgG1 was still predominant (61 +/- 4.1%). This observed dichotomy in the IgG subclass profiles of different anti-D sera may be a consideration in the selection of anti-D sera for the production of the immunoglobulin used in the prophylaxis of Rh-incompatible pregnancies.
ABSTRACT Dosimetry estimates of normal organs and tumors are presented for 34 lung cancer patient... more ABSTRACT Dosimetry estimates of normal organs and tumors are presented for 34 lung cancer patients after administration of 111In-CC49 tracer / 90Y-CC49 + / - adjuvant EDTA or DTPA chelator, or paclitaxel chemotherapy. Data were obtained from quantitation of serial gamma camera images and blood radioactivity. Radiation dose estimates were calculated by Medical Internal Radiation Dose (MIRD) formalism using lesion or organ dimensions obtained from CT images. The pharmacokinetics and dosimetry of the serum and whole body after a single IV administration of 90Y-CC49 were similar to that reported in multiple studies of 131I-CC49 (serum T1 / 2 45 + / - 15h), with a 2-fold range between the shortest and longest circulation time. Normal organs including liver, lung and kidney had ranges from 5-7 fold between the lowest and highest radiation dose while tumors had the widest range of 10 fold. Using specific liver masses for 20 patients resulted in dose estimates 0.5-1.7x that derived with the mass of a standard reference man model. Whole body radiation dose per unit of injected activity (cGy / mCi) was relatively consistent among 33 patients, varying between 2.0 and 2.6 with a mean of 2.4 despite modest but significant differences with chemotherapy or chelator. Paclitaxel in conjunction with the 90Y-CC49 resulted in a modest increase in whole body cGy / mCi but effects for other parameters measured were not statistically significant. The adjuvant use of EDTA or DTPA as a chelator for unbound radioactive metal resulted in small, although significant decreases, in whole body T1 / 2, and cGy / mCi for the whole body, lung and liver but did not significantly change plasma pharmacokinetics.
Multilayer thin films consisting of a-CN x :H/nc-Si:H layers prepared by radio-frequency plasma e... more Multilayer thin films consisting of a-CN x :H/nc-Si:H layers prepared by radio-frequency plasma enhanced chemical vapour (rf PECVD) deposition technique were studied. High optical reflectivity at a specific wavelength is one of major concern for its application. By using this ...
Objectives. To evaluate the safety, immunogenicity, and biologic effects of chimeric monoclonal a... more Objectives. To evaluate the safety, immunogenicity, and biologic effects of chimeric monoclonal anti-CD4 (cM-T412) in patients with refractory rheumatoid arthritis (RA), and to obtain preliminary data on the clinical response to this treatment.Methods. Twenty-five patients with active refractory RA were treated with incremental doses (10 to 700 mg) of cM-T412 in an open-label, escalating-dose phase I trial.Results. Infusion with cM-T412 was followed by an immediate, rapid decline in CD4+ T cells. The level of circulating CD4+ T cells remained depressed in most patients even at 6 months posttreatment. Following antibody infusion, proliferative responses of peripheral blood lymphocytes to mitogens and antigens were determined; mitogen and antigen responses were decreased compared with pretreatment responses. Mitogen responses tended to return to baseline values more rapidly than did responses to antigen. Adverse events included fever (19 patients), which was associated with myalgias, malaise, and asymptomatic hypotension; these symptoms were self-limited and appeared to correlate with transient elevations in interleukin-6. No significant human antibody response to the cM-T412 variable region was detected; only 2 patients developed transiently low levels of antibodies reactive with cM-T412. Significant clinical improvement, defined as ≥50% decrease in tender joint counts compared with baseline, was noted in 43% of patients at 5 weeks and 33% at 6 months following cM-T412 infusion.Conclusions. Treatment of refractory RA with cM-T412 appears to be safe and is associated with sustained decreases in circulating CD4+ T cell counts and depressed in vitro T cell responses. No significant human antichimeric antibody response was detected. Nonblinded assessment of clinical end points suggests that treatment with cM-T412 may have beneficial effects in these patients with refractory RA. A double-blind clinical trial is warranted to determine its clinical efficacy in treating RA.
A phase I trial was designed to examine the feasibility of combining interferon and Taxol with in... more A phase I trial was designed to examine the feasibility of combining interferon and Taxol with intraperitoneal radioimmunotherapy (177Lu-CC49). Patients with recurrent or persistent ovarian cancer confined to the abdominal cavity after first line therapy, Karnofsky performance status > 60, adequate liver, renal and hematologic function, and tumor that reacted with CC49 antibody were enrolled. Human recombinant alpha interferon (IFN) was administered as 4 subcutaneous injections of 3 x 10(6) U on alternate days beginning 5 days before RIT to increase the expression of the tumor-associated antigen, TAG-72. The addition of IFN increased hematologic toxicity such that the maximum tolerated dose (MTD) of the combination was 40 mCi/m2 compared to 177Lu-CC49 alone (45 mCi/m2). Taxol, which has radiosensitizing effects as well as antitumor activity against ovarian cancer, was given intraperitoneally (i.p.) 48 hrs before RIT. It was initiated at 25 mg/m2 and escalated at 25 mg/m2 increments to 100 mg/m2. Subsequent groups of patients were treated with IFN + 100 mg/m2 Taxol + escalating doses of 177Lu-CC49. Three or more patients were treated in each dose group and 34 patients were treated with the 3-agent combination. Therapy was well tolerated with the expected reversible hematologic toxicity. The MTD for 177Lu-CC49 was 40 mCi/m2 when given with IFN + 100 mg/m2 Taxol. Interferon increased the effective whole body half-time of radioactivity and the whole body radiation dose. Taxol did not have a significant effect on pharmacokinetic or dosimetry parameters. Four of 17 patients with CT measurable disease had a partial response (PR) and 4 of 27 patients with non-measurable disease have progression-free intervals of 18+, 21+, 21+, and 37+ months. The combination of intraperitoneal Taxol chemotherapy (100 mg/m2) with RIT using 177Lu-CC49 and interferon was well tolerated, with bone marrow suppression as the dose-limiting toxicity.
Although marrow suppression is usually the dose-limiting toxicity in non-marrow ablative radionuc... more Although marrow suppression is usually the dose-limiting toxicity in non-marrow ablative radionuclide therapy, calculated marrow dose has rarely been used for prescribing the radioactivity to be administered. This study assesses the correlation of myelotoxicity with mCi/m(2), patient-specific lean body dose, marrow dose from blood and body of reference man, or from blood and body using the patient-specific mass. Fourteen prostate cancer patients were treated with (131)I-CC49. Radioactivity in blood and body was determined and used to calculate their contributions to the marrow dose. Platelet nadir expressed as percentage (%) of the initial baseline was used as an indicator for myelotoxicity. Correlation between platelet nadir (%) and myelotoxicity predictors was evaluated. Platelet nadirs (%) varied substantially (5-33%) for a small range of injected radioactivity/m(2) (68-78 mCi/m(2), 2.5-2.9 GBq/m(2)). Patient-specific total body dose based on lean body mass exhibited a weak correlation (r = 0.48) with platelet nadir. Marrow dose from blood and body of reference man had a better correlation (r = 0.73). Patient-specific marrow dose from blood and body (or lean body) had a similar correlation (r = 0.74 or 0.73). Radioactivity in the remainder of the body contributed only 28% of the total dose, and thus changes to this dose component had small impact on total marrow dose. Marrow dose was a better predictor for myelotoxicity than mCi/m(2) or lean total body dose in this non-marrow targeting (131)I-antibody therapy with high blood contributions to total dose.
Severely immunocompromised individuals are highly susceptible to Candida infection of the esophag... more Severely immunocompromised individuals are highly susceptible to Candida infection of the esophagus. This randomized, double-blind study assessed the dose-response relationship of the new echinocandin antifungal, micafungin, compared with that of standard fluconazole treatment. A total of 245 patients (age, > or =18 years) with a prior diagnosis of acquired immunodeficiency syndrome/human immunodeficiency virus (HIV) infection and esophageal candidiasis, confirmed by endoscopy and culture, were randomized to receive micafungin (50, 100, or 150 mg per day) or fluconazole (200 mg per day). Both agents were administered once per day by a 1-h intravenous infusion for 14-21 days. The primary efficacy end point was endoscopic cure rate, defined as endoscopy grade of 0 at the end of therapy. The endoscopic cure rate (grade 0) was dose-dependent with 50, 100, and 150 mg of micafungin per day at 68.8%, 77.4%, and 89.8%, respectively. Symptoms improved or resolved rapidly (3-7 days of treatment in the majority of patients). The endoscopic cure rate for 100 and 150 mg of micafungin per day (83.5%) was comparable to that for 200 mg of fluconazole per day (86.7%; 95% confidence interval for the difference in endoscopic cure rate, -14.0% to 7.7%). The overall safety and tolerability was acceptable, with no important differences between micafungin (all doses) and fluconazole. The dose-response findings demonstrate a greater efficacy with micafungin at 100 and 150 mg per day than at 50 mg per day. This study also indicates that the efficacy of micafungin (at dosages of 100 and 150 mg per day) was comparable to that of fluconazole, suggesting that micafungin represents a valuable new treatment option for esophageal candidiasis in HIV-positive patients.
The authors developed quantitative radioimmunoassays to allow direct measurement of total human I... more The authors developed quantitative radioimmunoassays to allow direct measurement of total human IgG and individual IgG subclasses among antibodies bound to cell surfaces. The assays use four mouse monoclonal radioiodinated antibodies, one that reacts equally well with all four human IgG subclasses and three that are specific for human IgG subclasses 1, 2, or 3. The assays were used to analyze IgG subclass composition in 21 high-titer anti-D samples from Rh-negative volunteers immunized for Rh immunoglobulin production. Anti-D activity was restricted primarily to the IgG1 and IgG3 subclasses. Eleven of 21 sera demonstrated red cell antibodies with a marked predominance of IgG1 (87 +/- 3.6% of total IgG antibody, +/- SEM) and low levels of IgG3 (1.4 +/- 0.73%). In the remaining 10 sera, IgG3 made up a greater proportion of total IgG antibody (32 +/- 3.8%), although IgG1 was still predominant (61 +/- 4.1%). This observed dichotomy in the IgG subclass profiles of different anti-D sera may be a consideration in the selection of anti-D sera for the production of the immunoglobulin used in the prophylaxis of Rh-incompatible pregnancies.
ABSTRACT Dosimetry estimates of normal organs and tumors are presented for 34 lung cancer patient... more ABSTRACT Dosimetry estimates of normal organs and tumors are presented for 34 lung cancer patients after administration of 111In-CC49 tracer / 90Y-CC49 + / - adjuvant EDTA or DTPA chelator, or paclitaxel chemotherapy. Data were obtained from quantitation of serial gamma camera images and blood radioactivity. Radiation dose estimates were calculated by Medical Internal Radiation Dose (MIRD) formalism using lesion or organ dimensions obtained from CT images. The pharmacokinetics and dosimetry of the serum and whole body after a single IV administration of 90Y-CC49 were similar to that reported in multiple studies of 131I-CC49 (serum T1 / 2 45 + / - 15h), with a 2-fold range between the shortest and longest circulation time. Normal organs including liver, lung and kidney had ranges from 5-7 fold between the lowest and highest radiation dose while tumors had the widest range of 10 fold. Using specific liver masses for 20 patients resulted in dose estimates 0.5-1.7x that derived with the mass of a standard reference man model. Whole body radiation dose per unit of injected activity (cGy / mCi) was relatively consistent among 33 patients, varying between 2.0 and 2.6 with a mean of 2.4 despite modest but significant differences with chemotherapy or chelator. Paclitaxel in conjunction with the 90Y-CC49 resulted in a modest increase in whole body cGy / mCi but effects for other parameters measured were not statistically significant. The adjuvant use of EDTA or DTPA as a chelator for unbound radioactive metal resulted in small, although significant decreases, in whole body T1 / 2, and cGy / mCi for the whole body, lung and liver but did not significantly change plasma pharmacokinetics.
Multilayer thin films consisting of a-CN x :H/nc-Si:H layers prepared by radio-frequency plasma e... more Multilayer thin films consisting of a-CN x :H/nc-Si:H layers prepared by radio-frequency plasma enhanced chemical vapour (rf PECVD) deposition technique were studied. High optical reflectivity at a specific wavelength is one of major concern for its application. By using this ...
Objectives. To evaluate the safety, immunogenicity, and biologic effects of chimeric monoclonal a... more Objectives. To evaluate the safety, immunogenicity, and biologic effects of chimeric monoclonal anti-CD4 (cM-T412) in patients with refractory rheumatoid arthritis (RA), and to obtain preliminary data on the clinical response to this treatment.Methods. Twenty-five patients with active refractory RA were treated with incremental doses (10 to 700 mg) of cM-T412 in an open-label, escalating-dose phase I trial.Results. Infusion with cM-T412 was followed by an immediate, rapid decline in CD4+ T cells. The level of circulating CD4+ T cells remained depressed in most patients even at 6 months posttreatment. Following antibody infusion, proliferative responses of peripheral blood lymphocytes to mitogens and antigens were determined; mitogen and antigen responses were decreased compared with pretreatment responses. Mitogen responses tended to return to baseline values more rapidly than did responses to antigen. Adverse events included fever (19 patients), which was associated with myalgias, malaise, and asymptomatic hypotension; these symptoms were self-limited and appeared to correlate with transient elevations in interleukin-6. No significant human antibody response to the cM-T412 variable region was detected; only 2 patients developed transiently low levels of antibodies reactive with cM-T412. Significant clinical improvement, defined as ≥50% decrease in tender joint counts compared with baseline, was noted in 43% of patients at 5 weeks and 33% at 6 months following cM-T412 infusion.Conclusions. Treatment of refractory RA with cM-T412 appears to be safe and is associated with sustained decreases in circulating CD4+ T cell counts and depressed in vitro T cell responses. No significant human antichimeric antibody response was detected. Nonblinded assessment of clinical end points suggests that treatment with cM-T412 may have beneficial effects in these patients with refractory RA. A double-blind clinical trial is warranted to determine its clinical efficacy in treating RA.
A phase I trial was designed to examine the feasibility of combining interferon and Taxol with in... more A phase I trial was designed to examine the feasibility of combining interferon and Taxol with intraperitoneal radioimmunotherapy (177Lu-CC49). Patients with recurrent or persistent ovarian cancer confined to the abdominal cavity after first line therapy, Karnofsky performance status > 60, adequate liver, renal and hematologic function, and tumor that reacted with CC49 antibody were enrolled. Human recombinant alpha interferon (IFN) was administered as 4 subcutaneous injections of 3 x 10(6) U on alternate days beginning 5 days before RIT to increase the expression of the tumor-associated antigen, TAG-72. The addition of IFN increased hematologic toxicity such that the maximum tolerated dose (MTD) of the combination was 40 mCi/m2 compared to 177Lu-CC49 alone (45 mCi/m2). Taxol, which has radiosensitizing effects as well as antitumor activity against ovarian cancer, was given intraperitoneally (i.p.) 48 hrs before RIT. It was initiated at 25 mg/m2 and escalated at 25 mg/m2 increments to 100 mg/m2. Subsequent groups of patients were treated with IFN + 100 mg/m2 Taxol + escalating doses of 177Lu-CC49. Three or more patients were treated in each dose group and 34 patients were treated with the 3-agent combination. Therapy was well tolerated with the expected reversible hematologic toxicity. The MTD for 177Lu-CC49 was 40 mCi/m2 when given with IFN + 100 mg/m2 Taxol. Interferon increased the effective whole body half-time of radioactivity and the whole body radiation dose. Taxol did not have a significant effect on pharmacokinetic or dosimetry parameters. Four of 17 patients with CT measurable disease had a partial response (PR) and 4 of 27 patients with non-measurable disease have progression-free intervals of 18+, 21+, 21+, and 37+ months. The combination of intraperitoneal Taxol chemotherapy (100 mg/m2) with RIT using 177Lu-CC49 and interferon was well tolerated, with bone marrow suppression as the dose-limiting toxicity.
Although marrow suppression is usually the dose-limiting toxicity in non-marrow ablative radionuc... more Although marrow suppression is usually the dose-limiting toxicity in non-marrow ablative radionuclide therapy, calculated marrow dose has rarely been used for prescribing the radioactivity to be administered. This study assesses the correlation of myelotoxicity with mCi/m(2), patient-specific lean body dose, marrow dose from blood and body of reference man, or from blood and body using the patient-specific mass. Fourteen prostate cancer patients were treated with (131)I-CC49. Radioactivity in blood and body was determined and used to calculate their contributions to the marrow dose. Platelet nadir expressed as percentage (%) of the initial baseline was used as an indicator for myelotoxicity. Correlation between platelet nadir (%) and myelotoxicity predictors was evaluated. Platelet nadirs (%) varied substantially (5-33%) for a small range of injected radioactivity/m(2) (68-78 mCi/m(2), 2.5-2.9 GBq/m(2)). Patient-specific total body dose based on lean body mass exhibited a weak correlation (r = 0.48) with platelet nadir. Marrow dose from blood and body of reference man had a better correlation (r = 0.73). Patient-specific marrow dose from blood and body (or lean body) had a similar correlation (r = 0.74 or 0.73). Radioactivity in the remainder of the body contributed only 28% of the total dose, and thus changes to this dose component had small impact on total marrow dose. Marrow dose was a better predictor for myelotoxicity than mCi/m(2) or lean total body dose in this non-marrow targeting (131)I-antibody therapy with high blood contributions to total dose.
Severely immunocompromised individuals are highly susceptible to Candida infection of the esophag... more Severely immunocompromised individuals are highly susceptible to Candida infection of the esophagus. This randomized, double-blind study assessed the dose-response relationship of the new echinocandin antifungal, micafungin, compared with that of standard fluconazole treatment. A total of 245 patients (age, > or =18 years) with a prior diagnosis of acquired immunodeficiency syndrome/human immunodeficiency virus (HIV) infection and esophageal candidiasis, confirmed by endoscopy and culture, were randomized to receive micafungin (50, 100, or 150 mg per day) or fluconazole (200 mg per day). Both agents were administered once per day by a 1-h intravenous infusion for 14-21 days. The primary efficacy end point was endoscopic cure rate, defined as endoscopy grade of 0 at the end of therapy. The endoscopic cure rate (grade 0) was dose-dependent with 50, 100, and 150 mg of micafungin per day at 68.8%, 77.4%, and 89.8%, respectively. Symptoms improved or resolved rapidly (3-7 days of treatment in the majority of patients). The endoscopic cure rate for 100 and 150 mg of micafungin per day (83.5%) was comparable to that for 200 mg of fluconazole per day (86.7%; 95% confidence interval for the difference in endoscopic cure rate, -14.0% to 7.7%). The overall safety and tolerability was acceptable, with no important differences between micafungin (all doses) and fluconazole. The dose-response findings demonstrate a greater efficacy with micafungin at 100 and 150 mg per day than at 50 mg per day. This study also indicates that the efficacy of micafungin (at dosages of 100 and 150 mg per day) was comparable to that of fluconazole, suggesting that micafungin represents a valuable new treatment option for esophageal candidiasis in HIV-positive patients.
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