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Biomedical subjects

J L Murray

Publications and source records attributed to J L Murray.

At least 55 records · Page 3Linked to original sources
PubMed1996

Cellular resistance to the antimelanoma immunotoxin ZME-gelonin and strategies to target resistant cells.

The development of cellular resistance to immunotoxins has been demonstrated in a variety of models and can involve a number of mechanisms. For the present study, an immunotoxin was utilized composed of an anti-melanoma antibody ZME-018 recognizing a 240-kDa surface glycoprotein (gp 240) and the plant toxin gelonin. Human melanoma cells (A375-M) were grown in the presence of increasing amounts of ZME-gelonin and a clonal variant (A-375-ZR) was developed that was 100-fold resistant to ZME-gelonin compared to parental cells. Scatchard analysis showed that the A375-M parental cells had 260 X 10(3) ZME-gelonin-binding sites/cell with relatively low affinity (5 nM). In contrast, resistant A375-ZR cells demonstrated a reduced number of low-affinity sites (160 x 10(3)/cel1), but showed a small number (47 x 10(3)) of higher-affinity sites (0.8 nM). Internalization rates and degradation rates of 125I-labeled ZME-gelonin were identical in both the parental and resistant cells. A375-ZR cells were found to be more resistant to vincristine and doxorubicin than were parental cells. Both cell lines were almost equally sensitive to native gelonin, 5-fluorouracil (5-FU), cisplatin. melphalan, carmustine, interferon gamma (IFNgamma) and IFNalpha. In addition. both cell lines were equally sensitive to another gelonin antibody conjugate that binds to cell-surface, GD2 (antibody 14G2A). However, resistant cells were twice as sensitive to the cytotoxic effects of etoposide than were parental cells. Finally, a variety of agents were tested in combination with ZME-gelonin against A375-ZR cells in an attempt to identify agents to augment immunotoxin cytotoxic effects against resistant cells. The agents 5-FU, cisplatin, IFNgamma, IFNalpha, and etoposide were the most effective in augmenting the cytotoxicity of ZME-gelonin against resistant cells. These studies suggest that development of resistance to one immunotoxin does not cause development of cross-resistance to other gelonin immunotoxins. Further, specific biological response modifiers and chemotherapeutic agents may be effective in augmenting the effectiveness of immunotoxins and specifically targeting or reducing the emergence of immunotoxin-resistant cells.

Antineoplastic Agents↗
PubMed1996

Phase Ia/Ib trial of anti-GD2 chimeric monoclonal antibody 14.18 (ch14.18) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in metastatic melanoma.

We performed a phase Ia/Ib trial of chimeric anti-GD2 monoclonal antibody 14.18 (ch14.18) in combination with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to determine the maximum tolerated dose as well as immunologic and biologic responses to the regimen. Sixteen patients with metastatic malignant melanoma received escalating doses of ch14.18 (15-60 mg/m2) administered intravenously for 4 h on day 1. Twenty-four hours later, subcutaneous injections of rhGM-CSF were administered daily for a total of 14 days. Significant side effects were related to ch14.18 infusion and consisted of moderate to severe abdominal and/or extremity pain, blood pressure changes, headache, nausea, diarrhea, peripheral nerve dysesthesias, myalgias, and weakness. Dose-limiting toxicity was observed at 60 mg/m2 and consisted of severe hypertension, hypotension, and atrial fibrillation in one patient each, respectively. Significant increases in white blood cell count, granulocyte count, eosinophil count, and monocyte count occurred after rhGM-CSF treatment. Significant enhancement of in vitro and in vivo monocyte and neutrophil tumoricidal activity and antibody-dependent cellular cytotoxicity along with significant elevations in C-reactive protein and neopterin were observed. Despite these immunological and biological changes, no antitumor activity was seen. In short, the combination of ch14.18 and rhGM-CSF resulted in toxicity similar to that observed with ch14.18 alone without improvement in tumor response.

Antibodies, Monoclonal↗
PubMed1996

99Tcm-IMMU4 imaging in recurrent colorectal cancer: efficacy and impact on surgical management.

The aims of this study were to evaluate the efficacy of scintigraphy with the 99Tcm-labelled anti-carcinoembryonic antigen (CEA) monoclonal antibody Fab' fragment (IMMU4) in the diagnosis of recurrent colorectal carcinoma and to investigate its usefulness in the intraoperative surgical management of patients undergoing re-operation because of a rising serum CEA. We evaluated 24 patients prospectively who had rising serum CEA 6-19 months after initial surgery for colorectal carcinoma. Ten patients had lesions confirmed by computed tomography, ultrasound, magnetic resonance imaging, endoscopic examination or barium enema. Fourteen patients had negative findings on one or more of the above studies, but were suspected of having occult disease from their rising serum CEA. All patients were scheduled for surgery for restaging during a "second look' procedure. Planar and single photon emission tomography (SPET) imaging was performed in all patients. All scintigraphic findings were correlated with surgical and histopathological results. The overall sensitivity, specificity and accuracy were 81, 90 and 86% respectively when analysed by lesion, and 95, 60 and 88% respectively when analysed by patient. Ten of 14 (71%) patients with occult disease were correctly diagnosed as having recurrent disease. The SPET images were shown to have superior detectability (80%) compared with the planar images (35%). The surgeon judged the study to have had a neutral impact in 75% of the patients, but to have been helpful in 25%. We conclude that this antibody is potentially useful in detecting recurrent colorectal carcinoma in patients with rising serum CEA, especially when conventional imaging is negative or equivocal. It can also be helpful in altering planned surgery.

Adenocarcinoma↗
PubMed1996

Lovastatin effects on human breast carcinoma cells. Differential toxicity of an adriamycin-resistant derivative and influence on selenocysteine tRNAS.

Selenocysteine tRNA[Ser]Sec isoacceptors contain the modified nucleotide i6A immediately 3' to the anticodon. Because synthesis of i6A is expected to be inhibited by lovastatin, the status of tRNA[Ser]Sec isoacceptors was examined in human breast carcinoma cells. As part of the initial characterization of these cells, it was determined that an adriamycin resistant derivative of the MCF-7 cell line exhibited a dramatic increase in the sensitivity to the killing effects of lovastatin relative to the parental MCF-7 cells. When MCF-7Adr cells were incubated with high levels of lovastatin, there was a dramatic perturbation in the distribution of isoacceptors within the selenocysteine tRNA population. Lovastatin may therefore be a useful reagent for both the study of differential killing of drug-resistant tumor cells and selenoprotein biosynthesis.

Antibiotics, Antineoplastic↗
PubMed1995

Enhanced TAG-72 expression and tumor uptake of radiolabeled monoclonal antibody CC49 in metastatic breast cancer patients following alpha-interferon treatment.

The IFNs, alpha and gamma, have been shown to enhance the tumor-associated glycoprotein (TAG-72) on adenocarcinoma cells in vitro and in mice with human breast cancer xenografts, resulting in improved targeting of monoclonal antibody CC49. To determine the effect of IFN-alpha on biodistribution and tumor uptake of 131I-labeled CC49, patients with metastatic breast cancer were randomized to either receive or not receive IFN-alpha (3 million units daily for 14 days) by s.c. injection. Three days after beginning IFN-alpha, all patients received 10-20 mCi of 131I-CC49 (specific activity, 16.7 mCi/mg) i.v. Total-body Anger camera scans, along with total-body blood and plasma pharmacokinetics, were performed. Tumor biopsies were taken in all patients before and 48 h after IFN-alpha treatment. There were no significant differences in number of metastases imaged or whole-body, blood and plasma pharmacokinetics between IFN-alpha-treated and untreated patients. Quantitative immunohistochemistry on biopsy specimens from IFN-alpha-treated patients demonstrated a significant increase in mean +/- SEM TAG-72 expression (45.7 +/- 19.4%) compared to patients that were not given IFN-alpha (1.3 +/- 0.95%; P < 0.05). Although slight increases in the percent injected dose of 131I-CC49 in tumor occurred after IFN-alpha-treatment, the changes were not significant at the P < 0.05 level. These data suggest that IFN-alpha may be useful in enhancing TAG-72 antigen expression in vivo in humans, despite modest improvement in tumor uptake of CC49, possibly because of limited tumor access or other unknown factors.

Adenocarcinoma↗
PubMed1995

Phase I clinical and pharmacological study of suppression of human antimouse antibody response to monoclonal antibody L6 by deoxyspergualin.

Development of human antimouse antibody (HAMA) is a major limiting factor in the application of murine mAb for clinical use. A novel immunomodulatory drug, deoxyspergualin (DSG), has shown potential to suppress antimouse antibody response in preclinical model systems. We conducted a Phase I trial to determine the effect of DSG on HAMA response to murine mAb L6 administered to patients with advanced cancers (in previous trials, this antibody elicited HAMA in two-thirds of the treated patients). L6 mAb was administered at a fixed dose of 200 mg/m2 on days 1-5. DSG was administered at doses of 50 mg/m2 [dose level (dl) 1] or 150 mg/m2 (dls II and III) on days 1-7. Treatment courses were repeated every 6 weeks (dls I and II) or every 3 weeks (dl III). HAMAs were quantitated by a commercially available ELISA assay (ImmuSTRIP; anti-isotypic antibodies) and a radiometric assay (antiisotypic and anti-idiotypic antibodies). Pharmacokinetics of L6 and DSG was also studied in all consenting patients. Among 24 evaluable patients, 2 patients developed detectable HAMAs using the ELISA (one each at dls I and II) after a median follow-up of 122 days (P = 0.0001 as compared to historical controls). Even in the two patients who developed HAMA, the HAMA levels were quite low (160 and 181 ng/ml; historical experience, 70-38,744 ng/ml). The radiometric assay detected anti-L6 antibodies in 13 patients (4, 6, and 3 at dls I-III, respectively) after a median of 82 days. The median highest anti-L6 antibody level was 129 ng/ml (range, 21-2150). The highest anti-L6 antibody level at dl III was only 44 ng/ml. The results suggest suppression of anti-idiotypic response also. No clinical antitumor activity was observed, and no significant changes in T4/T8 subsets or immunoglobulins occurred (suggesting a lack of generalized immunosuppression). We conclude that DSG can suppress HAMA response to L6. A starting dose of 150 mg/m2/day is recommended for Phase II trials to confirm this observation.

Adult↗
PubMed1995

An antimelanoma immunotoxin containing recombinant human tumor necrosis factor: tissue disposition, pharmacokinetic, and therapeutic studies in xenograft models.

The ability of monoclonal antibody conjugates to re-direct plant or bacterial toxins, chemotherapeutic agents and radionuclides to selected target cells has been well-documented. Recombinant human tumor necrosis factor (TNF) is a macrophage-derived, non-glycosylated (17 kDa) peptide with a broad range of biological and immunological effects including antiviral activity, cytotoxic and cytostatic effects. A conjugate of the antimelanoma antibody ZME-018 and TNF in previous studies has shown melanoma-selective cytotoxic effects in vitro. Pharmacokinetic studies of the ZME-TNF immunotoxin showed that the agent cleared from plasma biphasically with alpha- and beta-phase half-lives similar to that of ZME itself (72 min and 36 h compared to 84 min and 41 h respectively). In contrast, TNF itself was cleared rapidly from plasma with a terminal-phase half-life of only 2.7 h. The clearance rate of ZME-TNF from plasma (Clp) was almost tenfold more rapid than for ZME (1.1 versus 0.16 ml/kg x min) but was threefold slower than the clearance for TNF itself (3.4 ml/kg x min). Tissue distribution studies in nude mice bearing human melanoma xenografts showed similar tumor localization of the immunotoxin compared to the free antibody and slightly higher concentrations in liver and kidney compared to ZME itself. Treatment of nude mice bearing well-developed A375 tumors with the immunotoxin resulted in a statistically significant (P < 0.002) suppression in tumor growth rate (fivefold increase) compared to saline-treated controls, which increased 20-fold over the same period. These studies demonstrate the feasibility of this approach and suggest that TNF may represent a non-antigenic alternative to immunotoxins containing plant and bacterial toxins.

Animals↗
PubMed1995

Pharmacokinetics, tissue distribution, and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin.

Antibody ZME-018 is directed against the gp240 glycoprotein on the surface of more than 80% of human melanoma cell lines and fresh biopsy specimens. Previous studies in our laboratory described the in vitro cytotoxicity and specificity of an immunoconjugate composed of mAb ZME-018 and the plant toxin gelonin. The present study described the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xenograft/nude mouse models. Pharmacokinetic studies of 125I-labeled ZME-018 and ZME-gelonin demonstrated a shorter terminal-phase plasma half-life of the immunoconjugate than native ZME (20.6 h compared to 41.3 h). The initial volume of distribution of the ZME-gelonin was also higher compared to that of ZME alone (2.85 ml compared to 1.94 ml) suggesting an enhanced distribution of the conjugate outside the vasculature. The corresponding area under the concentration/time curve for the ZME-gelonin conjugate was 40% lower than that of ZME alone (80.8 compared to 139.6 microCi.ml-1 x min). In nude mice bearing well-developed human tumor A375 melanoma xenografts, administration of 125I-labeled ZME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9 +/- 0.5 and 1.5 +/- 0.6 respectively by 72 h. Compared with ZME, ZME-gelonin conjugate caused an increase in the content of radiolabel in kidney, spleen and liver. Treatment of nude mice bearing well-developed (150 mm3) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelonin, or saline resulted in suppression of tumor growth in the immunotoxin group but virtually no retardation of tumor growth in the control groups. Using a murine model for a rapidly growing lethal metastatic human melanoma, treatment with ZME-gelonin resulted in a mean survival of 44 days, 213% increase in mean survival time compared with the saline treatment (14.2 +/- 2 day survival). Given these encouraging results, we are proceeding with further preclinical development of this immunotoxin.

Animals↗
PubMed1995

Changes in an HER-2 peptide upregulating HLA-A2 expression affect both conformational epitopes and CTL recognition: implications for optimization of antigen presentation and tumor-specific CTL induction.

The HER-2/neu protooncogene (HER-2) is overexpressed in a significant number of breast and ovarian tumors. Peptides of HER-2 sequence were recently found to reconstitute recognition of cytotoxic T lymphocytes (CTLs) from tumor-associated (TALs) and tumor-infiltrating (TILs) lymphocytes, indicating that they reconstitute natural epitopes recognized by CTLs on HLA-A2+ tumors. Because HER-2 is an important antigen (Ag) for tumor-specific CTL induction and the immunogenicity of peptides for CTL induction is dependent on their presentation as stable complexes with HLA-A2, we identified peptides of high and low stabilizing activity from the sequence of HER-2 and the folate-binding protein (FBP). Distinct sequence patterns in the region positions (P)3-P5 and P1 were found for peptides with high (HSA) and low (LSA) stabilizing ability. A low-HLA-A2-affinity HER-2 peptide, P1 of the CTL epitope, was found to be permissive to substitutions that enhanced HLA-A2-stabilizing ability and conserved CTL recognition. In contrast, the region P3-P5 was not permissive to sequence changes. We conclude that the selective permissivity of P1 and P9 in the tumor epitope sequence may have important implications for optimization of tumor Ag presentation, and "neoantigenicity" of self-antigens, aiming toward induction of tumor-reactive CTLs of defined affinity and specificity for target Ags.

Amino Acid Sequence↗
PubMed1995

Incidental asymptomatic orbital calcifications.

OBJECTIVE: To use modern computed tomography (CT) imaging to quantify the incidence of asymptomatic incidental orbital calcifications and describe their histological features. MATERIALS AND METHODS: One hundred orbital CT scans were reviewed. In addition, patients who had orbital calcification(s) detected on a brain CT scan were examined by the ophthalmology service. RESULTS: Of the orbital CT scans, 2% had bilateral drusen of the optic nerve head, 3% had calcified scleral plaques anterior to the medial or lateral rectus muscles, and 3% had bilateral ossification of the trochlear apparatus. Routine brain CT scans detected asymptomatic calcifications of the sclera and dura surrounding the proximal optic nerves. CONCLUSION: Incidental asymptomatic orbital calcifications are commonly encountered on modern high-resolution CT images of the brain and orbit. This article should help the clinician to confidently distinguish these densities from foreign bodies or pathological calcifications.

Adolescent↗
PubMed1994

Phase II radioimmunotherapy trial with 131I-CC49 in colorectal cancer.

BACKGROUND: Radiolabeled CC49, a second generation high affinity monoclonal antibody (MoAb) reactive with tumor-associated glycoprotein 72 (TAG72) has undergone previous Phase I testing in patients with colon cancer. Based on this report, the authors treated 15 refractory metastatic colon cancer patients with 131I-CC49 to determine its overall toxicity and the response to therapy of patients treated with it. METHODS: Patients received 75 mCi/m2 131I-CC49 (20 mg MoAb) intravenously for a period of 30-60 minutes. Whole body retention was derived from the measured dose-rate of I-131 monitored daily at 1 m using an ion chamber. Two whole-body and static-gamma camera images were taken of patients on days 4 and 7 after the infusion. RESULTS: Nonhematologic toxicity (Grade 1-2) consisted of nausea (two patients), arthralgias (three patients), transient fever and chills (two patients), and transient blood pressure changes (two patients). At 4-5 weeks posttreatment, reversible Grade 3-4 thrombocytopenia was observed in 7 of 15 patients, and reversible Grade 3-4 granulocytopenia was observed in 6 of 15 patients. Twelve of 13 patients tested developed human anti-mouse antibody (range, 161 to > 20,000 ng/ml) at 6-8 weeks postinfusion. Mean +/- SD whole-body half-life (whole-body retention) of 131I-CC49 was 57.3 +/- 13.4 hours. Tumors were seen in all patients. In two of three patients treated a second time, an increased whole body clearance rate correlated with elevated human anti-mouse antibody, reduced uptake in tumor, and enhanced uptake in the thyroid. Estimated tumor doses ranged from 19-667 rads. Red marrow dose estimated from whole body retention ranged from 60 to 117 rads and correlated with decreases in platelet count. No objective tumor responses (i.e., partial or complete) were observed. CONCLUSIONS: Despite minimal toxicity and favorable tumor uptake, efficacy has been limited at this dose and schedule.

Animals↗
PubMed1994

Comparative tumor localization of whole immunoglobulin G anticarcinoembryonic antigen monoclonal antibodies IMMU-4 and IMMU-4 F(ab')2 in colorectal cancer patients.

BACKGROUND: Previous studies in the literature have suggested that radiolabeled F(ab')2 fragments might be superior to whole immunoglobulin G (IgG) for imaging and therapy of cancer because of their greater penetration in tumors. To test this hypothesis, the authors compared tumor and normal tissue uptake along with plasma clearance of 125I-labeled monoclonal antibody (MoAb) IMMU-4 whole IgG with its 131I-labeled F(ab')2 fragment. METHODS: Five patients with either liver metastases from colorectal cancer (n = 4) or intact primary tumors (n = 1) received a combination of 125I-IMMU-4 IgG (2 mCi/1 mg) plus 131I-IMMU-4 F(ab')2 (10 mCi/1 mg) as a single 1-hour intravenous infusion on day 1. Serial blood samples were taken for up to 72 hours postinfusion to determine plasma clearance of each MoAb. On days 3-9, patients underwent exploratory laparotomy in which biopsies of tumor as well as normal tissues (liver, normal colon, lymph node, and blood) were obtained. Tissues were weighed and counted in a gamma counter, and the percent of injected dose per kilogram (%ID/kg) of each antibody, along with the radiolocalization index (RI), was computed (RI = %ID/kg tumor.%ID/kg normal tissue). RESULTS: Tumor uptake of both antibodies (2.3 +/- 0.53 %ID/kg) was significantly higher than that of normal tissues (0.56 +/- 0.12; P < 0.001), except for blood (2.8 +/- 0.83), resulting in an RI > or = 3. There were no significant differences in uptake (%ID/g) between F(ab')2 and IgG (F[ab']2 = 2.0 +/- 0.57; IgG = 2.6 +/- 0.94). The mean +/- SD of plasma T1/2 was slightly shorter for F(ab')2 (28.8 +/- 7.2 hours) than for IgG (45.9 +/- 16.7; P = 0.08). CONCLUSION: In short, the biodistribution and pharmacokinetics of IMMU-4 F(ab')2 were comparable to those of IMMU-4-IgG.

Animals↗
PubMed1994

Clinical pharmacology and tissue disposition studies of 131I-labeled anticolorectal carcinoma human monoclonal antibody LiCO 16.88.

Antibody LiCO 16.88 is a human IgM recognizing a 30- to 45-kDa intracytoplasmic antigen present in human adenocarcinoma cells. An 8-mg sample of antibody labeled with 5 mCi 131I was co-administered i.v. with 120 mg (three patients), 240 mg (three patients) or 480 mg (four patients) unlabeled antibody as a 4-h infusion. The plasma half-life was 24 +/- 1.2 h and the immediate apparent volume of distribution was 5.2 +/- 0.2 l at the 28-mg dose level. The plasma half-lives and the cumulative urinary excretion of radiolabel did not seem to vary significantly with increasing doses of unlabeled antibody. However, both the volume of distribution and the clearance rate from plasma increased significantly with increasing antibody dose. Uptake of antibody into tumor tissues obtained during laparotomy 8-9 days after administration varied between 0.00002% ID/g and 0.00127% ID/g. In five of seven patients, the tumor content of antibody was higher than that in adjacent normal tissue. Tumor-to-normal tissue ratios ranged from 0.8 to 10 (mean = 3.8 +/- 1.0). In general, the higher radioactivity(cpm)/g tumor was confirmed by both immunoperoxidase and autoradiography. Antibody 16.88 localizes in tumors after administration and may be considered for use in radioimmunotherapy trials.

Antibodies, Monoclonal↗
PubMed1994

Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors.

PURPOSE: The purpose of this phase I trial was to determine the toxicity and maximum-tolerated dose (MTD) of murine monoclonal antibody (Mab) 14G2a (anti-GD2) in cancer patients. PATIENTS AND METHODS: Following tracer doses of iodine-131-labeled 14G2a to determine tumor uptake, 18 patients with refractory melanoma, neuroblastoma, or osteosarcoma received unlabeled 14G2a at total concentrations of 50, 100, and 200 mg/m2 administered as daily 24-hour infusions for 5 days. RESULTS: The overall sensitivity of external immunoscintigraphy was 64 of 74 known metastases (86%). Toxicity from prolonged infusion of 14G2a consisted of severe generalized pain, hyponatremia, fever, rash, paresthesias, weakness, and chronic refractory postural hypotension (two patients). Toxicity was less severe in pediatric patients. The MTD of Mab was 100 mg/m2. Sixteen of 18 patients developed human antimouse antibodies (HAMA) to 14G2a. Terminal-phase half-life (T1/2) of unlabeled Mab was 6.6 +/- 1.8 hours for patients receiving 50 mg/m2 and 39.5 +/- 13.3 hours at the 100-mg/m2 level. Tumor biopsies from six melanoma patients were positive for GD2 antigen, but only two of six had trace amounts of 14G2a present. Three mixed responses (two melanoma, one osteosarcoma) and two partial responses (PRs; neuroblastoma) were observed. CONCLUSION: Mab 14G2a has modest antitumor activity at the expense of significant toxicity. Dose-limiting neurologic sequelae may significantly limit phase II studies other than in pediatric patients with neuroblastoma.

Adolescent↗
PubMed1993

Phase I trial of chimeric (human-mouse) monoclonal antibody L6 in patients with non-small-cell lung, colon, and breast cancer.

We report a single institution phase I trial of chimeric (mouse-human) monoclonal antibody (chL6) directed against a tumor-associated cell surface antigen expressed in non-small cell lung, colon, and breast cancer. The results of the study were contrasted with a previous trial of murine L6. ChL6 was administered intravenously to 18 patients with advanced cancer as a single, 4-16 infusion in doses ranging from 350 mg/m2 to 700 mg/m2. One patient received four weekly doses of 350 mg/m2. Patients were followed for side effects, localization of antibody to tumor cells, pharmacokinetics and the development of antibodies against chL6. Side effects associated with treatment were chills, fever, and nausea, which lasted 24-48 hours. Platelet count and absolute leukocyte count fell immediately after treatment, but returned to pretreatment levels by day 7. Localization of chL6 to tumor cells in vivo was seen at 350 mg/m2 and "saturation" at 700 mg/m2 and 350 mg/m2 per week x 4. The pharmacokinetics of this antibody appeared similar to its murine analogue. Human antibodies against chL6 were detected in only 4 of 18 patients. These antibodies were directed against murine variable regent and their titers were lower than those occurring in most patients who received murine L6 in an earlier trial. No tumor reductions were seen. Chimeric L6 appears to be a suitable antibody for delivering anti-tumor agents because of its low immunogenicity and favorable in vivo tumor binding characteristics.

Adult↗
PubMed1993

Tumor necrosis factor alpha and gamma-interferon enhancement of anti-epidermal growth factor receptor monoclonal antibody binding to human melanoma cells.

Previous studies have demonstrated that the expression of tumor-associated antigens can be regulated by cytokines. The purpose of this study was to determine whether tumor necrosis factor alpha (TNF alpha) and gamma-interferon (IFN gamma) were capable of modulating epidermal growth factor receptor (EGFr) immunorecognition on a human melanoma cell line in vitro. DX-3 melanoma cells treated for 24-72 h with various concentrations of each cytokine were incubated with an anti-EGFr monoclonal antibody (Mab) (A108) that recognizes an extracellular domain of the receptor, and differences in binding were analyzed by flow cytometry and radioimmunoassay. A dose- and time-dependent enhancement in EGFr immunorecognition was measurable in TNF alpha- and IFN gamma-treated cells. Combinations of these cytokines enhanced the recognition of EGFr on DX-3 cells to a level greater than that achieved with either TNF alpha or IFN gamma alone. Scatchard analysis of receptor binding curves revealed that there was no significant change in Mab affinity between control and cytokine-treated DX-3 melanoma cells, whereas a 1.5- to 1.8-fold enhancement in the number of Mab binding sites was measurable in TNF alpha- and IFN gamma-treated cells, respectively, when compared with controls. Immune complex kinase assay of EGFr showed threefold higher tyrosine kinase activity in TNF alpha-treated cells, but no change in kinase activity was observed following IFN gamma treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1992

Substrate preference of metalloproteinases secreted by ts-110 Moloney murine sarcoma virus-transformed normal rat kidney cells.

In this study, the two forms of affinity-purified transformation-associated proteins (TAPs) (68 and 64 kD) were shown to have different substrate preferences. For the 68-kD TAP, the order of substrate preference was collagen types I, III, and V; fibronectin; gelatin; and collagen IV. For the 64-kD TAP, the order of substrate preference was collagen I, III, and V and gelatin. The 64-kD TAP did not cleave collagen IV and fibronectin. We also found a 71-kD metalloproteinase in the concentrated purified TAPs that reacted only weakly with a TAP monoclonal antibody and showed this substrate preference: collagen I, III, and V; gelatin; and collagen IV. Whether this 71-kD TAP is a new member of the rat metalloproteinase family will be investigated.

Animals↗