PubMed Health⌕ Search

Biomedical subjects

A F LoBuglio

Publications and source records attributed to A F LoBuglio.

At least 55 records · Page 3Linked to original sources
PubMed1994

Tumor associated glycoprotein-72 is highly expressed in prostatic adenocarcinomas.

We examined the expression of two well-characterized oncofetal antigens, the tumor associated glycoprotein-72 (TAG-72) and carcinoembryonic antigen (CEA), in malignant prostatic tissues. Three specific monoclonal antibodies, B72.3, CC49 and CC83, were used to examine the expression of TAG-72. Immunoreactivity was detected in 63% of the malignant specimens using B72.3. CC49 and CC83 were more sensitive than B72.3 in detecting TAG-72 expression. Immunoreactivity was detected in approximately 80% of prostatic adenocarcinomas with CC49 or CC83. The pattern and localization of TAG-72 immunoreactivity were similar for the three antibodies with most immunoreactivity observed within the cytoplasm of malignant cells and within the lumens of malignant glands. TAG-72 immunoreactivity was not detected within benign epithelium or stroma, with the exception of focal epithelial expression in areas of acute prostatitis. The COL-1 antibody to CEA did not detect CEA in benign glands, stroma, or malignant cells of prostate specimens resected for prostatic adenocarcinoma. These results demonstrate that TAG-72, but not CEA, is frequently expressed in prostatic adenocarcinomas.

Adenocarcinoma↗
PubMed1994

Human immune response to monoclonal antibodies.

Monoclonal antibodies either of mouse, mouse/human chimeric, or human origin have been used safely in human trials for a decade. Considerable effort has been committed in investigations of manipulating endogenous immunological activity against tumors and targeting various cytotoxic agents to cancers. These studies have identified several problems that need to be resolved before any such reagents can be used routinely in patients. One of these problems has been the immunogenicity of these monoclonal antibodies. This review article discusses what is known regarding human immune response to monoclonal antibodies and their clinical consequences.

Animals↗
PubMed1994

Treatment of metastatic prostate carcinoma with radiolabeled antibody CC49.

UNLABELLED: A Phase II trial of 75 mCi/m2 131I-anti-TAG-72 high-affinity antibody CC49 was studied in 15 patients with hormone-resistant metastatic prostate cancer. METHODS: Patients had adequate renal, liver and hematopoietic function. No previous cytotoxic chemotherapy was allowed and previous radiation was limited to 20% of the active bone marrow. RESULTS: No acute adverse reactions occurred, but all patients had evidence of an immune response to CC49 by 4 wk. Six of 10 symptomatic patients had bone pain relief, but no patients met the radiographic or PSA criteria for objective response. Positive imaging of bone and/or soft-tissue lesions was noted for 13 of the 15 patients. CONCLUSIONS: CC49 had a high frequency of tumor localization with evidence of anti-tumor effects (pain relief).

Adenocarcinoma↗
PubMed1993

A phase I clinical trial of murine monoclonal antibody D612 in patients with metastatic gastrointestinal cancer.

In a phase I study, 21 patients with metastatic adenocarcinoma of the gastrointestinal tract received the murine monoclonal antibody D612. This antibody is directed at a M(r) 48,000 antigen restrictively expressed on tumors of the gastrointestinal tract and to a limited degree on normal gastrointestinal mucosa. Patients received total doses of 10-180 mg/m2 administered as single or multiple doses of 1-100 mg/m2 over an 8-day period. Dose-limiting toxicity was secretory diarrhea. A single dose of 100 mg/m2 exceeded guidelines for maximal tolerated dose. Higher total doses were achieved in subsequent patients by using repeated administration of lower doses. Three of five patients receiving 60 mg/m2 for 3 doses (180 mg/m2 total dose) experienced grade 3 diarrhea and could not complete the prescribed course. The dose of 40 mg/m2 administered on days 1, 4, and 8 (total dose, 120 mg/m2) has been selected as the dose for phase II studies. The pharmacokinetics of D612 is best described by a one-compartment model with a mean t1/2 of 48 +/- 3 h (SEM). Eighteen of 21 patients developed human anti-mouse antibody (HAMA). Patients who developed high levels of HAMA demonstrated a more rapid clearance of the day 8 dose than those who developed low levels of HAMA. In all patients studied, a component of HAMA was directed at the D612 variable region. With one exception, serum from all patients with detectable antibody to the D612 variable region demonstrated anti-paratope reactivity. Thirty-four % of known metastatic sites demonstrated uptake of radiolabeled D612. There were no objective antitumor responses in this phase I trial. The antitumor effect of D612 in vitro has been shown to be potentiated by interleukin 2 and recombinant human macrophage colony-stimulating factor. A phase II study of D612 administered in combination with cytokines that enhance human effector function is presently ongoing.

Adenocarcinoma↗
PubMed1993

Generation of a human anti-idiotypic antibody that mimics the GD2 antigen.

In a phase 1 trial, patients with metastatic melanoma received the anti-GD2 murine mAb 14G2a. All patients developed human anti-14G2a antibodies including anti-Id antibodies. Peripheral blood MNCs from one such patient were fused with the murine myeloma cell line Ag8. Four human anti-14G2a secreting hybridomas were generated and the mAb product of one of the hybridomas was characterized. The human mAb 4B5 (hu-IgG, lambda) binds to the variable region of murine 14G2a (anti-Id). The 4B5 binds to the antigen-combining site of 14G2a and inhibits its binding to GD2 expressing Mel-21 cells. Rabbits were immunized with the human anti-Id 4B5. Sera from the immunized rabbits demonstrated anti-4B5 antibodies and anti-Mel-21 and anti-GD2 reactivity. Furthermore, rabbit sera competitively inhibited binding of 14G2a to Mel-21 cells. Rabbits immunized with 4B5 developed a DTH response when challenged with 4B5 antibody and Mel-21 cells. These studies demonstrate that the human anti-Id 4B5 mimics the GD2 antigen and is capable of eliciting both a humoral and cellular anti-GD2 immune response. This antibody could be potentially used as a human anti-Id vaccine in patients with malignant melanoma.

Animals↗
PubMed1993

Use of a chimeric monoclonal anti-CD4 antibody in patients with refractory rheumatoid arthritis.

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 > or = 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.

Adult↗
PubMed1993

A phase I escalating-dose safety, dosimetry and efficacy study of radiolabeled monoclonal antibody LYM-1.

Thirteen patients with relapsed or refractory Non-Hodgkin's Lymphoma were treated with 131I-Lym-1 during the course of a dose escalation trial. Principal aims were to establish the maximum tolerated single dose (MTD), as well as to assess clinical and dosimetric effects of the MTD. Patients were eligible if > 25% of tumor cells bound Lym-1 on immunohistochemistry, stain intensity was +2/4 or greater and human anti-mouse antibody (HAMA) assay was negative. Radioimmunotherapy was performed with escalating doses at levels of 50 mCi, 65 mCi/m2 and 80 mCi/m2 (50-139 mCi total). Patients were eligible for retreatment after 6-10 weeks if there was no severe toxicity, their disease was at least stable and HAMA remained negative. Three were retreated. Four have achieved partial responses which lasted 11, 11, 18 and 22 weeks. Acute toxicities included rigors (69%), fever (62%), nausea (46%), vomiting (46%), pruritus (23%), urticaria (23%), chest pain (23%) and bronchospasm (15%). HAMA developed in 3 patients. Myelosuppression, manifested as thrombocytopenia and neutropenia, was dose-limiting and defined the single dose MTD at 65 mCi/m2. Plasma radioactivity clearance was biphasic, with a 0.9 hr alpha-T1/2 and a 19.8 hr beta-T1/2. At completion of Lym-1 infusion, a mean of 45% of the injected dose was recoverable in the circulation. Images obtained within the first 2 hours indicated mean hepatic and splenic uptake was 29% and 11%, respectively. Radiation absorbed doses to tumor ranged from 18-61 rads; mean doses to whole body ranged from 17 to 71 rads.

Adult↗
PubMed1993

An animal model to predict the immunogenicity of murine V regions in humans.

Clinical trials with genetically engineered chimeric mouse/human monoclonal antibodies have demonstrated that mouse variable regions differ dramatically in their degree of immunogenicity. These observations led us to search for an animal model that could predict mouse variable region (V region) immunogenicity prior to human clinical trials. We selected monoclonal antibodies 17-1A and B72.3 for study because human trials have demonstrated the very low immunogenicity of the mouse 17-1A V region and the high immunogenicity of the mouse B72.3 V region. Random-bred New Zealand white rabbits were injected intravenously with mouse 17-1A, B72.3, or both using a dose and schedule comparable to human trials. After initial injection only two of ten rabbits developed an antibody response to mouse 17-1A, while all five animals receiving a second injection developed antibody that was entirely mouse constant region-specific. On the other hand, nine of ten rabbits demonstrated an antibody response to initial infusion of mouse B72.3 that was greater than 90% specific for the complementarity-determining region components of the V regions. Competitive inhibition with isolated heavy and light chains demonstrated specificity for heavy or light chains (approximately 60%) or a requirement for both (40%). Thus, as in humans, the V region of 17-1A elicited little or no immune response in rabbits, while the V region of B72.3 was highly immunogenic.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Lack of T-cell immunity in humans with preexisting anti-mouse immunoglobulin reactivity.

We have identified five normal individuals without known exposure to mouse immunoglobulin with "preexisting" human anti-mouse antibody (HAMA) against a panel of four mouse monoclonal antibodies and polyclonal mouse IgG. Competitive inhibition by polyclonal mouse IgG of HAMA binding to monoclonal antibody coated beads demonstrates the mouse constant region specificity of these sera. Lack of such inhibition by polyclonal human IgG eliminates polyclonal rheumatoid factors as an explanation. Lymphoblastic transformation studies in these five persons failed to demonstrate a memory T-cell response to the four mouse monoclonals or polyclonal mouse IgG. Positive controls included T-cell responses to streptolysin O in these five individuals as well as responses to monoclonal antibody D612 in three patients following treatment with that antibody. This lack of T-cell immunity to mouse IgG suggests that "preexisting" HAMA is the product of inadvertent cross-reactivity with murine constant region by antibodies directed against other antigens. Therefore, "preexisting" HAMA should pose no risk of anamnestic or allergic response in patients considered for murine monoclonal therapy.

Animals↗
PubMed1992

Frequent anti-V-region immune response to mouse B72.3 monoclonal antibody.

The immune response of 56 colorectal cancer patients to a single infusion of 1 mg of radiolabeled (111In) mouse B72.3-GYK-DTPA immunoconjugate was examined using a double-antigen radiometric assay system. The incidence of antibody response was 48% to polyclonal mouse IgG, 71% to mouse B72.3, and 62% to chimeric B72.3. Twelve patients (23%) had an antibody response to B72.3 V region in the absence of binding to polyclonal mouse IgG. An antiidiotype response was demonstrated in sera from 36% of 25 patients examined and correlated well with chimeric B72.3-GYK-DTPA immunoconjugate binding (r = 0.72, moderately well with mouse B72.3 binding (r = 0.56), and not at all with polyclonal mouse IgG binding (r = 0.28). The peak antibody response occurred most frequently 2 weeks postinfusion, although a "delayed" peak response to chimeric B72.2 occurred in 29% of patients. This study suggests that mouse B72.3 causes an immune response in the majority of patients and that antibody response to the V region is common. Understanding the physiological significance of these antibody responses will require correlation with the kinetics and tumor localization of repeat infusions of such immunoconjugates.

Animals↗
PubMed1992

Advances in monoclonal antibody therapy of cancer.

Tumor-associated antigens can be seen as unique targets for the delivery of anti-cancer therapy. Monoclonal antibodies directed at such antigens are increasingly being seen as important biologic reagents that will complement the group of existing cytotoxic drugs. This report briefly overviews recent advances in the field of monoclonal antibody therapy of cancer and provides insight regarding the promises and limitations of this novel therapeutic approach.

Animals↗
PubMed1992

Dose fractionation of radiolabeled antibodies in patients with metastatic colon cancer.

Twelve patients with metastatic colon cancer were treated with 131I-chimeric B72.3 (IgG-4) at total doses of 28 or 36 mCi/m2 in two or three weekly fractions. Bone marrow suppression was the only significant side effect. The degree of bone marrow suppression adjusted for whole-body dose was modestly but statistically significantly (p = 0.04) less than that seen with identical doses given as a single infusion for the total dose of 36 mCi/m2. Nine of twelve patients developed an antibody response to ch B72.3, which altered the kinetics of radiolabeled antibody in four patients given a second course of therapy. One patient had a minor response that lasted 4 mo. Fractionation of this particular radiolabeled antibody at the dose schedule used produced a modest increase in the therapeutic window in regard to administered dose.

Adult↗
PubMed1992

Phase I trial of the chimeric anti-GD2 monoclonal antibody ch14.18 in patients with malignant melanoma.

The chimeric monoclonal anti-GD2 antibody ch14.18 is made up of the variable region of the murine anti-GD2 antibody 14.18 (or its IgG2a switch variant 14G2a) and the constant region of human IgG1k. Ch14.18 mediates antibody dependent cytotoxicity and complement dependent lysis in vitro. In a phase I trial, 13 patients with metastatic melanoma received ch14.18 as a single dose of 5-100 mg. Therapy was associated with an infusion-related abdominal/pelvic pain syndrome, which required intravenous morphine for control. The pharmacokinetics of ch14.18 best fit a two-compartment model with a T1/2 alpha of 24 +/- 1 hr and a T1/2 beta of 181 +/- 73 hr. Eight of 13 patients developed a weak-modest antibody response directed at the variable region of ch14.18. Clinical antitumor responses were not observed at the doses employed in this study. However, patients receiving greater than 45 mg of ch14.18 had antibody detectable on tumor cells analyzed by fluorescent activated cell sorter. Further modification of the therapeutic regime employing larger doses and frequent administration of ch14.18 are planned.

Adult↗
PubMed1991

Evidence for the elevation of serum carcinoembryonic antigen and tumor-associated glycoprotein-72 levels in patients administered interferons.

Sera were collected from 111 patients diagnosed with adenocarcinoma or nonadenocarcinoma malignancies who received different schedules of interferon (IFN)-gamma or IFN-beta ser alone or in combination. Serum carcinoembryonic antigen (CEA) and tumor-associated glycoprotein-72 (TAG-72) antigen levels were measured to determine whether interferon could enhance the tumor shedding and, thereby, the serum level of either tumor antigen. Less than 10% of the sera samples from patients diagnosed with nonadenocarcinoma malignancies (e.g., hairy cell leukemia, melanoma) had positive titers of TAG-72 or CEA, and interferon neither increased nor resulted in the appearance of either tumor antigen in those sera. In contrast, 59.2% and 75.4% of the patients with adenocarcinoma had positive serum levels of TAG-72 and CEA, respectively, prior to interferon. IFN-gamma and IFN-beta ser alone or in combination significantly increased serum TAG-72 or CEA in approximately 65% of those patients. The results suggest that interferon administration to patients with adenocarcinoma can result in increased serum levels of selected tumor-associated antigens used in the diagnosis of malignancy. These preliminary findings may be important in the development of new strategies to obtain more sensitive tumor antigen serum assays for the diagnosis and monitoring for disease progression of adenocarcinoma.

Adenocarcinoma↗
PubMed1991

In-111 labeled monoclonal anti-carcinoembryonic antigen antibody (ZCE025) in the immunoscintigraphic imaging of metastatic antigen-producing adenocarcinomas.

The carcinoembryonic antigen (CEA) is a clinically useful marker since it is expressed by adenocarcinomas of diverse origin. Detection and quantitation of circulating CEA levels is used to follow the clinical course of metastatic adenocarcinoma. In this phase I study, the toxicity, pharmacokinetics, and optimal imaging dose of an In-111 labeled monoclonal anti-CEA antibody (ZCE025) was studied in patients with colorectal carcinoma or any CEA-producing tumor. Twenty-four of 26 evaluable patients (92%) demonstrated at least one site of tumor-specific antibody uptake. Sixty-seven sites of metastatic cancer were identified by conventional diagnostic studies. Twenty-nine (43%) of these sites were demonstrable by radioimmune imaging using ZCE025. Twenty-five additional sites of antibody uptake were observed but could not be associated with metastatic deposits. Lymph node and visceral metastases were visualized more frequently than bone, subcutaneous, lung, or liver metastases. Neither tumor size nor antibody dose (2.5-40 mg) appeared to influence the frequency of tumor imaging. The pharmacokinetics of the In-111 labeled antibody fitted a two-compartment model, and patients receiving less than 10 mg of antibody showed a faster clearance of the antibody than those who received greater than 10 mg.

Adenocarcinoma↗
PubMed1991

Alternated versus syncopated CHOP-PVB: two studies for the treatment of non-Hodgkin's lymphoma by the Southwest Oncology Group.

Based on a preliminary trial that suggested that CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and PVB (cisplatinum, vinblastine, bleomycin), are at least partially non-cross-resistant, the Southwest Oncology Group treated patients with unfavorable histology, non-Hodgkin's lymphoma with CHOP and PVB. In the first study, 76 eligible patients were given three courses of CHOP, with complete or partial responders receiving three courses of PVB followed by three further courses of CHOP. Nonresponders after the initial three cycles of CHOP, received six courses of PVB. In the second study, 154 eligible patients were treated with alternating cycles of the two drug regimens. The overall objective antitumor response (CR + PR) was 77% for the first study and 58% for the second. The complete remission rates were 48% and 38%, respectively. The overall survival for both studies is similar. These results are interpreted in terms of the Goldie-Coldman hypothesis.

Antineoplastic Agents↗