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Biomedical subjects

D M Goldenberg

Publications and source records attributed to D M Goldenberg.

At least 235 records · Page 13Linked to original sources
PubMed1989

Two new monoclonal antibodies, EPB-1 and EPB-2, reactive with human lymphoma.

Using the Raji cell line as the immunogen source, we established stable murine hybridomas that secrete B-lymphocyte-specific monoclonal antibodies (MAbs). Two clones, designated EPB-1 and EPB-2, were selected for further study. Both EPB-1 and EPB-2 were typed by reaction with subclass-specific rabbit anti-mouse antibodies and were found to be IgG1 and IgG2a, with kappa-light chains, respectively. In radioimmunobinding and flow cytometric assays, EPB-1 and EPB-2 did not react with T-cell lines, nor with normal diploid cells. EPB-2, in contrast to EPB-1, did not react by flow cytometry with normal peripheral or bone marrow leukocytes. In normal lymphoid tissues, both antibodies were positive with germinal center and mantle zone B-lymphocytes. Additionally, EPB-1 also labeled interdigitating histiocytes in the T-cell zones. Both MAbs discriminated very well between lymphoid and nonlymphoid tissues; neither MAb cross-reacted with tested normal and solid tumor tissue specimens, or with cell lines of non-B-cell origin. Immunohistology also revealed that both MAbs stained malignant lymphoma tissue sections and cloned B-cell lymphomas, both in tissue culture and as human xenografts in nude mice. Due to the radiosensitivity of human lymphomas and the relative specificity of these two new MAbs, they appear to be potential radioimmunotherapeutic agents for human lymphoma.

Antibodies, Monoclonal↗
PubMed1989

Reduction by anti-antibody administration of the radiotoxicity associated with 131I-labeled antibody to carcinoembryonic antigen in cancer radioimmunotherapy.

Radiolabeled antibodies have been shown to have a therapeutic potential in tumor-bearing animal models. However, treatment with radiolabeled antibodies results in toxic effects to normal tissues, as monitored by losses in body weight and in peripheral wbcs. We have investigated the use of an anti-antibody, or second antibody (SA), as a means of reducing this toxicity. SA rapidly forms a complex with circulating radiolabeled antibody, causing an increase in the clearance rate of the radiolabeled antibody from the blood. Toxicity was significantly reduced in animals given the SA in comparison to the toxicity seen in animals given only the radiolabeled primary antibody (PA). The earlier the SA was administered, the lower was the toxicity. The therapeutic efficacy of radiolabeled antibody was not influenced by the administration of the SA given 48 hours after the PA. Thus, the controlled removal of circulating radiolabeled antibody by an anti-antibody can reduce the toxicity associated with radiolabeled antibody therapy without influencing the antitumor effect.

Animals↗
PubMed1989

Human lung carcinoma monoclonal antibody specific for the Thomsen-Friedenreich antigen.

A monoclonal antibody, RS1-114, was raised against the human adenocarcinoma of the lung cell line A549. By studying the reactivity of RS1-114 with A549 cells following chemical and enzymatic treatments, it was shown that the epitope is a galactose-containing carbohydrate, which is devoid of sialic acid. Hemagglutination of desialylated RBCs, enzyme-linked immunosorbent assay studies with glycoprotein antigens before and after desialylation, and competition studies using peanut agglutinin indicate that monoclonal antibody RS1-114 recognizes the Thomsen-Friedenreich antigen, a cryptic determinant on human erythrocytes which can be exposed by neuraminidase treatment. It is expressed in an unhidden form on a large percentage of carcinomas and is therefore an important human tumor marker. RS1-114 is reactive with cryptic determinants of the Thomsen-Friedenreich antigen on white blood cells as well as red blood cells, and it reacts with unhidden determinants on human tumor cell lines. The number of binding sites on carcinoma cells is further increased by neuraminidase treatment. By immunohistochemical staining, it was shown that 75% of the human tumors tested are reactive with RS1-114. These include tumors of the breast, colon, lung, kidney, ovary, and rectum.

Adenocarcinoma↗
PubMed1989

Syngeneic anti-idiotype monoclonal antibodies to murine anticarcinoembryonic antigen monoclonal antibodies.

BALB/c mice were immunized with either NP-3 or NP-4, two anticarcinoembryonic antigen murine monoclonal antibodies. Each animal produced anti-idiotype antibodies to the corresponding immunogen and no cross-reactivity between anti-NP-3 sera and anti-NP-4 sera was detected. Hybridomas were produced from these animals and two IgG1 anti-idiotype monoclonal antibodies were obtained: CM1 specific for NP-3 and CM11 specific for NP-4. CM1 and CM11 recognized determinants located within the antibody-combining site, since each anti-idiotype antibody inhibited the binding between the corresponding idiotype and carcinoembryonic antigens. Using an immunoblotting technique, neither CM1 nor CM11 reacted with isolated heavy or light chains of NP-3 or NP-4, whereas binding was observed with the intact molecule. This observation indicates that CM1 and CM11 are directed against conformational idiotypes resulting from the association of the variable regions of the heavy and light chains. Taken together, these results suggest that CM1 and CM11 might bear internal images of carcinoembryonic antigen epitopes, and that they are potential candidates as idiotype vaccines against colorectal tumors.

Animals↗
PubMed1989

Targeted cancer treatment.

The fourth international conference on monoclonal antibody immunoconjugates for cancer heard of great progress in the area of radioimmunoconjugates, and of continued research into the potential of immunotoxins, chemoimmunoconjugates and anti-immunoglobulin therapy as potential cancer therapies.

Antibodies, Monoclonal↗
PubMed1989

Sacral scintigraphy for bone marrow dosimetry in radioimmunotherapy.

Myelosuppression has been identified as the dose-limiting toxicity in radioimmunotherapy studies. Accurate bone marrow dosimetry is, therefore, necessary to evaluate bone marrow toxicity which may result from systemic cancer treatment with radiolabeled monoclonal antibodies. Dose to the red marrow was determined in 20 patient studies with 131I labeled anti-carcinoembryonic antigen, anti-alpha-feto-protein, or anti-human chorionic gonadotropin monoclonal antibody for diagnosis or treatment of diverse metastatic carcinomas, using a new technique involving sacral scintigraphy and a previously reported blood-based methodology. For the sacral technique, anterior and posterior gamma camera images of the pelvis were obtained at multiple times. Regions of interest were drawn around the sacrum in order to quantitate activity uptake as a function of time using the conjugate view counting method. Cumulated activity in red marrow was determined by curve integration and division by 0.099, since it has been estimated that 9.9% of the total red marrow is contained in the sacrum of the adult. Red marrow doses were then obtained by multiplying the cumulated activities by the appropriate S factor. These doses were compared to red marrow doses obtained from serial whole blood samples taken from these patients. Cumulated activity in the red marrow was determined from the blood with the assumption that the activity concentration in the blood and red marrow were equal. The mean red marrow dose per injected activity was 2.0 +/- 0.9 rad/mCi using the sacral data and 2.7 +/- 1.3 rad/mCi using the blood data (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1989

Imaging of colorectal carcinoma with radiolabeled antibodies.

Colorectal cancer has been the tumor type most frequently studied with radiolabeled antibodies. Among the various antibodies, a majority of patients with colorectal cancer have received xenogeneic polyclonal or monoclonal antibodies against carcino-embryonic antigen. This review summarizes the current status of colorectal cancer imaging with radiolabeled antibodies, ie, radioimmunodetection (RAID), and examines the published studies involving carcinoembryonic antigen (CEA) antibodies and 17-1A, 19-9, and B72.3, and other monoclonal antibodies. In order to better address the issue of the current and future clinical usefulness of this emerging technology, particular attention is given to the protocols, methods, and results of the published studies. Despite differences in study parameters, antibodies and forms, labels, administration routes and doses, and scanning instruments and methods, it has been found that (1) almost no adverse reactions have been evident; (2) antibody fragments are preferred over whole immunoglobulin G reagents because they achieve higher tumor-to-background ratios earlier, thus reducing or precluding the need for dual-isotope subtraction methods or long delays before imaging; (3) use of antibody fragments, including the monovalent Fab' form, permits imaging with short-lived radionuclides of excellent photon properties, such as 123I and 99mTc; (4) circulating antigens against which the imaging antibody is directed can complex with the injected antibody, but such complexes have not prevented successful RAID; (5) patients with high serum titers of the appropriate antigen target usually have higher rates of positive RAID; (6) patients who are seronegative for the tumor antigen being studied can have positive RAID findings, which can represent the detection of occult lesions; (7) single photon emission computed tomography appears to provide better image resolution than planar scanning; (8) regardless of the sensitivity reported in any particular study, almost all investigators have observed the disclosure of occult neoplasms by RAID; and (9) RAID, a more functional test of usually high specificity, can complement other radiological methods, such as computed tomography scans, which are limited to structural information.

Antibodies, Monoclonal↗
PubMed1989

Future role of radiolabeled monoclonal antibodies in oncological diagnosis and therapy.

This review discusses the current limitations and future prospects of radiolabeled antibodies in cancer imaging (radioimmunodetection, or RAID) and therapy (radioimmunotherapy, or RAIT). Aspects such as the antibody vehicle, antigen target, radiolabel, tumor, host, and RAID and RAIT procedures are considered. In the short timespan for the development of RAID, tumors as small as 0.5 cm, which are sometimes missed by other radiological methods, can now be imaged with antibody fragments labeled with suitable radionuclides (eg, 111In, 123I, and 99mTc), particularly when single photon emmission computed tomography (SPECT) scanning methods are employed. 99mTc is clearly the preferred label, and the recent development of simple and rapid methods to attach this isotope to antibodies should be a welcome advance for the more widespread use of RAID. In RAIT, radiosensitive neoplasms, such as lymphomas, are already showing impressive responses to 131I-labeled antilymphoma murine monoclonal antibodies. Therefore, the successful conjugation of beta- and alpha-emitters to "humanized" monoclonal antibodies should provide a new generation of promising cancer therapeutics.

Antibodies, Monoclonal↗
PubMed1989

Solving the problem of antibody interference in commercial "sandwich"-type immunoassays of carcinoembryonic antigen.

We evaluated the effect of human anti-murine antibodies (HAMA) on apparent concentrations of carcinoembryonic antigen (CEA) as measured in serum with commercial enzyme immunoassay (EIA) kits manufactured by Abbot ("two-step" double monoclonal antibody assay), Roche, and Hybritech (room-temperature protocol). In sera from patients given parenteral murine monoclonal antibody for experimental diagnostic and immunotherapy studies, HAMA titers were determined with Immunomedics' "ImmuSTRIP HAMA-EIA" kit reagents. "True" CEA titers were established by using the ImmuCEA/MA-EIA and heat-extraction to destroy HAMA before assay for CEA. The concordance of the ImmuCEA/MA assay with the Abbott and Roche CEA EIAs was established with sera from normal individuals and from patients who had not received parenteral injections of murine monoclonal antibody. At high (100 mg/L) concentrations of HAMA, false-positive results were observed with all three kits. The Hybritech and Roche assays were more sensitive to interference by HAMA than was the Abbott CEA-EIA, false-positive results being observed at HAMA concentrations between 1 and 10 mg/L. Similar sensitivity of the three kits to interference by primate anti-MAb sera was demonstrated. Use of primate anti-MAb sera to create controls with HAMA activity and of analyte is recommended to evaluate MAb assays for potential HAMA interference and for use to devise methods to eliminate HAMA interference.

Animals↗
PubMed1989

Murine monoclonal antibody adsorbed onto vinylidene fluoride floccules used to eliminate antibody interference in "sandwich"-type immunoassays.

We have previously reported that human anti-mouse IgG antibody (HAMA) can cause false-positive and false-negative results in "sandwich"-type monoclonal antibody (MAb) assays. To eliminate HAMA interference in "sandwich"-type MAb assays, we investigated the use of MAb on solid-phase, vinylidene fluoride floccules, which we have previously used as a solid-phase second antibody for RIA. The simple procedure effectively removes greater than 95% of HAMA from the most positive serum we have obtained from patients hyperimmunized to murine MAb, and it allows for accurate quantification of carcinoembryonic antigen. The solid-phase complex, added to blood, effectively removes HAMA and (or) "HAMA-type" heterophilic antibody from the sera or plasma.

Adsorption↗
PubMed1988

Reduction of radioantibody-induced myelotoxicity in hamsters by recombinant interleukin-1.

Recombinant human interleukin 1 (IL-1) administered i.p. to tumor-bearing hamsters results in a dose-dependent 2- to 5-fold increase in total peripheral white blood cells. These levels remain elevated for 2 to 3 wk and then decline to base-line levels. Pretreatment of animals with similar doses of IL-1 prevents radioimmunotherapy-induced destruction of the radiosensitive hematopoietic system. Furthermore, recovery from radio-immunotherapy-induced myelosuppression is possible if animals are given IL-1 1 wk after radioimmunotherapy treatment. Thus, both protection and rescue from the hematopoietic damage associated with radioantibody treatment are feasible by pre- or posttreatment with IL-1.

Animals↗
PubMed1988

Antiidiotype antibodies in cancer patients receiving monoclonal antibody to carcinoembryonic antigen.

The initial 10 patients of a Phase I clinical trial involving multiple injections of murine monoclonal anti-carcinoembryonic antigen (CEA) antibody, NP-2, were studied for the presence in their sera of antiidiotypic antibody. Most patients had advanced gastrointestinal adenocarcinoma and received 1 mg/m2 monoclonal antibody three times weekly, or once a week, resulting in five to 13 injections over 12 to 240 days. Antiidiotype antibody was detected with a blocking radioimmunoassay using [125I]NP-2-F(ab')2 binding to CEA-coated microwells and [125I]NP-4-F(ab')2 as a control antibody. Five out of 10 patients demonstrated 65-96% inhibition of NP-2 binding at 1/20 dilution of serum compared to NP-2 binding in the presence of pretreatment sera. The inhibitory activity was preserved after adsorption over a polyclonal mouse IgG immunoadsorbent whereas exposure to a NP-2 affinity column completely depleted the activity. Specificity testing, including the blocking effect of patient sera on the control antibody NP-4, and interference by the possible presence of circulating NP-2, circulating CEA, and human anti-CEA activity, confirmed that the inhibition observed was specific for NP-2 and was caused by an agent with CEA-like characteristics. Longitudinal studies demonstrated that elevated titers of antiidiotypic antibody appeared later in the course of immunization than did antibody against mouse immunoglobulin. These studies indicate that patients can be sensitized to the idiotype (anti-combining site and/or combining site-related) of monoclonal antibodies to CEA following multiple infusions.

Adenocarcinoma↗
PubMed1988

Site-specific linkage of methotrexate to monoclonal antibodies using an intermediate carrier.

The site-specific conjugation of methotrexate, 4-amino-N10-methylpteroylglutamic acid, to a monoclonal anti-carcinoembryonic antigen (CEA) antibody, using an intermediate amino-dextran carrier system, resulted in a ratio of 30-50 molecules of MTX per molecule of immunoglobulin. The immunoreactivity of the conjugate was analyzed using flow cytometry or a competitive binding assay, which showed that the conjugate has significant retention of the antigen-binding activity. The pharmacokinetic behavior of the immunoconjugate in BALB/c mice and tumor localization in hamsters indicated that the conjugate remained in the circulation with higher concentration than free antibody, and could recognize the tumor as efficiently as the unconjugated antibody. The high degree of drug incorporation with retained immunoreactivity makes this method preferable to direct antibody conjugation.

Animals↗
PubMed1988

Radioimmunotherapy of human colonic cancer xenografts with 90Y labeled monoclonal antibodies to carcinoembryonic antigen.

Monoclonal antibodies (MAbs) to carcinoembryonic antigen (CEA) or alpha-fetoprotein (AFP) were conjugated with diethylenetriaminepentaacetic acid and radiolabeled with 90Y at a specific activity of 4.0-6.0 mCi/mg. Approximately 50% of the radiolabeled anti-CEA antibody (90Y-labeled NP-2) bound to an immunoadsorbent containing CEA while analysis by high performance liquid chromatography revealed that 95-98% of the 90Y was associated with immunoglobulin. Less than 5% of the 90Y dissociated from either MAb after incubation in plasma for 48 h at 37 degrees C. After injection into nude mice, 98% of the circulating radioactivity remained associated with antibody and no loss of immunoreactivity was observed at 3 days. To evaluate 90Y-labeled NP-2 as a therapeutic agent, varied doses (10-100 microCi) were administered as a single i.v. injection into groups of nude mice bearing s.c. implants (0.3-0.4 g) of a CEA-producing human colonic cancer xenograft, GW-39. At the 10-microCi dose, no inhibition of tumor growth was observed. After 28 days, tumor growth was inhibited by as much as 77% in mice treated with 50 microCi of 90Y-labeled NP-2 as compared to tumor growth in control animals given 90Y-labeled anti-AFP. Doses higher than 50 microCi (75 and 100 microCi) were toxic to most of the animals, killing them within 2-3 weeks after administration. Marked suppression of circulating leukocytes was observed with 20 and 50 microCi by 1-2 weeks postinjection, but they returned to normal levels 3-4 weeks later. These studies show that treatment with 90Y-labeled MAbs against CEA can produce significant antitumor effects. However, toxicity to the bone marrow may limit the therapeutic efficacy of systemically administered 90Y-labeled MAbs.

Animals↗
PubMed1988

Temperature affects binding of murine monoclonal IgG antibodies to protein A.

Murine IgG subclasses show different affinities when they react with protein A. The temperature of application of the sample to protein A-Sepharose markedly influences the interaction of certain antibodies with this specific adsorbent. Elution of weakly bound mouse IgG could be carried out by mild temperature changes instead of lowering the pH, and this should be advantageous with certain immunoglobulins that are labile under acidic conditions.

Animals↗
PubMed1988

Factors influencing anti-antibody enhancement of tumor targeting with antibodies in hamsters with human colonic tumor xenografts.

The injection of an antiantibody (second antibody, SA) can enhance the clearance rate of a radiolabeled antitumor antibody (primary antibody, PA) from the blood. We have studied how the dose of the SA and the timing of the SA administration influence the rate of PA clearance and thereby improve tumor/nontumor ratios. Adult hamsters bearing the carcinoembryonic antigen-producing, GW-39 human colonic tumor xenograft were given injections of 131I-labeled, goat anti-carcinoembryonic antigen antibody, and after 6, 24, or 48 h, an injection of donkey anti-goat immunoglobulin was given at SA:PA ratios of 25, 50, 100, or 200:1. In comparison to a control group of animals that were only given 131I-PA, the administration of the SA improved tumor/blood ratios regardless of the SA:PA ratio or time the SA was given. The most important factor in optimizing this procedure was the timing of the SA injection. Significantly improved tumor/nontumor ratios were found when the SA was given between 24 and 48 h after the PA in comparison to 6 h. This was because maximum accretion of radiolabeled PA in the tumor was not achieved until 24 h. At SA:PA ratios of 25:1, only tumor/blood ratios were significantly improved in comparison to the control group. In addition, at SA:PA ratios of 25:1 and 50:1, tumor/spleen and tumor/kidney ratios were lower than the control group, whereas at higher SA:PA ratios, all tumor/nontumor ratios were significantly improved. These studies suggest that for this model, a ratio of SA:PA of 100:1 or higher given at 24 to 48 h after the PA is the best combination for maximizing tumor/nontumor ratios.

Animals↗
PubMed1988

Comparison of tumor targeting of mouse monoclonal and goat polyclonal antibodies to carcinoembryonic antigen in the GW-39 human tumor-hamster host model.

We have evaluated 4 radioiodinated mouse monoclonal anticarcinoembryonic antigen antibodies (MAbs) by using the GW-39 human colorectal tumor xenograft transplanted i.m. in immunocompetent hamsters to determine whether there were any differences in their tumor localization properties. Additional comparisons were made to affinity-purified goat anticarcinoembryonic antigen antibody. Statistically significant differences were found in the percentage/g of tumor uptake and tumor/nontumor ratios among the antibodies, so that the antibodies could be ranked according to their tumor localization properties (NP-2 greater than NP-4 = goat antibody greater than NP-1 greater than NP-3). Although statistical differences were found, tumor/nontumor values generally were not distinguished by a factor of more than 1.5, suggesting that these differences may not be biologically significant. F(ab')2 fragments of NP-2 were found to be superior to NP-4 F(ab')2 fragments, giving tumor/liver and tumor/blood ratios of 16 and 11.5, respectively, within 3 days, in comparison to 5.4 and 3.8 for NP-4 F(ab')2 fragments. Mixtures of all of the MAbs or a mixture of NP-2 and NP-4 did not improve tumor localization, in comparison to NP-2 alone. These studies suggest that mixtures of these anticarcinoembryonic antigen MAbs may not afford better tumor imaging than the use of a certain single antitumor MAb.

Animals↗