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D M Goldenberg

Publications and source records attributed to D M Goldenberg.

At least 181 records · Page 10Linked to original sources
PubMed1992

Localization by whole-body autoradiography of intact and fragmented radiolabeled antibodies in a metastatic human colonic cancer model.

In this report, we have employed macroautoradiography to compare the tumor targeting of 125I-labeled anti-carcinoembryonic antigen (CEA) MAb (NP-4) to 125I-labeled anti-colon-specific antigen-p (CSAp) MAb (Mu-9) and their labeled F(ab')2 and Fab' fragments, in nude mice each bearing large dorsal human colonic tumor xenografts, and small nodular tumors in the liver and lungs. Using intact MAbs (NP-4 and Mu-9), clearance of background radioactivity was delayed to 3-7 days post-treatment. Treatment with F(ab')2 and Fab' fragments of both NP-4 and Mu-9 MAbs, however, promoted clearance of background 125I-radioactivity which was well advanced by 6-24 h and complete by 24-48 h after injection. Localization of 125I-radioactivity in large and micrometastatic tumor perimeters was the most characteristic uptake pattern observed for both intact and fragmented MAbs. Qualitative analysis of macroautoradiographic images and quantitative densitometry indicated that the higher tumor-to-blood ratios achieved with labeled F(ab')2 and Fab' fragments at early time points, compared to labeled whole immunoglobulin, appeared to be more a function of rapid plasma clearance, tumor mass, location of xenografts and specific tumor growth patterns than increased tumor penetrance by lower molecular weight univalent and bivalent immune fragments.

Absorptiometry, Photon↗
PubMed1992

Haematological effects of radioimmunotherapy in cancer patients.

The haematologic effects of radioimmunotherapy (RAIT) in cancer patients have been studied in order to better understand the aetiology of RAIT-associated myelosuppression. Evaluations were performed on patients treated with 131I-anti-carcinoembryonic antigen (CEA) and 131I-LL2, a monoclonal antibody (MAb) reactive with non-Hodgkin's B-cell lymphoma. Both groups of patients experienced decreases in WBC and platelets. Nadirs were observed 42-51 d post first injection in the lymphoma patients, and 49-66 d post first injection (30-43 d post high-dose therapeutic injection) in the carcinoma patients. Within the WBC population, B cells were the most radiosensitive. The evaluations of the binding of these MAbs to peripheral blood cells and the effect of RAIT on lymphocyte subpopulations indicated a drop of 26-92% in the percentage of B lymphocytes within 1 week following treatment with both 131I-LL2 and 131I-anti-CEA MAbs even though only LL2 binds to B cells. The percentage of T lymphocytes was not affected by the 131I-antibody treatments. These observations suggest that the marked drop in circulating B lymphocytes and platelets after the administration of radioiodinated antibodies is a nonspecific radiation effect, and not necessarily related to the binding of MAb to normal B cells. Thus, among WBCs, B cells are uniquely radiosensitive, and will be unusually affected by antibody-directed internal radiation.

Adult↗
PubMed1991

Direct radiolabeling of monoclonal antibodies with generator-produced rhenium-188 for radioimmunotherapy: labeling and animal biodistribution studies.

The use of 188Re from an alumina-based 188W/188Re generator has been investigated for antibody radiolabeling. It was found that, with simple labeling techniques, 188Re can be used immediately after elution. The direct radiolabeling of intact antibodies with 188Re is described. Lyophilized antibody preparations have been reconstituted with 188Re taken directly from the generator at specific activities of up to 15 mCi of 188Re per mg of antibody. Radiolabeling yields of 90 to 98% have been obtained, with the incorporation rate being dependent upon time and the relative concentrations of the reagents. It was determined that the conjugates were immunoreactive and stable when challenged by serum in vitro, with 188Re-immunoglobulin G showing adequate resistance to reoxidation with no transfer of 188Re to serum protein. 188Re-antibody conjugates were shown to clear from the blood faster than the corresponding 131I-labeled antibody, giving rise to good tumor/nontumor ratios at 24 to 72 h postinjection, while serum samples taken from the animals have shown that the circulating 188Re remained bound to immunoglobulin G. The combination of the technologies of the 188W/188Re generator, the direct labeling methodology, and the use of single-vial lyophilized antibody makes the use of 188Re-radiolabeled monoclonal antibodies a simple and convenient method of cancer radioimmunotherapy with a beta-emitting radionuclide.

Animals↗
PubMed1991

Anthracycline immunoconjugates prepared by a site-specific linkage via an amino-dextran intermediate carrier.

Anthracycline, either daunomycin or doxorubicin, was site specifically attached to the carbohydrate moiety of a monoclonal anticarcinoembryonic antigen antibody by using amino-dextran as the intermediate carrier. The reaction resulted in an immunoconjugate that contains approximately 20 to 25 molecules of drug per molecule of immunoglobulin G. Flow-cytometric studies revealed the retention of the antibody-binding activity. The immunoconjugate was cytotoxic to the target cells, as examined by the 75selenomethionine incorporation studies, and remained efficient for targeting a human colonic tumor (GW-39) in the nude mouse model. The conjugate possessed a greater antitumor activity against the subcutaneous tumor than either the free drug or an irrelevant antibody conjugate, and it was well tolerated by the animals at a much higher dose level than was the unconjugated drug.

Animals↗
PubMed1991

Rapid blood clearance of immunoglobulin G2a and immunoglobulin G2b in nude mice.

An extremely rapid blood clearance rate of murine IgG2a antibodies was found in all strains tested of outbred Swiss nu/nu mice, including mice from the major commercial suppliers. The clearance half-life was less than 5 h, in comparison to a 4-5-day half-life in BALB/c mice. Therefore, most of the IgG2a antibody injected i.v. in such mice is cleared before it can reach interstitial fluid, which interferes with immunotherapy and immunodetection experiments. Individual nude mice varied greatly in their IgG2a clearance rates, which hampered investigation of the phenomena. In our experience, approximately three-fourths of nude mice had a rapid or intermediate clearance rate, whereas the remainder had an approximately normal clearance rate. The clearance rate in nude mice was age-dependent, at least in some instances, in that a rapid clearance rate was observed at 2 months of age, whereas the same mice retested at 4 months of age had a normal clearance rate. Rapid clearance could be inhibited by increasing the dose injected: 100 micrograms/mouse resulted in a normal clearance rate, whereas 30 micrograms/mouse was insufficient to inhibit rapid clearance. The clearance rate of IgG2b antibodies was affected similarly to that of IgG2a, whereas the clearance rate of IgG1 and IgG3 was not affected. The Fc region of IgG2a was required in order for rapid clearance to occur. Biodistribution experiments demonstrated that rapid blood clearance was due, at least partially, to binding to the liver and spleen. To determine the genetic basis for rapid IgG2a clearance, approximately 20 inbred and outbred mouse strains were tested. Unexpectedly, nu/+ as well as nu/nu outbred Swiss mice displayed rapid clearance, whereas control +/+ mice did not, so this phenotype appears to be a dominant effect of the nu mutation. BALB/c nu/nu and nu/+ mice did not display rapid clearance, which may be due to expression of the Igh-1a gene, which codes for the IgG2a present in BALB/c mice and in the monoclonal antibodies used in these studies. In conclusion, this clearance effect must be considered in experiments involving murine IgG2a or IgG2b antibodies in outbred Swiss nude mice, except those in which high antibody doses of greater than 0.1 mg/mouse are used. One method of circumventing this problem is to increase the antibody dose injected; a better but more long-range method is to develop strains of outbred nude mice that do have this characteristic.

Animals↗
PubMed1991

Successful radioimmunotherapy for lung metastasis of human colonic cancer in nude mice.

The potential for radioimmunotherapy as an adjuvant treatment for early disseminated colonic cancer was investigated in an experimental lung metastasis model. Nude mice receiving intravenous injection with a suspension of human colonic cancer cells (GW-39) developed multiple (10-100) tumor nodules throughout the lungs, and more than 50% of the animals died of extensive tumor involvement within 5-10 weeks. Groups of eight or nine animals bearing 7-day-old tumor transplants were treated with a single intravenous injection of radioiodinated agents: either 0.15 or 0.30 mCi of whole IgG of the NP-4 murine monoclonal antibody (MAb) against carcinoembryonic antigen (CEA) or 0.15 or 0.30 mCi of whole IgG of Immu-31, an anti-alpha-fetoprotein (anti-AFP) MAb. Treatment of animals with 0.15 or 0.30 mCi of 131I-labeled NP-4 IgG 7 days after injection of tumor cells resulted in survival for 23 weeks after tumor implantation in four of eight and seven of nine animals, respectively. Microscopic examination revealed that over 90% of the lung tumor colonies had no evidence of surviving cells. Animals treated with 0.30 mCi of anti-AFP, an irrelevant MAb, survived 4 weeks longer than controls. Toxicity was evident in four of the 17 animals given 0.30 mCi of NP-4 IgG (specific) or anti-AFP IgG (irrelevant) MAb. These animals died within 1-3 weeks after radioantibody injection, suggesting that death was related to the radiation dose. None of the animals given 0.15 mCi of 131I-MAb died within this period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Human response against NP-4, a mouse antibody to carcinoembryonic antigen: human anti-idiotype antibodies mimic an epitope on the tumor antigen.

Anti-idiotype antibodies (Ab2) were purified from a cancer patient treated with NP-4, a murine monoclonal antibody to carcinoembryonic antigen (CEA). These Ab2 were specific for NP-4 and inhibited the binding between NP-4 and CEA. BALB/c mice immunized with these human Ab2 produced anti-Ab2 antibodies that were also reactive with the CEA epitope recognized by NP-4. These results indicate that human Ab2 to NP-4 can antigenically mimic the CEA epitope recognized by NP-4.

Adenocarcinoma↗
PubMed1991

Galactose-conjugated antibodies in cancer therapy: properties and principles of action.

Galactose conjugation of antibodies causes them to be recognized by the hepatic asialoglycoprotein receptor and therefore cleared very rapidly from the blood. In these investigations, some effector functions of galactose-conjugated antibodies were assayed, and several applications to experimental tumors in vivo were demonstrated. Galactose conjugation did not interfere with two antibody functions in addition to antigen binding, namely complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. This conjugation procedure was originally developed for its potential use in localized immunotherapy, such as i.p. Injection of galactose-antibody conjugates i.p. demonstrated, more conclusively than other methods that have been used, that the presence of ascites causes prolonged retention of antibody in the peritoneal cavity and that this effect is correlated with the volume of ascites present. In mice bearing i.p. tumor xenografts, i.p. injection of galactose-antibody conjugates resulted in high tumor/nontumor ratios at 28 h after antibody injection, with values of 40:1, 43:1, 77:1, and 11:1 for the blood, kidney, lung, and spleen, respectively, although the ratio was only 4:1 for the liver. Control experiments demonstrated that i.p. injection of unconjugated antibody or a galactose-conjugated nonreactive antibody produced much lower tumor/nontumor ratios. In investigations of possible systemic application of galactose-antibody conjugates, we found that injection of large amounts of an inhibitor that binds competitively to the hepatic receptor, asialo-bovine submaxillary mucin, can block clearance of galactose-conjugated antibodies for 2-3 days. In this way, high blood levels of antibody can be maintained for 2-3 days, thus allowing penetration and binding to solid tumors, followed by very rapid blood clearance. With this approach, using a human carcinoma growing s.c. in nude mice, high tumor/nontumor ratios were obtained 4 days after injection, with mean values of 43:1, 18:1, 17:1, and 15:1 for the blood, kidney, lung, and spleen, respectively, although the ratio for the liver was only 1.7:1. The blood level at this time was 0.04 +/- 0.02% (SD) of the injected dose/g, while the tumor level was 1.69 +/- 1.29% of the injected dose/g. In conclusion, galactose-conjugated antibodies appear to have diverse applications in regional or systemic immunotherapy.

Animals↗
PubMed1991

Normal tissue reactivity of four anti-tumor monoclonal antibodies of clinical interest.

Normal tissue reactivity on frozen sections was examined with 4 monoclonal antibodies (MAbs) that were reported previously to be negative or weakly reactive with normal tissues, and strongly reactive with some types of carcinoma. All 4 antibodies reacted strongly with certain normal epithelial cells. The antibodies tested include 2 antibodies to ovarian cancer, MOv18 and MOv19, one antibody to breast cancer, H23, and one antibody reactive with a range of carcinomas, B72.3. MOv18, MOv19 and H23 reacted with many normal glandular and ductal epithelial cells, while B72.3 reacted most strongly with secretions of the small intestine epithelium and the suprabasal squamous epithelial cells of the esophagus. Since the tissue distribution of MOv19 was very similar to that of another antibody described previously, MW207, these two antibodies were compared by competitive binding inhibition, and found to recognize the same epitope. Our data emphasize the importance of repeated, independent tests of antibody specificity.

Antibodies, Monoclonal↗
PubMed1991

The effect of antibody protein dose on the uniformity of tumor distribution of radioantibodies: an autoradiographic study.

The inaccessibility of radiolabeled antibody to poorly vascularized regions of solid tumors may reduce the therapeutic efficacy of these macromolecules. Theoretical mathematical models have predicted that increasing the protein dose administered would reduce the heterogeneity of radioantibody distribution. This investigation was undertaken to evaluate this hypothesis in experimental animal models. We have utilized the technique of macroautoradiography to demonstrate an increase in tumor penetration of the lower-affinity 125I-labeled NP-4 or higher-affinity Immu-14 anti-carcinoembryonic antigen (anti-CEA) mAbs into small (60.25-0.4 g) and large (0.8-1.5 g) GW-39 and LS174T human colonic xenografts, grown subcutaneously in the nude mouse, when 400 micrograms unlabeled antibody is administered simultaneously with 10 micrograms (100 microCi) radioantibody. Further increases in protein to 800 micrograms result in a reduction in total tumor uptake of the antibody. These in a reduction in total tumor uptake of the antibody. These differences in mAb distribution could be visualized as early as 1 day after antibody injection. Improved mAb penetration was also achieved for the Mu-9 anti-CSAp (anti-mucin) antibody using 800 micrograms unlabeled antibody. An irrelevant antibody (AFP-7-31) was found to be homogeneously distributed 3 days after injection, even at a low protein dose. Attempts to improve mAb penetration by increasing the protein dose in the GS-2 colorectal tumor, a model that has low NP-4 accretion as a result physiological barriers separating antibody from antigen, were not successful. These results suggest that a more homogeneous distribution of radioantibody can be achieved by carefully selecting a dose of unlabeled antibody to coadminister. Work is currently in progress to determine the effect of improved tumor distribution of radioantibody on the therapeutic potential of a single dose of radioantibody.

Adenocarcinoma↗
PubMed1991

Improved radioimmunotherapy of colorectal cancer xenografts using antibody mixtures against carcinoembryonic antigen and colon-specific antigen-p.

Radioimmunotherapy of GW-39 human colonic tumor xenografts grown in the hamster cheek pouch with 131I-labeled NP-4 anti-(carcinoembryonic antigen) (CEA) and 131I-labeled Mu-9 anti-(color-specific antigen-p) (CSAp) murine monoclonal antibodies, administered in combination, was more effective than using either antibody alone for tumor masses less than 0.5 cm3 in size. The antibody mixture had no therapeutic advantage for larger tumors. Therapeutic efficacy was determined by measuring the change in tumor size over time, quantifying the absolute number of tumors responding to radioantibody therapy, and determining the percentage growth inhibition of each treatment at various times after radioantibody administration. Several mechanisms are discussed to explain the improved tumoricidal effect of the antibody mixture noted in this model system, such as (a) the possibility that an antibody mixture could target a greater number of tumor cells, (b) the potential for antibody mixtures to provide better tumor distribution and (c) the possibility that antibodies administered in combination can increase the magnitude of tumor uptake of individual radioantibodies, thereby resulting in a greater radiation dose delivered to the tumor.

Animals↗
PubMed1991

Labeling of monoclonal antibody conjugates with 90Y.

An anti-carcinoembryonic antigen (CEA) antibody, NP-4, was labeled with 90Y using p-isothiocyanatobenzyl DTPA (SCN-Bz-DTPA) and its derivatives 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4- isothiocyanatobenzyl-DTPA (MX-DTPA) as the chelating agents. The 90Y conjugates were purified from unbound 90Y by two different methods, HPLC or acrylamide size exclusion gel chromatography, in order to evaluate the best purification method. Labeling efficiency, reaction kinetics and immunoreactivity were compared to the same antibodies labeled with [111In]citrate. Labeling efficiency, as determined by either HPLC or ITLC (instant thin layer chromatography), was consistently higher by ITLC than HPLC for 90Y-labeled MAb, but equal for 111In-labeled MAbs. Discrepancies between the 2 methods were linked to impurities in the 90Y that remained at the origin of ITLC plates. After purification by acrylamide gel filtration, recovery was 50-60% of loaded 90Y activity, but was more than 87% for the 111In compounds. Using HPLC, the recovery measured 85% for 90Y-labeled MAb and more than 93% for 111In-labeled conjugates. Immunoreactivity of the [90Y]MAb was comparable to the 111In-labeled conjugates. These studies indicate that HPLC purification of the [90Y]MAbs improves recovery of activity, and suggests that impurities found in the 90Y and metal-binding properties of acrylamide may have contributed to the poor recoveries from acrylamide gels.

Antibodies, Monoclonal↗
PubMed1991

A new murine monoclonal antibody against human hepatoma.

A murine monoclonal antibody (MAb 336) reactive with human hepatocellular carcinoma has been raised after immunizing BALB/c mice with whole HepG2 cells. MAb 336 (IgG1) was reactive with HepG2 (whole cells and membrane fractions), but not normal liver or peripheral blood cells. Immunohistological studies indicated that 12/16 hepatocellular carcinoma and 6/11 cirrhotic livers expressed MAb 336-associated antigen, and most normal human tissues and tissues derived from other cancers were unstained. Direct and competitive binding assays ruled out the possibility that this MAb reacts with alpha-fetoprotein, carcinoembryonic antigen, or ferritin. Western blot analysis indicated that MAb 336 reacts with an antigen of approximately 30,000 daltons. This MAb may be potentially useful for studying antigenic expression in hepatocellular carcinoma and as a targeting agent for radioimmunodetection and immunoconjugate therapy.

Animals↗
PubMed1991

Suppression of tumor vascular activity by radioantibody therapy: implications for multiple cycle treatments.

Autoradiographic analysis of the intratumor location of radioiodinated Mu-9 anti-CSAp antibody within 7 days of administration reveals a restricted distribution within 3-6 cell layers surrounding tumor vessels. Within 7-14 days after suboptimal radioantibody treatment (approximately 3000 rads), tumor vessel morphology and physiology are altered. Vessel number is reduced by 60-70%, vessel diameter is reduced, and remaining vessels are surrounded by fibrotic tissue. Vascular volume (VV) is reduced by 75%, blood flow rate (BF) is reduced 65%, and vascular permeability (VP) to an IgG is reduced by 60%. The change in VV is reversible by day 35 but BP and VP remain suppressed. Normal tissue (liver and lung) vasculature experience only small pertubations in physiology. These functional changes in tumor vessels reduce the magnitude of accretion of a second dose of radioantibody in tumor but not in normal tissue.

Animals↗