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Biomedical subjects

D M Goldenberg

Publications and source records attributed to D M Goldenberg.

At least 217 records · Page 12Linked to original sources
PubMed1990

Patterns of antigen distribution in human carcinomas.

Ten epithelial-specific monoclonal antibodies, including monoclonal antibodies to antigens that have been used extensively in immunodiagnosis and immunotherapy experiments, were tested for reactivity with 20 human carcinomas each of the colon, lung, and breast. The antibodies tested included B72.3, OC125, and antibodies to carcinoembryonic antigen, the 17-1A antigen, and the milk fat globule mucin antigen (epithelial membrane antigen). Striking differences in the pattern of antigen distribution were seen, with each antibody having a fairly consistent staining pattern, which was dependent on the tumor type. Two antibodies reacted with most or all tumor specimens and, when positive, reacted homogeneously with apparently every cell in the specimen. Other antibodies consistently produced a variegated staining pattern, typically with areas of positive cells surrounded by areas of negative tumor cells. A third pattern was strong localization to the luminal edge and/or secretions of glandular tumors; this pattern was seen primarily in colon carcinomas which have more well-developed glandular structures than breast or lung carcinomas. A correlation with biochemical properties of the antigens was evident, in that mucins or mucin-related antigens generally produced variegated staining of lung and breast carcinomas and luminal edge/secretion staining of colon carcinomas. Such differences in antigen distribution are likely to be a major factor in developing methods for immunodiagnosis and immunotherapy.

Antibodies, Monoclonal↗
PubMed1990

Use of whole-body autoradiography in cancer targeting with radiolabeled antibodies.

Methods of single-tracer whole-body autoradiography (WBAR) have been developed in our laboratory which allow imaging and measurement of the zonal distribution of radioiodinated antibodies and their fragments within GW-39 colon carcinoma xenografts varying in size from large, cystic masses with necrotic cores to micrometastases. The whole-animal distribution of 90Y-labeled anti-carcinoembryonic antigen monoclonal antibody NP-2 was evaluated by WBAR in nude mice bearing s.c. implants of GW-39 colon cancer and revealed antitumor uptake specifically as well as significant accumulation of 90Y in the bones. Dual-tracer qualitative WBAR methods have also been applied in order to examine the biodistribution of labeled immunoglobulins in the GW-39 animal tumor model as a function of the underlying rapid cell proliferation index ([3H]-thymidine assay) in the same tumor. In addition, extension of the WBAR method was made to permit imaging of the biodistribution of 10B compounds in mice bearing Harding-Passey melanoma implants by using a track-etch procedure to produce alpha-particle WBAR. Further applications of single and multiple radionuclide WBAR are offered and discussed as an effective means of assessing the degree of penetration of immunoglobulins in tumors in which vascular patterns, local glucose metabolism, protein synthesis, and rapid cell proliferation indices may be characterized.

Animals↗
PubMed1990

Clinical studies of cancer radioimmunodetection with carcinoembryonic antigen monoclonal antibody fragments labeled with 123I or 99mTc.

Seventy-three patients with diverse cancers containing carcinoembryonic antigen received 123I-labeled anti-carcinoembryonic antigen monoclonal antibody F(ab')2 fragment [38 patients], 99mTc-labeled anti-carcinoembryonic antigen monoclonal antibody Fab' fragment [23 patients], or both reagents at different times [6 patients] for evaluation of antibody targeting and imaging [radioimmunodetection (RAID)], using planar and single-photon emission computed tomography. The results indicated that antibody fragments are preferred for early tumor imaging (within 24 h). Rapid targeting and clearance from blood and normal organs of the antibody fragments (blood median t1/2 elimination of 26.5 and 13.2 h for the F(ab')2 and Fab' fragments respectively) permitted the use of short-lived radionuclides, such as 123I (13.3 h) and 99mTc (6 h), and confirmed that selective antibody accretion in tumors occurred very soon after administration, such as between 2 and 5 h. Scan interpretations at 24 h for the 123I-labeled F(ab')2 and at 2-5 h for the 99mTc-labeled Fab' revealed overall sensitivities, on a tumor site basis, of 95.9 and 94.9%, respectively. On a site basis, the overall accuracies were 94.2 and 93.8% for the 123I and 99mTc immunoconjugates, respectively. In the 6 patients studied with both radioimmunoconjugates, a high concordance in detection was found. Both imaging agents also revealed a high number of putatively new tumor sites not disclosed by other radiological methods at the time of the RAID studies, of which 40.0 and 20.5% were subsequently confirmed as tumor for the 123I and 99mTc agents, respectively, within an 11-month follow-up period. This represented 24 proven occult tumor sites in 19 patients given the 123I-immunoconjugate and 16 proven occult tumor sites in 9 patients receiving the 99mTc agent. The new lesions were found up to 17 and 7 months earlier for 123I-RAID and 99mTc-RAID, respectively, than with other detection methods. The smallest tumors identified were below 0.5 cm, especially with the 99mTc immunoconjugate and single-photon emission computed tomography imaging. The findings of this study confirm previous evidence that RAID is a safe and a potentially useful new method of cancer detection. Despite the excellent results with the 123I-F(ab')2 antibody fragment, its poor availability and high cost limit its clinical use. Therefore, the 99mTc agent, which is made by an instant, 1-step, 1-vial, direct labeling method, appears to be the method of choice for rapid and accurate detection of cancer by RAID.

Adolescent↗
PubMed1990

Biological considerations for radioimmunotherapy.

We have examined three methods that may be useful for improving the therapeutic efficacy of antibody-targeted radionuclides. The principal limitation of radioimmunotherapy is myelotoxicity and thrombocytopenia. These are due mainly to the length of time the radioantibody remains in the blood. The clearance time of a radiolabeled immunoglobulin G (IgG) may be decreased by using fragments prepared from the IgG. Using murine monoclonal antibodies against human colonic cancer in an animal model with a transplantable human colonic tumor, we have shown that fractionated doses of 131I-labeled F(ab')2 fragments can provide similar tumoricidal activity as a single injection of IgG, but toxicity to the normal tissues is reduced significantly at this tumoricidal level. Thus, it is expected that improved tumoricidal activity may be achieved by further escalating the dose of F(ab')2 that is administered at each injection. An anti-antibody (second antibody) may also be used to remove an anti-tumor antibody rapidly from the blood. By allowing intact IgG to be used instead of fragments, a higher percentage of the radiolabeled anti-tumor antibodies may be concentrated in the tumor to provide higher tumor doses, yet toxicity to the normal tissues may be controlled by the removal of the radiolabeled antibody from the blood. We have shown that the injection of a second antibody 48 h after 131I-labeled anti-carcinoembryonic antigen antibody is given can reduce toxicity at least 2-fold without affecting the tumoricidal activity of the radioantibody. A third method for reducing the myelotoxicity of radioantibody treatment involves the use of cytokines to increase the production of white blood cells. For example, interleukin 1 may be given prior to, or sometime after, radioantibody treatment to increase the number of circulating white blood cells and thereby reduce myelotoxicity. Thus, modification of some of the biological factors limiting radioimmunotherapy may provide for improvements in cancer treatment with radiolabeled antibodies.

Animals↗
PubMed1990

Use of hematopoietic growth factors to control myelosuppression caused by radioimmunotherapy.

Therapeutically efficacious doses of 131I-antibody result in a loss in circulating white blood cells; the granulocyte population is suppressed by 80-85% and the agranulocytes by 60-65% following 2 mCi of 131I-antibody in hamsters. The administration of 100,000 units of human recombinant interleukin 1 24 h prior to radioantibody can prevent the loss in WBC from 1 mCi of radioantibody and reduce the loss from 2 mCi of antibody. Recombinant murine granulocyte-macrophage colony-stimulating factor is also a potent stimulator of myelopoiesis and may also be useful as a method of reducing radioantibody-induced myelosuppression. The tumor uptake of radioantibody in animals treated with recombinant interleukin 1 is reduced by 30% 1 day after injection of radioantibody but returns to levels seen in animals not treated with the cytokine at 96 and 168 h. Therapeutic efficacy is not compromised by doses of interleukin 1 used to prevent myelosuppression. Therefore, the use of cytokines will permit the use of higher doses of radioantibody for greater tumor therapy with less myelotoxicity than in the absence of cytokine treatments.

Animals↗
PubMed1990

Effects of methotrexate-carcinoembryonic-antigen-antibody immunoconjugates on GW-39 human tumors in nude mice.

Methotrexate (MTX) was conjugated to an anti-carcinoembryonic antigen monoclonal antibody (NP2) by using amino-dextran as an intermediate carrier. The drug was chemically linked to amino-dextran (average Mr = 40,000), and the resulting MTX-dextran was then site-specifically attached to the carbohydrate moiety of the antibody. Athymic nude mice that carried human colonic GW-39 tumors (s.c.) were treated with the immunoconjugate. In this study, the specific conjugate caused a greater inhibition of the tumor growth than either free MTX or its conjugate with dextran and an irrelevant antibody. The intermediate MTX-dextran and the unlinked mixture of MTX-dextran with NP2 were both relatively ineffective in inhibiting tumor growth. The greatly reduced host toxicity permitted the use of the MTX-dextran-NP2 in a high-dose therapy of this tumor system.

Animals↗
PubMed1990

Biological and clinical perspectives of cancer imaging and therapy with radiolabeled antibodies.

Cancer and other diseases that elaborate increased quantities of antigenic substances can be targeted with suitable antibodies labeled with radionuclides. Factors influencing this targeting include the nature, pharmacology, and physiology of the antibodies, the composition and physiology of the tissue targets, the character and linkage of the radionuclide to the antibody, the choice of radionuclide, and the method of administration of the radioimmunoconjugate. The current state of cancer imaging with gamma-emitting radiolabeled antibodies, using the more optimal Fab' antibody fragments conjugated with 99mTc and imaging by single-photon emission computed tomography, permits high detection rates (90% range) of tumors at or below 0.5 cm, thus disclosing lesions missed by conventional radiographic methods. In radioimmunotherapy, severe limitations are due to low antibody accretion in tumors (resulting in low target rad doses), inadequate conjugation of radiometals to antibodies, high red marrow toxicity, and human anti-antibody responses when foreign immunoglobulins are administered. However, radiosensitive tumors, such as lymphomas, have shown impressive clinical responses.

Antibodies, Monoclonal↗
PubMed1990

Evaluation of a remote radioiodination system for radioimmunotherapy.

This report describes a remote radioiodination system which is inexpensive, easy to assemble, disposable, and capable of radioiodinating curie levels of activity safely. In addition to the safety afforded by this system, an immobilized oxidant and anion exchange resin are used to generate electrophilic iodine and remove free iodine, respectively. Reducing agents are not used and, therefore, when radioiodinating F(ab')2 fragments, degradation does not occur. In contrast, chloramine-T, sodium metabisulfite (CT/SMB) iodinations of F(ab')2 fragments resulted in products with up to 40% Fab' fragments. Radiolabeling yields (65.8% +/- 8.1%) and antibody immunoreactivity (68.8% +/- 8.0%) were not statistically different (p less than 0.001) from those obtained in remote CT/SMB iodinations. The system is currently being used to radioiodinate both IgG and F(ab')2 monoclonal antibodies with up to 450 mCi 131I for clinical radioimmunotherapy trials.

Antibodies, Monoclonal↗
PubMed1990

Metabolism of indium-111-labeled murine monoclonal antibody in tumor and normal tissue of the athymic mouse.

We have studied the fate of radiometal metabolism in vivo by analyzing the molecular form of radiolabeled anti-carcinoembryonic antigen (CEA) in tissues. Athymic mice bearing colonic tumor xenografts were injected i.v. with 111In-isothiocyanate-benzyl-DTPA-(SCN-Bz-DTPA) IgG or 111In-(SCN-Bz-DTPA) F(ab')2, and then killed daily for up to four days. Liver, kidney, and tumor were extracted and the supernatants, plasma and urine samples were analyzed by HPLC, ITLC, HPIEC and SDS-PAGE. By HPLC, the activity in normal tissue and tumor was associated principally with two major components. The first was native MAb and the second was a low molecular weight component (LMWF). On Day 1, the native-sized IgG was the predominant form (greater than 65%), but progressively decreased to less than 20% by Day 4. For the F(ab')2, even by Day 1 approximately 90% of the activity was associated with the LMWF. This LMWF was resolved further by HPIEC and SDS-PAGE into several metabolites that appear to be 111In-SCN-Bz-DTPA and 111In-SCN-Bz-DTPA bound to peptide fragments.

Animals↗
PubMed1989

Influence of animal host and tumor implantation site on radio-antibody uptake in the GW-39 human colonic cancer xenograft.

The magnitude and kinetics of tumor uptake of a monoclonal antibody (MAb) directed against carcinoembryonic antigen (CEA) in the GW-39 human colorectal cancer xenograft differ according to the animal used (nude mouse or hamster) and the site of implantation of the tumor within the animal (cheek pouch, leg muscle, subcutaneous or liver). Several physiological factors have been evaluated in an attempt to explain these differences in radio-antibody accumulation. The following observations have been made: (1) The animal host with the slower blood clearance of radio-antibody and the higher non-tumor tissue uptake has the higher tumor uptake; (2) the xenografts with a higher blood-flow rate, vascular volume and/or vascular permeability have a higher specific radio-antibody targeting; (3) the smaller, more viable tumors take up more radio-antibody per gram than the larger tumors; and (4) tumors with higher specific antigen content accrete more radio-antibody. These results are discussed in terms of the feasibility of clinical tumor imaging and therapy with radiolabelled antibodies.

Animals↗
PubMed1989

Comparison of therapeutic efficacy and host toxicity of two different 131I-labelled antibodies and their fragments in the GW-39 colonic cancer xenograft model.

The in vivo uptake, therapeutic potential, and host toxicity were evaluated for both the intact IgG and F(ab')2 fragment of 2 murine monoclonal antibodies (MAbs) directed against either carcino-embryonic antigen (CEA), called NP-4, or colon-specific antigen-p (CSAp), called Mu-9, in the GW-39 human colorectal carcinoma grown in the hamster cheek pouch. Mu-9 IgG and F(ab')2 were retained longer by the tumor than was the NP-4 IgG or F(ab')2, respectively. Localization of the two antibodies by micro-autoradiography revealed two distinct patterns. Mu-9 was seen densely around whole acini of tumor cells, whereas NP-4 was found around each individual cell, albeit less densely. The anti-tumor effects of 131I-labelled Mu-9 and NP-4 IgG were equal, but the therapeutic effectiveness of Mu-9 F(ab')2 was significantly higher than NP-4 F(ab')2, as measured by change in tumor size. A dose-dependent increase in host toxicity, as measured by change in body weight and change in peripheral white blood cells (p-WBCs), was observed with 0.5 to 3.0 mCi doses of 131I-IgG regardless of the MAb used. A 10-22% loss in body weight lasting 3-7 weeks and a 50-80% loss in pWBCs lasting 6-8 weeks were observed in these animals. In contrast, 3 x 2 mCi doses of 131I-NP-4 or Mu-9 F(ab')2 given at 3-day intervals, a schedule which was equally therapeutic to a single 2-mCi dose of 131I-IgG, resulted in only a 9% loss in body weight and a 50% loss in pWBCs that lasted only 1 week. This was followed by a complete recovery over the next 2-3 weeks. These data suggest that multiple doses of F(ab')2 can be as tumoricidal as a single dose of an intact MAb IgG, but significantly less toxic to the host.

Animals↗