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D M Goldenberg

Publications and source records attributed to D M Goldenberg.

At least 199 records · Page 11Linked to original sources
PubMed1991

SPECT anti-CEA monoclonal antibody detection of occult colorectal carcinoma metastases.

Radioimmunodetection (RAID) using Tc-99m labeled Fab' fragments of the anti-CEA monoclonal antibody IMMU-4 was performed in a 68-year-old man for preoperative evaluation of colonic metastases. Planar images at 3 and 18 hours showed uptake within known metastases in the left lobe of the liver that had been observed with CT and at surgery during the preceding month. SPECT images at 3 hours demonstrated two additional unsuspected lesions. All sites were surgically confirmed the following day using intraoperative sonographic guidance, with the smallest occult lesion measuring only 6 x 9 mm. This case illustrates the limitations of CT and surgery, the potential of RAID for the detection of occult metastases, the increased sensitivity of SPECT over planar images for detecting lesions less than 1 cm in diameter, and the value of intraoperative guidance for small nonpalpable lesions.

Aged↗
PubMed1991

CD5+ B cells and naturally occurring autoantibodies in cancer patients.

We have determined the percentage of CD5+ B lymphocytes in the peripheral blood of cancer patients and healthy controls, using antibodies directed at the CD5 and CD19 (pan-B) markers. The frequencies of CD5+ B cells, expressed as a percentage of total B cells, ranged from 14.3 to 57.5% in the controls and from 14.8 to 82.8% in the patient population. One-third of the cancer patients had frequencies greater than 2 s.d. above the mean of the control population. The CD5+ B cell fraction expressed as a percentage of total lymphocytes was also significantly elevated in this group of cancer patients. These results suggest that the CD5+ B cell compartment may be affected by the malignant process or by the therapy modality employed. The plasma levels of several naturally occurring autoantibodies, the products of the CD5+ B cells, were also assessed in cancer patients and controls. No significant differences were observed when reactivity to several autoantigens was measured. These included nuclear components and phospholipids.

Adolescent↗
PubMed1991

Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody.

Sixteen patients with non-Hodgkin's lymphoma were infused with 6.2 to 58.2 mCi (0.2 to 3.9 mg) doses of radioactive iodine (131I)-labeled LL2 immunoglobulin G (IgG) or F(ab')2, in order to study antibody distribution, pharmacokinetics, dosimetry, toxicity, tumor targeting, and therapy. LL2 is a murine IgG2a monoclonal antibody (MAb) reactive with B cells and non-Hodgkin's B-cell lymphoma. In a series of five assessable therapy patients, doses as small as 30 mCi 131I-LL2 IgG or F(ab')2 resulted in tumor responses (two partial remissions, two mixed and minor responses, and one no response), while one patient receiving diagnostic doses as low as 6.2 mCi showed a partial remission for 1 year and a complete remission after a second low radiation dose. No acute toxicities were noted, and only myelotoxicity accompanied therapeutic doses, with grade IV marrow toxicity seen in three of seven patients receiving total doses of about 50 mCi. Dosimetry calculations showed spleen and tumor dose rules of about 4.6 cGy/mCi, which was three to four times the dose to other organs. Despite the administration of relatively low doses of LL2 (0.2 to 3.9 mg), 82% of 60 known extrasplenic lymphoma sites were imaged. Serum clearance showed an average distribution half-life (T1/2) of 2.1 hours and an elimination T1/2 of 32.0 hours. The average total-body clearance T1/2 was 43 to 45 hours. LL2's antigenic target does not appear to be shed in high amounts into the circulation. Three of eight patients having at least two injections showed a human antimouse antibody response. These patients may have been presensitized to animal protein. An interesting observation in this study was the marked drop in circulating B lymphocytes after the administration of radioiodinated LL2 or anticarcinoembryonic antigen MAbs, suggesting that this is a nonspecific radiation effect and not necessarily related to the binding of MAb to normal B cells.

Adult↗
PubMed1991

Imaging and therapy of gastrointestinal cancers with radiolabeled antibodies.

Radiolabeled antibodies are gaining in application for the imaging and therapy of cancers. Much progress has been made in the use of these new biological reagents for tumors of the gastrointestinal system, and the current status, problems and prospects are reviewed in this paper. It is apparent that murine monoclonal antibodies against cancer-associated antigens are safe and useful for revealing a high percentage of sites of tumor, including some missed by conventional radiological methods. Tumors as small as 0.5 cm can be disclosed, even in organs that are difficult for CT scan interpretation. Major advances in cancer imaging have involved the use of antibody fragments and simple, direct labeling methods for 99mTc, the most widely used radionuclide in nuclear medicine. The use of radiolabeled antibodies for cancer therapy has been a more difficult endeavor, particularly because of the delivery of inadequate rad doses to tumor. Advances include humanization of monoclonal antibodies and the improved attachment of therapeutic radionuclides, such as 90Y and 186Re or 188Re.

Carcinoma, Hepatocellular↗
PubMed1990

A fluorouridine-anti-CEA immunoconjugate is therapeutically effective in a human colonic cancer xenograft model.

5-fluorouridine (FUR), an antineoplastic agent, was site-specifically conjugated to the carbohydrate moiety of a anticarcinoembryonic antigen (CEA) monoclonal antibody (MAb) by using amino-dextran as the intermediate carrier. The final immunoconjugate contains approximately 30-35 molecules of FUR per molecule of immunoglobulin, has immunoreactivity retained as examined by flow cytometry, and is cytotoxic to the target cells as examined by 75selenomethionine incorporation studies. In the GW-39/nude mouse model, the conjugate remained efficient in targeting the human colonic tumor and possessed greater inhibitory growth effects on the subcutaneous tumor than free FUR or an irrelevant antibody conjugate. In addition, the reduced host toxicity of the conjugate may permit the use of this agent in a high-dose therapy of this tumor system.

Animals↗
PubMed1990

Murine monoclonal antibodies to colon-specific antigen p.

A previous report described the production of monoclonal antibodies Mu-1, -2, -3, and -4 against colon-specific antigen p. We now report the tissue distribution of the reactive epitopes. Each of the monoclonal antibodies was reactive with epitopes shared by the entire length of the intestine, with Mu-2 and Mu-3 determinants being present in the stomach as well. Mu-1 and Mu-4 appeared to have a more restricted distribution than did Mu-2 and Mu-3, which were present in several nongastrointestinal tissues. Unfortunately, these MAbs were not ideal for in vivo use against colorectal carcinoma. Mu-1 was not present in neoplastic colon tissue, Mu-2 and Mu-4 were reactive with granulocytes, and Mu-3 was reactive with kidney tubules and connective tissue. An additional fusion was performed from which Mu-9 was selected for further study. Among normal adult tissues this monoclonal antibody gave reactivity restricted to the intestines. The stomach and all nonintestinal tissues were negative by immunoperoxidase. Among colon tumors 60% were positive for the Mu-9 epitope. The data suggest Mu-9 may be a good candidate for in vivo targeting of diagnostic and therapeutic agents to colon cancer.

Adenocarcinoma, Mucinous↗
PubMed1990

Baboon anti-idiotype antibodies mimic a carcinoembryonic antigen epitope.

A baboon was immunized with NP-4, a murine monoclonal antibody (MAb) to carcinoembryonic antigen (CEA). Anti-idiotype antibodies were purified from the baboon serum by affinity chromatography on a NP-4-coupled matrix, followed by adsorption of the non-specific antibodies on an irrelevant MAb. Baboon anti-idiotype antibodies inhibited specifically the binding between NP-4 and CEA. Mice immunized with baboon anti-idiotype antibodies produced antibodies to the CEA epitope recognized by NP-4. These results indicate that baboon anti-idiotype antibodies functionally mimic a CEA epitope and that they can be suitable for idiotype therapy of human CEA-producing carcinomas.

Animals↗
PubMed1990

Selection of a DTPA chelate conjugate for monoclonal antibody targeting to a human colonic tumor in nude mice.

Our previous studies with a 90Y-labelled antibody against carcinoembryonic antigen (CEA) conjugated to the cyclic anhydride-DTPA (CA-DTPA) indicated that the accretion of 90Y in the bone may limit the application of 90Y-labelled antibodies for therapy. In this report, we have compared the tumor targeting of CA-DTPA-conjugated antibody to antibody conjugated with 4 isothiocyanatobenzyl (ITC-Bz) derivatives of DTPA in nude mice bearing a human colonic tumor xenograft. In biodistribution studies using an 111In-labelled anti-CEA murine monoclonal antibody (MAb), the CA-DTPA-conjugated MAb showed lower tumor uptake, faster blood clearance, and higher accretion in the liver than any of the 4 ITC-Bz-DTPA-conjugated MAbs. There were smaller differences among the 4 ITC-Bz-DTPA conjugates. Whole-body autoradiography of animals given 90Y-MAb prepared with the CA-DTPA or the ITC-Bz-DTPA showed less radioactivity in the bone with the ITC-Bz-DTPA-MAb than the CA-DTPA-MAb. 90Y uptake in the bone corresponded with regions of low proliferative activity as defined by 3H-labelled thymidine, suggesting that the 90Y was in the cortex rather than the marrow. These studies clearly show an advantage of the ITC-Bz-DTPA derivatives for 90Y and 111In labelling of MAbs.

Animals↗
PubMed1990

Murine monoclonal antibodies against carcinoembryonic antigen: immunological, pharmacokinetic, and targeting properties in humans.

We have examined three 131I-labeled murine monoclonal antibodies (MAbs) against carcinoembryonic antigen (CEA), NP-2, NP-3, and NP-4, after i.v. injection in patients with diverse cancers. Although the MAbs had a similar tumor-targeting ability, several important features were discovered that have led us to the selection of one of these MAbs for further clinical evaluation. We found that it is important to evaluate MAbs with a high immunoreactivity. For example, the MAb NP-2 was used initially in patients with an immunoreactivity between 35 and 50%. Although the tumor-imaging properties of this MAb compared favorably with the affinity-purified, goat anti-CEA antibody that we used previously, further purification of NP-2 to an immunoreactivity greater than 70% uncovered a previously unknown cross-reactivity with human granulocytes. It was also discovered that the MAbs differed in their ability to complex with CEA in the blood. Plasma samples were analyzed by gel filtration at 1 or 24 h after injection. The formation of complexes with circulating CEA was dependent on the CEA:MAb ratio in the blood. NP-3 complexed to a greater degree with CEA than NP-4, but NP-2 did not complex with CEA even at CEA:NP-2 ratios of 55 to 1. NP-3 commonly showed enhanced uptake in the colon by external scintigraphy, and examination of the radioactivity in the stool showed that most of the radioactivity was associated with whole IgG and large-sized fragments of NP-3. We also compared the rate of elimination of radioactivity from the blood for all of the MAbs and compared the clearance of NP-3 to NP-4 at three different ranges of MAb protein doses (less than 1.0 mg, 1 to 5 mg, and 5 to 20 mg). The blood clearance rate for NP-3 was fastest among the other MAbs at protein doses exceeding 1.0 mg. Patients given less than 1.0 mg of NP-4 had a significantly (P less than 0.005) shorter elimination half-life than patients given more than 1.0 mg of NP-4. By virtue of NP-4's good targeting properties in patients and its limited complexation with circulating CEA, it was selected as the MAb of choice for CEA tumor imaging.

Animals↗
PubMed1990

Biodistribution and radiation dose estimates for yttrium- and iodine-labeled monoclonal antibody IgG and fragments in nude mice bearing human colonic tumor xenografts.

An anti-carcinoembryonic antigen murine monoclonal antibody designated NP-4, and its F(ab')2 and Fab' fragments, were coupled to the 1/1 mixture of 1-isothiocyanato-benzyl-3-methyl- and 1-methyl-3-isothiocyanato-benzyl-diethylenetriaminepentaacetic acid chelate and labeled with 111In or 88Y. Biodistribution studies in nude mice bearing a human colonic tumor xenograft were performed with these labeled conjugates, and comparisons were made to unconjugated NP-4 IgG and fragments labeled with 131I. Regardless of the labeling method, higher tumor uptake was found with the intact IgG than with the fragments, but due to faster blood clearance, tumor/blood ratios were higher for the fragments than for the IgG. Tumor uptake for the radiometal-labeled NP-4 was generally higher than the 131I-labeled NP-4. Tumor/nontumor ratios for the liver, kidney, and spleen were higher for the 111In- and 88Y-labeled NP-4 IgG than the respective radiometal-labeled fragments, but tumor/nontumor ratios for the 131I-NP-4 fragments were higher than the 131I-NP-4 IgG. Radiometal uptake in the kidney was approximately 8 and 150 times higher than the 131I-NP-4 F(ab')2 and Fab', respectively, and the clearance of radiometal activity in the kidneys was approximately 10 times slower than the radioiodine. Quantitation of 88Y or 111In activity in the femur showed 3-5%/g for the IgG and F(ab')2 and only 1-2%/g for the Fab'. The amount of radioactivity in the femur remained constant over time, and between 60 and 100% of the 88Y activity remained after flushing the core of the femur with saline, whereas 50-70% of the 111In and only 25-30% of the 131I activity remained after washing. Radiation dose estimates derived from these studies suggest that at the maximal tolerated dose 131I-NP-4 IgG would deliver 5.9 times the dose to the tumor as 90Y-labeled NP-4 IgG. 90Y-labeled fragments would not be useful due to higher doses to the kidneys than to the tumor. However, with 131I-labeled IgG and fragments there is greater flexibility to permit tumoricidal doses without excessive toxicity to the normal tissues.

Animals↗
PubMed1990

Murine monoclonal antibodies raised against human non-small cell carcinoma of the lung: specificity and tumor targeting.

The tumor targeting properties of murine monoclonal antibodies (MAbs) generated in our laboratory against non-small cell carcinoma of the lung have been investigated in nude mouse xenograft models. The MAbs selected for evaluation, RS5-4H6, RS7-3G11, and R511-51, have pancarcinoma reactivity, as shown by immunoperoxidase staining of the majority of tumors from the lung as well as breast, colon, kidney, and ovary. The localization of the three MAbs which bind to distinct antigens, and exhibit different levels of cross-reactivity with normal human epithelial tissues, are compared. The MAbs are of the IgG1 isotype. Since these MAbs were reactive with Calu-3, a human adenocarcinoma of the lung cell line grown as xenografts in nude mice, this system was selected as our initial tumor target. The MAbs were found to localize preferentially to the heterotransplanted tumors, with from 6.6 to 8.6% of the injected dose per gram accreting in the tumor at 7 days. Tumor/nontumor ratios of up to 9.7 were seen with one MAb at day 14. The targeting of MAb RS11-51 and F(ab')2 fragments of RS11-51 in GW-39, a human colon cancer grown in nude mice, was also studied. Accretion of intact RS11-51 and F(ab')2 fragments into GW-39 was greatly increased compared to Calu-3. In view of the high frequency of antigen expression on a wide variety of tumors, and the ability to target in vivo, these new MAbs may have potential use in the imaging and therapy of cancer.

Animals↗
PubMed1990

Carcinoembryonic antigen and alpha-fetoprotein expression and monoclonal antibody targeting in a human hepatoma/nude mouse model.

Hep G2, a human hepatocellular carcinoma, was grown s.c. in nude mice, as well as in tissue culture. This line retains the normal liver parenchymal cell capacity to synthesize human plasma proteins such as albumin, but there is no indication that it harbors the hepatitis B virus. We have detected the oncofetal antigens alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) in both Hep G2 xenografts and spent tissue culture media by Ouchterlony double diffusion assays, enzyme-linked immunosorbent assay, and immunohistology. By enzyme-linked immunosorbent assay, the AFP levels were 544.9 ng/ml in the cell culture and 1.6 microgram/g in saline extracts of the xenograft. The CEA levels were 35.2 ng/ml in the cell culture and 5.4 micrograms/g in the xenograft. The biodistribution of a radioiodinated anti-AFP murine monoclonal antibody and an anti-CEA monoclonal antibody were studied separately in nude mice bearing s.c. Hep G2 xenografts in comparison to an isotype-matched irrelevant IgG (Ag8). Anti-CEA antibody showed a preferential localization for Hep G2, but anti-AFP antibody did not. Immunohistochemical studies of the Hep G2 tumor, using biotinylated anti-AFP and anti-CEA, indicate both cytoplasmic and luminal staining of CEA and AFP in the tumor. These results suggest that Hep G2 may be a useful cell line for radioimmunodetection and radioimmunotherapy studies using anti-CEA and possibly anti-AFP monoclonal antibodies.

Animals↗
PubMed1990

Monoclonal antibody targeting of human non-small cell carcinoma of the lung.

Murine monoclonal antibody RS5-4H6 is an IgG1, which was raised against a crude membrane preparation of Calu-3, a human adenocarcinoma of the lung cell line. MAb RS5-4H6 reacts with the majority (14 of 15) of surgical specimens of non-small cell carcinomas of the lung by immunoperoxidase staining. Reactivity with this antibody was not limited to tumors of the lung but rather exhibited pancarcinoma reactivity, staining 87% of tumors from all organs tested. In this study we examined the potential of radiolabeled RS5-4H6 to target Calu-3 xenografts in nude mice. The monoclonal antibody was found to localize preferentially to the heterotransplanted tumors, with 6.6% of the injected dose/g accreting in the tumor at 7 days, a 3-fold higher level than an anti-carcinoembryonic antigen monoclonal antibody which was used as a negative control.

Animals↗
PubMed1990

Tumor, red marrow, and organ dosimetry for 131I-labeled anti-carcinoembryonic antigen monoclonal antibody.

Tumor-, red marrow-, and organ-absorbed doses were calculated for patients receiving 131I-labeled monoclonal antibodies against carcinoembryonic antigen for either diagnosis or therapy. Ten patients with confirmed liver tumors who received doses ranging from 10.79 to 200 mCi were evaluated. Urine and blood samples were taken in order to determine total body and red marrow activity, respectively. Anterior and posterior gamma camera images were obtained at multiple times postinjection in order to quantitate activity uptake using the conjugate view counting method for the following organs and regions: lungs, liver, spleen, kidneys, and the liver tumors. In addition, sacral regions of interest were drawn to generate red marrow-absorbed dose estimates for comparison to those obtained by blood sampling. Tumor volumes were obtained from volumetric analysis of the patient's computed tomographic study and tumor S values were obtained by assuming uniform distribution of the 131I-labeled monoclonal antibody in spherical tumor regions considering all emitted electrons, beta-particles, and photons. The following mean absorbed doses in rads/mCi injected were obtained: lungs, 2.3 +/- 1.6 (SD); liver, 1.4 +/- 0.7; spleen, 2.6 +/- 1.4; kidneys, 3.1 +/- 1.5; total body, 0.7 +/- 0.5; red marrow from blood sampling, 2.9 +/- 1.9; red marrow from sacral scintigraphy, 1.7 +/- 1.2; and liver tumors, 69.3 +/- 92.5. Tumor volumes ranged from 1 to 216 g and the percentage of uptake/g of monoclonal antibody into these tumors ranged from 0.0006 to 1.040. There was a statistically significant difference between the two techniques for estimation of red marrow dose (P less than 0.01). This methodology, permits calculation of tumor, red marrow, and organ dosimetry using planar gamma camera imaging.

Antibodies, Monoclonal↗
PubMed1990

Human immune response to anti-carcinoembryonic antigen murine monoclonal antibodies.

We previously demonstrated that patients with carcinoembryonic antigen [CEA]-producing neoplastic tumors, treated with murine monoclonal antibody to CEA, produced antibodies directed against the constant regions [human anti-mouse antibody (HAMA)] and the idiotypes [anti-Id] of these murine immunoglobulins. In this study, we describe a method for analyzing the presence of such antibodies in the sera of these patients. The HAMAs were measured by enzyme immunoassay and removed by immunoadsorption on Affi-Gel mouse IgG. The unabsorbed fraction contained the anti-Id antibodies; their presence was demonstrated by binding to the CEA monoclonal antibody (Ab1). The specificity of the binding was assessed by preincubating the sera with Ab1 and measuring the residual nonspecific binding. When specific binding was detected, the anti-Id antibodies were isolated by adsorption and elution on Affi-Gel Ab1. The anti-Id antibodies were fixed on enzyme immunoassay plates and incubated with a panel of mouse anti-human immunoglobulin to determine their isotypes. In a first series of 24 patients, HAMAs were found in 20 cases and anti-Id antibodies in 19 cases. The isolation of a specific IgG to Ab1 was achieved in 2 cases. In an ongoing series, the HAMA and anti-Id antibodies were detected in all five patients given injections of another monoclonal antibody to CEA. In two patients an IgG1 kappa anti-Id was isolated from the serum. The potential therapeutic effect of these antibodies is under investigation.

Animals↗
PubMed1990

Preclinical evaluation of an "instant" 99mTc-labeling kit for antibody imaging.

This communication presents information on the quality and stability of a new conjugate of 99mTc to an anticancer antibody fragment and results of animal imaging and distribution studies. Clinical studies have proved that this labeled antibody can image tumors within 2 hours of i.v. injection. It is produced using an "instant kit," merely requiring addition of [99mTc]pertechnetate to a lyophilized vial containing the fragment and a pertechnetate-reducing agent. Within 5 min of addition of pertechnetate to the vial containing the fragment, [99mTc]pertechnetate is reduced and quantitatively bound to an intrinsic high-affinity receptor present in the Fab'. The Fab'-bound 99mTc is completely stable to challenge with diethylenetriaminepentaacetic acid and human serum albumin. Minimal oxidation and release of 99mTc bound to the fragment were observed when the labeled fragment was incubated for 24 h at 37 degrees C. Animal biodistribution studies were consistent with the known metabolic elimination of a radiolabeled Fab' fragment by the kidney. Tumor localization studies in athymic nude mice bearing xenografts of human colonic carcinoma (GW-39) predicted the positive results later demonstrated in clinical studies.

Animals↗
PubMed1990

Comparison of tumor targeting in nude mice by murine monoclonal antibodies directed against different human colorectal cancer antigens.

Tumor targeting of five radioiodinated murine monoclonal antibodies (MAbs) directed against human colorectal cancer were studied in nude mice bearing the GW-39 human colonic tumor xenograft. All of the MAbs are of the IgG1 isotype. Two of the MAbs (NP-4 and MN-14) are directed against a Class III carcinoembryonic antigen-specific epitope, but they differ 10-fold in their affinity. The other three MAbs recognize mucins found in colonic cancer. Mu-9 recognizes a peptide determinant similar to that described previously for a polyclonal goat anti-colon-specific antigen p. G9 identifies an organ-specific, tumor-associated carbohydrate epitope. The tumor targeting of these MAbs was compared to that of B72.3, another anti-mucin MAb. The tumor uptake of all the MAbs were similar on days 1, 3, and 7, with an average maximum accretion of between 30 and 40%/g tumor occurring by day 3. This tumor uptake was maintained for 14 days with the anti-mucin MAbs, whereas the percentage of injected dose/g in the tumor for 2 anti-carcinoembryonic antigen MAbs decreased 2-fold by day 14. Although no statistical difference could be found between the percentage of injected dose/g in the tumor for NP-4 and MN-14 (carcinoembryonic antigen MAbs), in a paired-labeled study using 131I-MN-14 and 125I-NP-4, MN-14 uptake in the tumor was consistently 1.3 times higher than that of NP-4 on all days tested. F(ab')2 fragments showed lower tumor uptake (maximum uptake for NP-4 and Mu-9 was 11% on day 1), but the faster clearance resulted in a 4- to 40-fold increase in tumor/blood ratios on day 3 in comparison to the whole IgGs. Fab' fragments had the lowest tumor uptake of the 3 forms of immunoglobulin, with a maximum of only 5%/g 6 h after injection. However, tumor/blood ratios on day 1 for the Fab' fragments were improved 3-fold over that of F(ab')2. All of these MAbs, except Mu-9, identify epitopes that can be detected in plasma, but none of the MAbs complexed appreciably when mixed in vitro with plasma containing antigen at antigen/MAb ratios anticipated to be encountered most frequently in imaging or therapy applications in humans. However, complexation of the MAbs will occur if antigen in the plasma is markedly elevated. These studies suggest that if used clinically, tumor targeting of colorectal cancer with any of these MAb IgG may be similar if these antigens are present at relatively similar concentrations in tumor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗