anti-CEA Monoclonal Antibody Research Articles

Gamma-interferon administration after 90yttrium radiolabeled antibody therapy: Survival and hematopoietic toxicity studies

Hematopoietic toxicity is the dose-limiting factor for radioimmunotherapeutic regimens. Cytokines have been shown to decrease hematopoietic toxicity in animals exposed to whole-body irradiation. The purpose of this study was to investigate the effects of murine gamma-interferon (gamma-IFN) on survival and hematopoietic toxicity in mice treated with high dose 90yttrium labeled anticarcinoembryonic antigen (CEA) monoclonal antibody. Balb/c nu/nu mice were injected intravenously with 250 Ci 90Y-T84.66 (a murine anti-CEA monoclonal antibody). Thirty thousand units of gamma-IFN was administered i.v. 24 h later. Control mice received either 250 Ci 90Y-T84.66 alone or 30,000 units gamma-IFN alone. Survival, antibody biodistribution, and bone marrow histologic studies were then performed. Only 7% of the animals treated with 90Y-T84.66 survived up to 40 days posttreatment, when the study was terminated. In contrast, 52% of the mice treated with both 90Y-T84.66 and gamma-IFN survived 40 days posttherapy. No toxic deaths were seen in the control group administered gamma-interferon alone. Histologic examination of the bone marrow of animals receiving 90Y-T84.66 and gamma-IFN showed cellular depletion of 40-70% of the hematopoietic cells by 48 h. Cell depletion was 50-70% and 20% by 72 h and 8 days posttherapy, respectively. The marrow of the 90Y-T84.66-treated control group was depleted to a level of 50-80% at 48 h, and remained depleted at 90% at 72 h and 8 days posttherapy. No marrow cell reduction was seen in the gamma-IFN-only treated group. Biodistribution studies showed no alterations in antibody biodistribution or kinetics that could account for the changes in bone marrow toxicity after gamma-IFN. These results demonstrate that gamma-IFN can reduce the hematologic toxicity resulting from high dose radioimmunotherapy. Histologic studies of bone marrow suggest that gamma-IFN acts primarily to accelerate myelorestoration of the bone marrow. Further studies exploring the use of gamma-IFN as an adjunct to radioimmunotherapy are therefore warranted.

Spectrum of carcinoembryonic antigen immunoreactivity from isolated ductal hyperplasias to atypical hyperplasias associated with infiltrating ductal breast cancer.

To study the immunohistochemical expression of carcinoembryonic antigen (CEA) in ductal hyperplasia of the breast and to investigate its putative relation with atypia and co-existing infiltrating ductal carcinoma. Paraffin wax embedded tissue from 37 cases of isolated ductal hyperplasia (five with atypia and 32 without atypia) and 25 cases of ductal hyperplasia associated infiltrating ductal carcinoma (IDC) (seven with atypia and 18 without atypia) was stained with a monoclonal anti-CEA antibody using a standard avidin biotin immunoperoxidase method. CEA immunoreactivity was observed in eight (12.8%) ductal hyperplasia cases. The percentage of CEA positivity in ductal hyperplasia cases with atypia (33.3%) was substantially higher than that observed in cases of ductal hyperplasia without atypia (8.0%). Six cases of ductal hyperplasia associated IDC reacted with CEA; in these six cases the neoplastic cells of the co-existing carcinoma were also CEA positive. The percentage of CEA immunoreactivity in ductal hyperplasia associated IDC was higher than that observed in isolated ductal hyperplasia (24.0 v 5.4%). The percentage of CEA immunoreactivity in atypical ductal hyperplasia associated IDC was similar to that observed in IDC alone (42.9 v 40.0%). The presence of CEA immunoreactivity has been confirmed in benign proliferative breast lesions. The prevalence of such immunoreactivity increases from 3.1% in isolated, nonatypical ductal hyperplasia to 42.9% in atypical ductal hyperplasia associated IDC. This finding and the similarity of the frequency of CEA positivity in atypical ductal hyperplasia associated IDC and in IDC alone suggests that there is a pathogenetic link between ductal hyperplasia and some types of breast cancer.

Anti-CEA Labelling Kit BW 431/26

SummaryIn seven European countries a multicenter trial with the 99mTc-labelled monoclonal anti-CEA antibody BW 431/26 was conducted in 730 patients. The antibody is used for the immunoscintigraphic visualisation of CEA-expressing tumours. Investigated were in particular colorectal tumours, bladder and breast carcinoma, medullary thyroid carcinoma, adenocarcinoma of the lung and gastric carcinoma. The main area of use is the detection of recurrences and screening for foci in patients with rising serum CEA. The sensitivity amounts to at least 80% in case of primary colorectal tumours (n = 129) and their abdominal or pelvic metastases (n = 33) and to 90% for their recurrences (n = 107). HAMAs were detectable in less than 15% of patients investigated for the first time. In 17% of the patients examined, immunoscintigraphy was the only technique to visualize the lesion whereas all other diagnostic methods had failed. The procedure yielded additional information in 24-51 % of cases.

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Using carboxymethyl dextran (CMdex) as the intermediate drugcarrier, carboplatin (2 cis-diammin platin II, CBDCA : Bristol-Myers-Squibb) was conjugated to anti-CEA monoclonal antibody (MoAb : 1B2)with bridging agents 1-ethyl-3(3-dimethylaminopropyl)-carbodiimide and N-hydroxy-succinimide. MoAb and CMdex were mixed in the molar ratios of from 1 : 1 through 1 : 3000, but CMdex/CBDCA ratios were fixed at 1 : 100 in molar. The conjugation efficiency by this method was that when initially mixed molar ratio of carboplatin to MoAb was more than 10000, 80% of given carboplatin was found to be coupled to MoAb-CMdex, and maximally 626 mg of carboplatin could be conjugated to 1 mg of MoAb. The cytotoxicity and immunoreactivity of the immunoconjugates were evaluated by colony formation method, and by an enzyme immunoassay using Ag-coated beads, respec tively. The cytotoxicity of the immuno-conjugates was dependent only on the drug concentration, equal to that of unconjugated drug, and irrespective to the CBDCA/MoAb ratio. The immuno-reactivity of the conjugates was found no remarkable decrease in comparison with unconjugated antibody. Then we conclude that this conjugation method might be of use, at least significant on the conjugation of carboplatin to monoclonal antibodies.

Differences in biodistribution of the anti-(carcinoembryonic antigen) murine monoclonal antibody CE-25, its F(ab')2 fragment and its intact mainly human chimeric form CE 4-8-13. Dependence on tumour size and amount of antibody injected.

The effect of the size of the tumour and the amount of antibody injected on the biodistribution of a family of radioiodinated antibodies was studied. The intact mouse anti-(carcinoembryonic antigen) (anti-CEA) monoclonal antibody CE-25, its F(ab')2 fragment and the intact human-mouse chimeric from CE 4-8-13 were evaluated in a model system using the human CEA-producing colon xenograft T 380 grown in nude mice. The relative retention (the percentage of the injected dose per gram of tissue), of mouse mAb and F(ab')2 in tumour and most normal tissues 1 day after injection was independent of the antibody dose; after 4 days the mAb values increased with increasing antibody dose. The relative retention of chimeric mAb increased with increasing antibody dose 1 day after injection and also slightly after 4 days. The relative retention in tumour tissue was lower in bigger xenografts for all antibodies. The relative retention of mouse mAb in small tumours increased from day 1 to day 4; for chimeric mAb this value decreased. In normal tissues the relative retention of mouse mAb decreased from day 1 to day 4, but the relative retention of chimeric mAb in normal tissue dropped rapidly and changed little afterwards. Thus the biokinetics of antibodies is "species"-dependent: foreign, mainly human, chimeric antibody clears faster from normal mouse tissue than mouse antibody and reaches lower concentrations.

Effect of interleukin-2 on the biodistribution of technetium-99m-labelled anti-CEA monoclonal antibody in mice bearing human tumour xenografts

We have evaluated whether interleukin-2 (IL-2) at low doses can enhance delivery of radionuclides to tumour sites by improving the access of the radio-labelled antibody. The effects of 1000 or 2000 units of IL-2 on the biodistribution of technetium-99m-labelled anticarcinoembryonic antigen (CEA) monoclonal antibody, ZCE025, in athymic mice bearing human CEA-positive tumour (MKN45) xenografts were investigated. Treatment with IL-2 resulted in a significantly higher tumour uptake (1.2-1.5-fold) compared with the control group. Some normal organs, such as heart, lung, liver, spleen and kidneys, showed increased 99mTc uptake following the IL-2 treatment. Pretreatment with IL-2 also induced an enhancement of the permeability index for mouse IgG in tumours and in normal organs, whereas the blood flow in both normal organs and tumours remained at control levels. The effects of IL-2 were found to be dose-dependent. The IL-2 treatment increased the plasma CEA levels but not the CEA content in tumour tissues, suggesting that IL-2 enhanced the leakage of CEA from tumour to blood. The enhancement ratios of the tumour 99mTc-ZCE025 uptake following treatment with IL-2 were 1.4 and 1.8 in mice bearing small and large tumours, respectively. Our experimental results indicated that the low dose of IL-2 enhanced the vascular permeability sufficiently to increase the amount of antibody delivered to the tumour target. Administration of IL-2 would render radioimmunotherapy more effective, especially in patients with large tumour burdens.

The expression of Lewisx on carcinoembryonic antigen (CEA)-related glycoproteins of normal and inflamed oesophageal squamous mucosa

Carcinoembryonic antigen (CEA)-related antigens were detected histologically in normal and inflamed oesophageal squamous mucosa using polyclonal anti-CEA antisera and monoclonal antibodies recognizing CEA or NCAs (non-specific cross-reacting antigens). Expression was limited to the surface of more mature squames. Immunoblotting of detergent extracts of oesophageal mucosa separated on polyacrylamide gels using polyclonal anti-CEA antisera showed a number of CEA-related proteins, of 195, 145, and 80 kDa. CEA-specific monoclonal antibodies recognized only the 195-kDa glycoprotein. The lower molecular weight species were recognized by anti-NCA antibody DD9 and a CD66 antibody. The carboyhydrate antigen Lewisx (Lex, CD15), previously shown to be a marker of mature squames, was present predominantly on a subpopulation of the 195-kDa antigen and was demonstrable on the higher molecular weight component of a doublet recognized by the CEA antibodies. Expression of Lex carbohydrate antigens in inflamed oesophageal squamous mucosa was shown to be significantly reduced relative to the expression seen in normal tissue. A suprabasal layer of CEA-positive, Lex-negative cells became apparent in inflamed tissue showing altered glycosylation of the CEA under these conditions. It is postulated that CEA plays a role in maintaining the integrity of the squamous mucosa.

Staging potential of the anti-CEA monoclonal antibody scintigraphy in lung cancer

Staging potential of the anti-CEA monoclonal antibody scintigraphy in lung cancer

Internalization of an intact doxorubicin immunoconjugate.

An immunoconjugate between doxorubicin and anti-(carcinoembryonic antigen) (CEA) was prepared by using aminodextran (M(r) = 40,000) as the intermediate carrier, and the carbohydrate moiety of the antibody as the linking site. The resulting immunoconjugate was subjected to an in vitro evaluation for the internalization on the target cells (Lo Vo), and compared to that of unconjugated antibody, as well as the cellular uptake of unconjugated doxorubicin. The internalization was evaluated microscopically by following the translocation of the red fluorescence of doxorubicin and the green fluorescence of the fluorescein-isothiocyanate-labeled goat anti-(mouse Ig) antibody, which visualizes the location of the primary mouse antibody. Anti-CEA monoclonal antibody (NP-4) was found to internalize into Lo Vo cells. The immunoconjugate made with this antibody was similarly internalized, and the doxorubicin was found to distribute with the primary antibody. The cell surface and cytoplasm were the major compartments of their distribution. These results indicate that the drug molecules were indeed delivered into the cells by the antibody as an intact conjugate. Unconjugated doxorubicin, on the contrary, was quickly absorbed by the cells and concentrated in the nucleus within 30 min, and never showed a distribution in the cytoplasm or cell membrane as in the nucleus by this procedure. The intermediate drug conjugate, doxorubicin-dextran, did not show internalization. The internalization of NP-4 antibody (or the doxorubicin conjugate) was also confirmed by studying the intracellular catabolism of the cell-bound antibody (or conjugate). The release of the degraded antibody by the cells, as differentiated by trichloroacetic acid precipitation techniques, was considered an indication of internalization. Lysosomes were involved in the degradation, since the process was markedly inhibited in the presence of the lysosomal enzyme inhibitor, ammonium chloride.

Mimicry of a carcinoembryonic antigen epitope by a rat monoclonal anti-idiotype antibody.

Anti-idiotype antibodies (Ab2) that immunologically mimic tumor antigens are auspicious agents for the active immunization of cancer patients. We have developed W12, a rat monoclonal IgG1 Ab2 to MN-14, a murine anti-carcinoembryonic antigen (CEA) monoclonal antibody. W12 is specific for MN-14 and does not react with other isotype-matched anti-CEA monoclonal antibodies. Moreover, W12 inhibits the binding between MN-14 and CEA. Anti-CEA antibodies can be induced by immunization with W12 (but not with control rat IgG) in xenogenic animals (mice or rabbits). Immunoblotting studies indicate that the internal image determinant borne by W12 is conformational and requires the association of the heavy and light chains of the Ab2 molecule. This study indicates that W12 is a potential idiotype vaccine in patients with CEA-producing cancers.

Carcinoembryonic antigen‐like reactivity in malignant mesothelioma. A comparison between different commercially available antibodies

Immunohistochemical reactivity to carcinoembryonic antigen (CEA) is often used to exclude the diagnosis of malignant mesothelioma. In a study comprising 61 malignant mesotheliomas and 20 adenocarcinomas, the reactivity against one polyclonal and five different monoclonal anti-CEA antibodies was tested. Thirteen of the mesotheliomas showed distinct reactivity to the polyclonal antiserum, even after absorption with spleen powder. Of the monoclonal preparations, those staining granulocytes and macrophages also showed varying reactivity to some of these 13 mesotheliomas. Only one monoclonal antibody showed no such reactivity and labeled no mesothelioma case, while its capacity to stain adenocarcinomas remained. Mesotheliomas may contain substances that share epitopes with the CEA molecule. Only one of the tested monoclonal antibodies seemed sufficiently specific to be used diagnostically as a single immunohistochemical parameter to exclude malignant mesothelioma.

A rapid colorimetric assay for carcinoembryonic antigen (CEA)-mediated cell adhesion and analysis of CEA domains involved in the adhesion.

A colorimetric microadhesion assay that allows the quantitative determination of carcinoembryonic antigen (CEA)-mediated homophilic cell adhesion to CEA immobilized on 96-well polyvinyl chloride plates is described. Chinese hamster ovary (CHO) cells transfected with a full-length CEA cDNA were used as indicator cells. After dislodging nonadherent cells, specifically bound cells were quantified by a colorimetric analysis based on the ability of live cells to reduce the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to a blue formazan product. The domains of CEA responsible for the homophilic cell adhesion were analyzed by inhibition assays using anti-CEA monoclonal antibodies whose reactive domains were already known. The involvement of domain N and possibly subdomain A3 of CEA in the homophilic cell adhesion has been suggested.

A RESECTED CASE OF DUCTECTATIC TYPE CYSTADENOMA OF THE PANCREAS

It is not always easy to make a differential diagnosis of cystic lesion of the pancreas whether it is a cyst, cystadenoma, or cystadenocarcinoma. Particularly cystic lesions with the size of less than several centimeter which can be detected by ERP, ultrasonography, and CT scan often have atypical papillary hyperplasia, which poses a problem whether it is reactive or tumorous. This paper describes our experience with a case of ductectatic type cystadenoma of the pancreas which was difficult to differentiate from mucous-producing cancer of the pancreas preoperatively. A 53-year-old was admitted to the hospital because of right hypochondraligia. Computed tomographic examination showed a low density area in the head of the pancreas. Pancreaticoduodenectomy was performed when endoscopic retrograde pancreaticography (ERP) showed dilatation of the main pancreatic duct and cystic dilatation of the lesser ducts with a filling defect. Pathological findings revealed atypical papillary hyperplasia with staining by anti-CEA monoclonal antibody and goblet cell metaplasia. Further investigations to diagnose the pancreatic cystic lesions whether cancerous or not are necessary measuring oncogene expression such as K-ras point mutation.

Antibody-directed enzyme prodrug therapy (ADEPT)

Antibody-directed enzyme prodrug therapy (ADEPT) has been studied in a human ovarian carcinoma xenograft grown subcutaneously in nude mice. Radioimmunoassay of supernatants obtained from tumor homogenates showed these to contain carcinoembryonic antigen (CEA). Biodistribution studies with 125I-labeled monoclonal anti-CEA antibody, A5B7, and its F(ab')2 fragment showed localization in these xenografts. The AB57-F(ab')2 fragment conjugated to a bacterial enzyme, carboxypeptidase G2 (CPG2), and, radiolabeled with 125iodine, also localized in the xenografts. The radiolabeled conjugate cleared from blood faster than the antibody alone. The percentage of injected dose per gram in tumor at 24 h postinjection was about fivefold lower than antibody alone. Tumor-to-blood ratio at 72 h after injection of the radiolabeled conjugate was 7 and the tumor-to-normal tissue ratios at this time point ranged from 20 (liver) to 75 (colon). A three-phase ADEPT antitumor study was carried out in which A5B7-F(ab')2-CPG2 was allowed to localize and was followed by accelerated inactivation/clearance of blood CPG2 by a galactosylated anti-CPG2 antibody (SB43gal). A benzoic acid mustard-derived prodrug was injected 24 h after the conjugate, which led to growth delay in this tumor compared to the control untreated group. Further antitumor studies in this model are in progress.

Carcinoembryonic antigen is expressed on endothelial cells

Carcinoembryonic antigen (CEA) is a highly glycosylated cell surface protein. It is produced in large amounts in essentially all colon and several other adenocarcinomas. It has therefore been widely used as a clinical tumor marker. CEA is also a member of the immunoglobulin superfamily. Members of this family, such as ICAM-1, ICAM-2, VCAM-1 and NCAM, are known to participate in cell-cell adhesion. Similarly, the intercellular adhesion properties of CEA have been documented: it has been shown to mediate homotypic adhesion of cultured human colon adenocarcinoma cell lines. In this study we show for the first time that CEA is expressed on cultured human umbilical vein endothelial cells and on the endothelial cell line Ea.hy926. The expression of CEA on cultured endothelial cells can be enhanced by TNF-alpha or IFN-gamma, and decreased by IL-4. We demonstrate using immunohistochemistry that anti-CEA monoclonal antibody reacted with FVIII-positive endothelium in tissue sections prepared from lymph nodes. Finally, we were able to show that CEA-positive breast carcinoma cells bind to purified CEA protein, whereas CEA-negative breast carcinoma cells do not. These results reveal for the first time that endothelial cells express CEA on the cell surface and suggest that CEA-expressing adenocarcinomas could adhere to endothelial cells via CEA-CEA interaction, thus facilitating tumor cell extravasation and hematogenic metastasis.

Conjugates of COL-1 monoclonal antibody and β-D-galactosidase can specifically kill tumor cells by generation of 5-fluorouridine from the prodrug β-D-galactosyl-5-fluorouridine

5'-O-beta-D-galactosyl-5-fluorouridine is a prodrug that can be converted by the enzyme beta-D-galactosidase to the potent antineoplastic drug 5-fluorouridine. The prodrug is more than 100x less toxic than the drug to bone marrow cells in Balb/c mice. The ratio of the IC50 of the prodrug to that of the drug determined on a variety of tumor cell lines in vitro ranged from 500:1-1000:1. An antibody-enzyme conjugate (AEC) was synthesized and purified. Maleimide-substituted COL-1 anti-CEA monoclonal antibody was linked to free thiol groups of beta-D-galactosidase. The conjugate was purified by size exclusion and ion exchange chromatography. It retained full immunoreactivity and enzyme activity. After binding to antigen-positive tumor cells, the conjugate was able to activate the prodrug and specifically kill the cells. We are continuing to investigate this model for its potential use in antibody-directed enzyme prodrug therapy (ADEPT).

Direct comparison of a radioiodinated intact chimeric anti-CEA MAb with its F(ab')2 fragment in nude mice bearing different human colon cancer xenografts

Tumour localisation and tumour to normal tissue ratios of a chimeric anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb), in intact form and as an F(ab')2 fragment labelled with 125I and 131I, were compared in groups of nude mice bearing four different colon cancer xenografts, T380, Co112 or LoVo, of human origin, or a rat colon cancer transfected with human CEA cDNA, called '3G7'. For each tumour, three to four mice per time point were analysed 6, 12, 24, 48 and 96 h after MAb injection. In the different tumours, maximal localisation of intact MAb was obtained at 24 to 48 h, and of F(ab')2 fragment 12 to 24 h after injection. Among the different tumours, localisation was highest with colon cancer T380, with 64% of the injected dose per gram (% ID/g) for the intact MAb and 57% for its F(ab')2 fragment, while in the three other tumours, maximal localisation ranged from 14 to 22% ID g-1 for the intact MAb and was about 11% for the F(ab')2. Tumour to normal tissue ratios of intact MAb increased rapidly until 24 h after injection and remained stable or showed only a minor increase thereafter. In contrast, for the F(ab')2 fragment, the tumour to normal tissue ratios increased steadily up to 4 days after injection reaching markedly higher values than those obtained with intact MAb. For the four different xenografts, tumour to blood ratios of F(ab')2 were about 2, 3 and 5 to 16 times higher than those of intact antibodies at 12, 24 and 96 h after injection, respectively.

Carcinoembryonic antigen mediates in vitro cell aggregation induced by interferon-gamma in a human colon cancer cell line: requirement for active metabolism and intact cytoskeleton.

The homotypic cell aggregation of a carcinoembryonic antigen (CEA) positive colon cancer cell line (Colo 205) was induced in vitro by interferon-gamma (IFN-gamma) treatment. Divalent cations were required for this aggregation, as it was inhibited by EDTA. The partial inhibition by cytochalasin B and the complete inhibition by a mixture of sodium azide and 2-deoxyglucose suggests that the aggregation requires the integrity of cytoskeleton and active metabolism. The expression of CEA was increased in the cytoplasm and on the membrane of Colo 205 by IFN-gamma treatment. Furthermore, this aggregation was inhibited completely by anti-CEA monoclonal antibody (mAb) and partially by mAb against intercellular adhesion molecule-1. This in vitro study suggests that CEA molecule participates in the IFN-gamma induced homotypic adhesion of some CEA positive cancer cells and that IFN-gamma has an important role in the regulation of cell-cell interaction mediated by CEA molecule.

Tumor‐necrosis factor can enhance radio‐antibody uptake in human colon carcinoma xenografts by increasing vascular permeability

Marked differences in the tumor uptake of a 125I-labeled monoclonal antibody (MAb) directed against carcinoembryonic antigen (CEA) were observed in 4 serially transplanted human colorectal carcinomas in nude mice. A comparative study showed that elevated values of measurable tumor vascular parameters, such as permeability, blood flow and blood volume, correlated better with high MAb tumor uptake than the concentration of target antigen in the tumor. In an attempt to modify the vascular parameters and to determine if this could increase antibody uptake by the tumor, rhTNF alpha (TNF) was injected i.t. or i.v. and antibody localization experiments were performed immediately thereafter. Results showed that the permeability of the tumor vessels increased 8 to 10 fold 1 hr after i.t. injection of TNF as compared to control tumors injected with saline. Tumor uptake of 125I-labeled anti-CEA MAb, was 3 times higher 2 hr after i.v. injection and still 27% higher 22 hr later, as compared to results from controls. Intravenous injection of TNF simultaneously with the 125I-labeled anti-CEA MAb also resulted in a 2-fold increase in tumor uptake 4 hr after injection, but the increase was no longer significant 24 hr after injection. Interestingly after i.v. injection of TNF, the MAb concentration in the blood and other normal tissues, such as liver, kidneys, lungs and heart was decreased, resulting in significantly higher ratios of tumor to normal tissue. Taken together the results demonstrate that injection of TNF can increase tumor vascular permeability and improve radio-antibody uptake. This raises the possibility of increasing the radiation dose delivered by antibody to the tumor in the course of radioimmunotherapy.

Comparison of radioimmunotherapy and external beam radiotherapy in colon cancer xenografts

Radioimmunotherapy and external beam radiotherapy were compared in a nude mouse human colon cancer model. Radioimmunotherapy was delivered by intraperitoneal injection of 90Y-labeled anticarcinoembryonic antigen monoclonal antibody (anti-CEA MAB). Single fraction external beam radiotherapy was delivered using a 60Co teletherapy unit. Control groups received saline, unlabeled anti-CEA monoclonal antibody and labeled nonspecific monoclonal antibody. Subcutaneous CEA-expressing LS174T human colon carcinoma tumors were measured over time. Tumor growth suppression was expressed as delay to reach 2g compared to saline controls. Unlabeled anti-CEA monoclonal antibody and labeled nonspecific monoclonal antibody had no effect. External beam radiotherapy of 300, 600, 1000 and 2000 cGy produced growth delays of 3, 12, 17, and 22 days, respectively. Radioimmunotherapy with 120 μCi, 175 μ.Ci, and 225 μCi resulted in growth delays of 20, 34, and 36 days. Estimated absorbed tumor dose was 1750 cGy in the 120 μCi group. Similar comparisons were done with the more radioresistant WiDr human colon carcinoma cell line. External beam radiotherapy doses of 400, 800, 1200, and 1600 cGy resulted in growth delays of 6, 21, 36 and 48 days, respectively. Radioimmunotherapy of 120 μCi and 175 μCi resulted in growth delays of 9 and 19 days, respectively. The 120 μCi dose delivered an estimated absorbed tumor dose of I080 cGy to WiDr tumors. In summary, for the radiosensitive LS 174T line, radioimmunotherapy produced biologic effects that were comparable to a similar dose of single fraction external beam radiotherapy. For the more radioresistant WiDr tumor, radioimmunotherapy produced a biologic effect which was less than a similar dose of single fraction external beam radiotherapy. These studies suggest that a tumor's response to radioimmunotherapy relative to that of external beam radiotherapy is, in part, dependent on tumor radiosensitivity and repair capacity.