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PubMed2000

Synthesis and evaluation of antiproliferative activity of a geldanamycin-Herceptin immunoconjugate.

Geldanamycin was modified with 1,4-diaminobutane to introduce a primary amine that was subsequently employed to provide a maleimide for protein linkage. Monoclonal antibody Herceptin was then derivatized to generate thiol groups that reacted with the maleimide derivative to produce the immunoconjugate. The product showed antiproliferative activity greater than native Herceptin.

Antibodies, Monoclonal↗
PubMedDate not supplied

Determination of immunoreactivity of doxorubicin antibody immunoconjugates by a Le(y) competitive RIA.

Many monoclonal antibody-drug immunoconjugates have been evaluated for their ability to deliver cytotoxic drugs to tumors. It is essential to establish that the ability of the conjugates to bind antigen, i.e. their immunoreactivity, is not adversely affected by the drug conjugation procedure. We have described herein a measurement of the immunoreactivity of BR96-DOX, a conjugate comprised of BR96, a chimeric monoclonal antibody specific for the Le(y) tetrasaccharide commonly expressed on human carcinomas, and doxorubicin, an anticancer agent in widespread clinical use. We have employed a competitive RIA, in which microtiter wells were coated with synthetic Le(y) conjugated to human serum albumin and then incubated with 125I-labeled antibody BR96 in the presence of test conjugate or intact BR96 mAb. The test conjugates were found to compete as effectively as unconjugated BR96. This assay is highly applicable to QC processes with the intra-assay CV = 2.0% and the interassay CV = 4.3%.

Antibodies, Monoclonal↗
PubMedDate not supplied

Synthesis, metal chelate stability studies, and enzyme digestion of a peptide-linked DOTA derivative and its corresponding radiolabeled immunoconjugates.

By directly coupling a tetrapeptide to DOTA through an amide bond, we synthesized a novel DOTA derivative, DOTA-glycylglycylglycyl-L-p-nitrophenylalanine amide. We converted this new precursor bifunctional chelating agent to DOTA-glycylglycylglycyl-L-p-isothiocyanatophenylalanine++ + and conjugated it to monoclonal antibody Lym-1. Serum stability studies show that the radiolabeled conjugates are kinetically inert under physiological conditions. The rates of loss of radiometals in human serum are 0.1 +/- 0.1% per day for InIII, 0.02 +/- 0.15% per day for YIII, and 0.3 +/- 0.2% per day for CuII labeled immunoconjugates. In the presence of the liver enzyme cathepsin B, an in vitro digestion of 114mIn-labeled conjugate yields a small fragment containing 114mIn. Characterization of the cleavage products shows that this liver enzyme hydrolyzes the peptide linkage before the phenylalanine residue, freeing the In-DOTA-triglycine complex from the conjugate. However, the liver enzyme cathepsin D does not cleave the linkage over the span of 7 days.

Amino Acid Sequence↗
PubMedDate not supplied

Boronated starburst dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture therapy.

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy or thermal neutrons (< or = 0.025 eV) to yield high LET alpha particles and recoiling 7Li nuclei [10B + nth-->[11B]-->4He(alpha) + 7Li + 2.39 MeV]. Approximately 10(9) boron-10 atoms must be delivered to each target cell in order to sustain a lethal 10B(n,alpha)7Li reaction. If MoAbs are to be used for targeting boron-10, then it is essential that they recognize a surface membrane epitope that is highly expressed on tumor cells and that a large number of boron-10 atoms be attached to each antibody molecule. In order to heavily boronate MoAbs, we have utilized starburst dendrimers (SD), which are precise, spherical macromolecules composed of repetitive poly(amidoamino) groups. Second- and fourth-generation dendrimers, having 12 and 48 reactive terminal amino groups and molecular weights of 2414 and 10,632 Da, respectively, were boronated using an isocyanato polyhedral borane, Na(CH3)3NB10H8NCO. The boronated starburst dendrimers (BSD), in turn, were derivatized with m-maleimidobenzoyl N-hydroxysulfosuccinimide ester (sulfo-MBS). The MoAbIB16-6, which is directed against the murine B16 melanoma, was derivatized with N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP). The MBS-derivatized BSD and SPDP-derivatized MoAb were reacted to yield stable immunoconjugates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Characterization of ribosome-inactivating proteins isolated from Bryonia dioica and their utility as carcinoma-reactive immunoconjugates.

Two ribosome-inactivating proteins (RIPs) were isolated and characterized from the roots of Bryonia dioica. One of these was a novel 27-kDa protein termed bryodin 2 (BD2), while the second was a previously reported RIP, referred to here as bryodin 1 (BD1). The amino-terminal sequence obtained for BD2 was similar, but distinct from BD1, ricin A chain, trichosanthin, and momorcharin. BD2-specific monoclonal antibodies were generated and found not to react with BD1 or ricin A chain. Purified BD1 and BD2 RIP inhibited protein synthesis in a cell-free in vitro translation assay at EC50 values of 7 and 9 pM, respectively. Intravenous administration of BD1 was less toxic to mice than BD2, with LD50 values of > 40 for BD1 and 10-12 mg/kg for BD2. Primary human endothelial cells were 5-8-fold less sensitive to BD1 and BD2 than compared to ricin A chain. BD1 and BD2 were constructed as immunoconjugates with the chimeric form of BR96 (chiBR96), a carcinoma-reactive, internalizing antibody. ChiBR96-BD1 and chiBR96-BD2 were found to bind to and kill BR96 antigen-positive carcinoma cells while not killing antigen-negative carcinoma cells. Bryodins represent RIPs that may be useful in constructing immunotoxin conjugates with reduced toxicity and vascular sensitivity, as compared to ricin A chain immunotoxins.

Amino Acid Sequence↗
PubMedDate not supplied

Cobra venom factor immunoconjugates: effects of carbohydrate-directed versus amino group-directed conjugation.

Human IgM monoclonal antibody 16-88, derived from patients immunized with autologous colon carcinoma cells, was derivatized with two different cross-linkers, S-(2-thiopyridyl)-L-cysteine hydrazide (TPCH), which is carbohydrate-directed, and N-succinimidyl-3-(2- pyridyldithio)propionate (SPDP), which is amino group-directed. Two antibody functions, antigen binding and complement activation, were assayed upon derivatization with TPCH and SPDP. TPCH allowed for extensive modification (up to 17 TPCH molecules per antibody) without impairment of antigen binding activity, while this function was significantly compromised upon derivatization with SPDP. Antibody molecules derivatized with 16 SPDP residues showed almost complete loss of their antigen binding function. The complement activating ability of antibody 16-88 was significantly decreased after derivatization with TPCH or SPDP. In the case of SPDP derivatization, this decrease of the complement activating ability is predominantly a consequence of the impaired binding function. Upon conjugation of cobra venom factor (CVF), a nontoxic 137-kDa glycoprotein which is capable of activating the alternative pathway of complement, the antigen binding activity of SPDP-derivatized antibody was further compromised, whereas that of TPCH-derivatized antibody remained unaffected even after attachment of three or four CVF molecules per antibody. In both conjugates CVF retained good functional activity. CVF was slightly more active when attached to SPDP-derivatized antibody, suggesting a better accessibility of amino group-coupled CVF for its interaction with other complement proteins. These results indicate that carbohydrate-directed conjugation compromises the antibody function of complement activation, but allows for the generation of immunoconjugates with unimpaired antigen binding capability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity.

The anticancer drug doxorubicin (DOX) has been linked to chimeric BR96, an internalizing monoclonal antibody that binds to a Lewis(y)-related, tumor-associated antigen, through two lysosomally cleavable dipeptides, Phe-Lys and Val-Cit, giving immunoconjugates 72 and 73. A self-immolative p-aminobenzyloxycarbonyl (PABC) spacer between the dipeptides and the DOX was required for rapid and quantitative generation of free drug. DOX release from model substrate Z-Phe-Lys-PABC-DOX 49 was 30-fold faster than from Z-Val-Cit-PABC-DOX 42 with the cysteine protease cathepsin B alone, but rates were identical in a rat liver lysosomal preparation suggesting the participation of more than one enzyme. Conjugates 72 and 73 showed rapid and near quantitative drug release with cathepsin B and in a lysosomal preparation, while demonstrating excellent stability in human plasma. Against tumor cell lines with varying levels of BR96 expression, both conjugates showed potent, antigen-specific cytotoxic activity, suggesting that they will be effective in delivering DOX selectively to antigen-expressing carcinomas.

Animals↗
PubMed2000

Phase I open study of the effects of ascending doses of the cytotoxic immunoconjugate CMB-401 (hCTMO1-calicheamicin) in patients with epithelial ovarian cancer.

PURPOSE: We have performed a phase I study of the cytotoxic immunoconjugate CMB-401 in women with epithelial ovarian cancer (EOC). CMB-401 is a directed chemotherapy that comprises a genetically engineered human antibody against polymorphic epithelial mucin, to which is attached covalently two to three molecules, on average, of the cytotoxic antibiotic calicheamicin. The primary objectives of this two-centre study were to identify end-organ toxicities and to establish the maximum tolerated dose (MTD). PATIENTS AND METHODS: Thirty-four patients aged 37-75 years with progressive EOC not amenable to platinum/standard therapy, and with satisfactory WHO performance status (0-2) were recruited. Patients had received a mean of 3.2 previous chemotherapeutic regimens with a median interval since last chemotherapy of 182 days (range 34-1217). Patients received up to four cycles of a dual infusion of 35 mg/m2 hCTMO1 'predose' followed by doses of CMB-401 which were increased for each cohort--a regimen which minimises drug uptake in normal tissues whilst enhancing delivery to the ovarian tumour. CMB-401 dosing commenced at 2 mg/m2 and progressed via seven cohorts to 16 mg/m2. RESULTS: CMB-401 was generally well tolerated. However, transient fever and emesis occurred, necessitating routine prophylaxis, and increasingly significant malaise was reported as the dose increased. WHO grade 3-4 toxicities, irrespective of causality, included: anaemia 21%, granulocytopenia 9%, thrombocytopenia 9%, liver transaminases 3%, sepsis 3%, haemorrhage 6%, nausea/vomiting 76%; pulmonary 6%, and conscious state/somnolence 6%. The MTD was reached at 16 mg/m2. During the study four patients had a greater than 50% reduction in CA125, and three patients had radiological evidence of reduction in tumour bulk. CONCLUSIONS: CMB-401 appears to have an acceptable toxicity profile with demonstrable activity against EOC.

Adult↗
PubMed1995

Stabilization of chimeric BR96-doxorubicin immunoconjugate.

Chimeric BR96-doxorubicin conjugate (BR96-DOX) is an immunoconjugate designed to specifically target and kill certain tumor cells. The linker between the chimeric BR96 antibody and DOX is an acid-labile hydrazone group which was designed to undergo lysosomal hydrolysis to release DOX in vivo. Stability studies indicated that acid-catalyzed hydrazone hydrolysis was the major degradation route in vitro. Even under optimal conditions of pH and temperature, the stability of BR96-DOX in solution was not acceptable for long-term storage. Lyophilization of BR96-DOX in the presence of added sugars, such as lactose or sucrose, and subsequent storage of the lyophile under refrigeration significantly improved the stability. Therefore lyophilization appears to be a viable approach for achieving long-term stabilization of BR96-DOX.

Antibodies, Monoclonal↗
PubMed1994

Photoimmunotherapy and biodistribution with an OC125-chlorin immunoconjugate in an in vivo murine ovarian cancer model.

Photodynamic therapy (PDT) is an experimental approach to the treatment of neoplasms in which photosensitisers (PSs) accumulated in malignant tissues are photoactivated with appropriate wavelengths of light. The target specificity of PSs may be improved by linking them with carrier macromolecules such as monoclonal antibodies (MAbs). OC125 is a murine MAb that recognises the antigen CA 125, which is expressed on 80% of non-mucinous ovarian tumours. A chlorin derivative conjugated to OC125 was shown to be selectively phototoxic to ovarian cancer and other CA 125-positive cells in vitro and ex vivo. We now report in vivo studies using an ascitic Balb/c nude mouse ovarian cancer model. Ascites was induced by intraperitoneal injection of cells from the human ovarian cancer cell line NIH:OVCAR3. Six weeks after injection, when the animals had developed ascites, biodistribution studies were carried out by injecting the immunoconjugate (IC) or free PS intraperitoneally and sacrificing the animals at 3, 6, 12, 24, 48, 72 and 168 h later. The PS was quantitated by extraction and fluorescence spectroscopy. For both the IC and free PS, peak tumour concentrations were reached at 24 h; however, the absolute concentrations for the IC were always higher (2- to 3-fold) than the free PS. Tumour to non-tumour ratios at 24 h for the IC were 6.8 for blood, 6.5 for liver, 7.2 for kidney, 5.7 for skin and 3.5 for intestine. Evaluation of viable tumour cells in ascites following in vivo PDT with a single light exposure demonstrated a dose-dependent relationship with fluence and IC concentration. However, there was significant treatment-related toxicity at all fluences. With multiple low-dose treatments, the percentage of viable tumour cells was also significantly reduced and there were no treatment-related deaths. These data suggest that, while photoimmunotherapy remains promising as a new treatment modality for ovarian cancers, careful quantitative dosimetry of both IC and light may need to be combined with multiple treatments (as with radiation therapy and chemotherapy) to control malignant disease yet maintain acceptable toxicity in vivo.

Animals↗
PubMed1998

Homogeneous immunoconjugates for boron neutron-capture therapy: design, synthesis, and preliminary characterization.

The application of immunoprotein-based targeting strategies to the boron neutron-capture therapy of cancer poses an exceptional challenge, because viable boron neutron-capture therapy by this method will require the efficient delivery of 10(3) boron-10 atoms by each antigen-binding protein. Our recent investigations in this area have been focused on the development of efficient methods for the assembly of homogeneous immunoprotein conjugates containing the requisite boron load. In this regard, engineered immunoproteins fitted with unique, exposed cysteine residues provide attractive vehicles for site-specific modification. Additionally, homogeneous oligomeric boron-rich phosphodiesters (oligophosphates) have been identified as promising conjugation reagents. The coupling of two such boron-rich oligophosphates to sulfhydryls introduced to the CH2 domain of a chimeric IgG3 has been demonstrated. The resulting boron-rich immunoconjugates are formed efficiently, are readily purified, and have promising in vitro and in vivo characteristics. Encouragingly, these studies showed subtle differences in the properties of the conjugates derived from the two oligophosphate molecules studied, providing a basis for the application of rational design to future work. Such subtle details would not have been as readily discernible in heterogeneous conjugates, thus validating the rigorous experimental design employed here.

Animals↗
PubMed1992

Potential use of immunoconjugates for AIDS therapy.

More than a dozen of hybrid proteins possessing reactivity with human immunodeficiency virus-type 1-(HIV-1) infected cells and cytotoxicity have been produced and studied by several groups. These proteins are prepared either by chemical cross-linking of a toxin and a carrier molecule or by expressing fused genes of the two moieties. These cytotoxic agents have been investigated to eliminate HIV-1-infected cells in vitro. The ID50 of these agents range from pM to nM. This article compares the results of the various approaches and discusses the limits and potential of immunoconjugates for AIDS therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Abeta-immunotherapy for Alzheimer's disease using mannan-amyloid-Beta peptide immunoconjugates.

In Alzheimer's disease (AD) the accumulation of pathological forms of the beta-amyloid (Abeta) peptide are believed to be causal factors in the neurodegeneration that results in the loss of cognitive function in patients. Anti-Abeta antibodies have been shown to reduce Abeta levels in transgenic mouse models of AD and in AN-1792 clinical trial on AD patients; however, the clinical trial was halted when some patients developed meningoencephalitis. Theories on the cause of the adverse events include proinflammatory "primed patients," a Th1-inducing adjuvant, and Abeta autoreactive T cells. New immunotherapy approaches are being developed to eliminate these putative risk factors. Mannan, which is recognized by pattern recognition receptors of the innate immune system, can be utilized as a molecular adjuvant to promote a Th2-mediated immune response to conjugated B cell epitopes. The N-terminus of Abeta was conjugated to mannan, and used to immunize mice with low concentrations of immunoconjugate, without a conventional adjuvant. Mannan induced a significant and highly polarized toward Th2 phenotype anti-Abeta antibody response not only in BALB/c, but also in B6SJL F1 mice. New preclinical trials in AD mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse immune response that occurred in the first clinical trial.

Alzheimer Disease↗
PubMed1988

Effects of anti-epidermal growth factor (EGF) receptor antibodies and an anti-EGF receptor recombinant-ricin A chain immunoconjugate on growth of human cells.

The effects of antiepidermal growth factor (EGF) receptor monoclonal antibodies (MAbs) 528 and 225 and a 528-ricin A conjugate on the growth of normal and malignant human cells were tested in vitro. Malignant human cell lines with EGF receptor numbers ranging from 0 to 4 X 10(5) receptors/cell, human fetal fibroblasts, and normal marrow granulocyte/macrophage progenitors (CFU-gm) showed no effect when grown with 10(-12) M to 10(-7) M MAb 225 or 528. MAbs 225 and 528 and EGF also had no effect on the ability of marrow stromal cells to maintain CFU-gm viability in long-term marrow cultures. Reversible growth inhibition of A431 epidermoid and MDA-468 breast carcinoma cells with 2 and 3 X 10(6) EGF receptors/cell, respectively, was observed with both antibodies and with 10(-8) M EGF. In contrast, an immunoconjugate prepared with MAb 528 and recombinant ricin A chain (528-rRA) showed dose-dependent killing over a concentration range of 10(-12) M to 10(-8) M against cells with greater than or equal to 1.2 X 10(5) EGF receptors/cell [concentration that causes 50% inhibition of growth (IC50) values, approximately 10(-12) M to 10(-10) M]. Human fetal fibroblasts (5.6 X 10(4) EGF receptors/cell), melanoma cells without detectable EGF receptors, and human CFU-gm showed IC50 values of greater than 10(-8) M. Killing of KB epidermoid carcinoma cells and 547 ovarian carcinoma cells with 4 and 1.2 X 10(5) EGF receptors/cell by 10(-10) or 10(-11) M 528-rRA was time dependent, but cytotoxicity to 547 cells was not complete even with 48 hours of immunotoxin treatment. Cytotoxicity of 528-rRA was not enhanced by chloroquine or verapamil. In vitro, anti-EGF receptor MAbs cause reversible antiproliferative effects only against malignant cell lines with amplified EGF receptor expression. In contrast, 528-rRA shows potent, specific toxicity to cells with greater than 50,000 EGF receptors/cell. However, kinetics of cell killing with 528-rRA are protracted, suggesting that prolonged exposure may be required for in vivo antitumor effects.

Antibodies, Monoclonal↗
PubMed1995

Phase I study of monoclonal antibody-ricin A chain immunoconjugate Xomazyme-791 in patients with metastatic colon cancer.

The immunoconjugate XMMCO-791/RTA consists of ricin A chain bound to a murine monoclonal antibody MoAb 791T. This monoclonal antibody (MoAb) binds to a glycoprotein of 72 kD, which is expressed on human colorectal carcinoma, ovarian carcinoma, and osteogenic sarcoma. XMMCO-791/RTA was tested in a Phase I trial with proposed dose escalation steps of 0.02, 0.04, 0.15, and 0.2 mg/kg per day. Twelve patients with metastatic colorectal carcinoma were treated at 0.02, 0.03, and 0.04 mg/kg per day dose levels administered over 1 hour on days 1-5. Study-related toxicities were hypotension (6 patients); greater than 10% weight gain (6 patients); peripheral edema (9 patients); fever (4 patients); confusion (3 patients); diarrhea (3 patients); proteinuria, as identified by dipstick (3 patients), greater than 0.6 mg/dl decrease in serum albumin (11 patients); greater than 25% decrease in oncotic pressure (10 patients), and a decrease in ionized calcium (8 patients). Six patients received a second course of treatment. HAMA levels developed in 9 patients and titers increased with number of courses administered. Decreased overall toxicity, in comparison to the first course, was noted, but one patient had an allergic-type response (hypotension, crushing chest pain, diaphoresis) after the test dose of the second course (HAMA level > 10,000 IgG). Life-threatening toxicity in the form of fluid shift, resulting in noncardiac pulmonary edema and third-spacing occurred after course 1 in 1 of 3 patients at the 0.04 mg/kg per day level. No further dose escalation was attempted and no antitumor activity was seen.

Adenocarcinoma↗
PubMed2000

Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model.

OBJECTIVE: To evaluate dose intensification with osmotic blood-brain barrier disruption (BBBD) and the potential use of drug targeting with monoclonal antibody (MAb) BR96 conjugated to doxorubicin (BR96-DOX, now called SGN15) for treatment of intracerebral and subcutaneous human LX-1 small cell lung carcinoma xenografts in rats. METHODS: LX-1 tumors with high, low, or heterogeneous levels of the Lewis(y) antigen for BR96 were evaluated. Rats were treated with intracarotid or intravenous BR96-DOX, with or without osmotic BBBD. RESULTS: Both BR96-DOX and MAb BR96 treatment resulted in significant regression of subcutaneous tumors, in contrast to control groups including doxorubicin alone, saline, or nonbinding doxorubicin immunoconjugate. BR96-DOX delivered with BBBD to brain tumors with low antigen expression resulted in significantly (P < 0.001) increased rat survival time compared with animals that received intravenous or intra-arterial BR96-DOX. CONCLUSION: The combination of an effective drug such as doxorubicin with a MAb to facilitate tumor-selective localization and osmotic BBBD to increase tumor delivery may have practical application in the clinic, because an increased delivery of drug to tumor can be obtained without increasing the dose of systemic drug.

Animals↗
PubMed1993

Evidence that an anthracycline-anti-CD8 immunoconjugate, idarubicin-anti-Ly-2.1, prolongs heart allograft survival in mice.

To examine the potential use of immunoconjugates of drugs and antibodies as immunosuppressive agents, mice were treated with a short course (4 days) of T-cell-specific anti-Ly-2.1 monoclonal antibody, or MAB conjugated to an anthracycline, idarubicin (IDA). The anti-Ly-2.1 MAB had no significant effect on the survival of BALB/c (Ly-2.2) heart allografts in CBA (Ly-2.1) mice, but was a potent immunosuppressive agent when coupled to IDA, with most grafts surviving for > 100 days following treatment with doses ranging from 10 to 120 micrograms IDA, covalently coupled to 1-8 mg MAB. IDA-MAB treated mice with long-surviving heart grafts showed donor-specific tolerance. They did not reject donor-type skin grafts (these survived for > 50 days), but rejected third-party skin in 10-14 days. Heart allografts in these mice survived for > 100 days. Allografts placed 30 days after treatment were rejected, showing a recovery of peripheral T cell function at this time. Newly derived thymic T cells were, however, not required for this recovery since adult thymectomized, IDA-MAB treated animals also recovered T cell function and rejected heart allografts. FACScan analysis of T cells from mice treated with 80 micrograms IDA-4 mg MAB, which had received a heart allograft, showed 95% T cell depletion in the spleen compared with ungrafted, IDA-MAB treated animals, and untreated controls with or without allografts. Splenic T cell depletion was however not significant in CBA mice immunosuppressed with the lower dose of 10 micrograms IDA-MAB. Thus rapid depletion of splenic T cells was not required for immunosuppression induced by IDA-MAB conjugates. However, the minor subpopulation of Ly-2+, which was activated by alloantigen while carrying IDA-MAB, may be depleted during the T cell response to the allograft, resulting in a state of alloantigen-specific tolerance in mice with long-surviving heart allografts.

Animals↗
PubMed1988

Radioimmunotherapy with alpha-particle-emitting immunoconjugates.

Alpha particles are energetic short-range ions whose higher linear energy transfer produces extreme cytotoxicity. An alpha-particle-emitting radioimmunoconjugate consisting of a bismuth-212-labeled monoclonal immunoglobulin M specific for the murine T cell/neuroectodermal surface antigen Thy 1.2 was prepared. Analysis in vitro showed that the radioimmunoconjugate was selectively cytotoxic to a Thy 1.2+ EL-4 murine tumor cell line. Approximately three bismuth-212-labeled immunoconjugates per target cell reduced the uptake of [3H]thymidine by the EL-4 target cells to background levels. Mice inoculated intraperitoneally with EL-4 cells were cured of their ascites after intraperitoneal injection of 150 microcuries of the antigen-specific radioimmunoconjugate, suggesting a possible role for such conjugates in intracavitary cancer therapy.

Alpha Particles↗