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PubMedDate not supplied

Paclitaxel immunoconjugate for the specific treatment of ovarian cancer in vitro.

A paclitaxel derivative was used for the preparation of a drug immunoconjugate for the specific targeting to ovarian cancer cells by the BCM43/2E5 monoclonal antibody. To determine the efficiency of conjugation we developed two reproducible immunoassays. Paclitaxel was detected on the conjugate by a paclitaxel immunoassay and the activity of the antibody was determined by a competition assay with BCM43/2E5 antibody. Paclitaxel-BCM43/2E5 immunoconjugate was tested on five human cell lines. This conjugate was cytotoxic for ovarian teratocarcinoma cells, ovarian adenocarcinoma and breast cancer cells, while the activity was negligible for normal cells. These results describe, for the first time, the synthesis of a soluble tumor specific- paclitaxel immunoconjugate which may establish a new mode for the use of this drug in cancer therapy for limiting side effects.

Antibodies, Monoclonal↗
PubMed2000

Chemical conjugation of a novel antibody-interleukin 2 immunoconjugate against c-erbB-2 product.

OBJECTIVE: To develop a new chemical method to produce a monoclonal antibody (MoAb) 520C9/recombinant human interleukin 2 (rhIL-2) conjugate. METHODS: MoAb 520C9 reactive with the protooncogene c-erbB-2 product P185 was chemically conjugated with rhIL-2 by using a simple two-step method. First, the rhIL-2 was activated by Sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate, a heterobifunctional linker, and N-succinimidyl s-acetylthioacetate was introduced onto 520C9. Then SATA on the 520C9 was reacted with the maleimide group on the activated rhIL-2 to generate 520C9-rhIL-2 immunoconjugate. RESULTS: The immunoconjugate retained the antigen binding activity compared to the respective native antibody as determined by an indirect live cell binding assay. The immunoconjugate also possessed IL-2 activity as measured by the standard CTLL-2 cells proliferation assay and the stimulation of human peripheral blood mononuclear cells (PBMCs) into lymphokine-activated killer cells. CONCLUSION: Our method of conjugation of rhIL-2 to 520C9 preserves the binding activity of the antibody and the cytokine function of IL-2. This simple and efficient method of conjugation should be applicable to other types of MoAbs and recombinant cytokines.

Animals↗
PubMed1994

A pilot study of anti-CD5 ricin A chain immunoconjugate in systemic lupus erythematosus.

OBJECTIVE: To determine the safety and clinical and biological effects of a murine monoclonal anti-CD5 ricin A chain immunoconjugate (CD5 Plus) in patients with systemic lupus erythematosus (SLE). METHODS: An open label phase I study of CD5 Plus. A dose of 0.1 mg/kg was administered intravenously on 5 consecutive days. A second course of immunoconjugate was given to patients who failed to show any clinical response one to 2 months later. RESULTS: Six patients (4 with glomerulonephritis and 2 with thrombocytopenia) were studied. Improvement was documented in 2 patients with nephritis; no effect on thrombocytopenia was observed. Adverse effects were mild and transient. Relative to pretreatment lymphocyte counts, the mean reduction in CD3+ T cell count was 69% at 2 weeks, 32% at one month, and 34% at 6 months following initial treatment. A comparable decrease in all subpopulations of mature T cells was noted, using a variety of surface markers, including CD4 and CD8. The mean percentage of T cells expressing the activation markers HLA-DR and interleukin 2R (IL-2R) was high before treatment, and remained so. There was a transient decrease in CD5+ B cells, but no persistent depletion of total B cell numbers. There was no consistent change in natural killer cell populations. CONCLUSION: Anti-CD5 ricin A chain immunoconjugate is well tolerated in patients with SLE, causes modest T cell depletion which may persist for months, and may have some clinical efficacy in lupus nephritis.

Antibodies, Monoclonal↗
PubMed1994

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.

Antibodies, Monoclonal↗
PubMed1992

Sn-chlorin e6 antibacterial immunoconjugates. An in vitro and in vivo analysis.

Monoclonal antibody-Sn-chlorin e6 immunoconjugates were prepared by the site-selective covalent modification of the monoclonal oligosaccharide moiety. By carefully controlling the reaction conditions and introducing triethanolamine groups as axial ligands of the Sn moiety, conjugates with in vivo biodistribution properties similar to underivatized IgG were prepared. By varying the reaction conditions, conjugates were reproducibly prepared with a range of photosensitizer to mAb molar ratios from 1.6 to 10. Based on a competitive inhibition radioimmunoassay, conjugates prepared by this method showed selectivity and binding affinity comparable to the unmodified antibody. The immunoconjugates had only slightly lower singlet oxygen yields than that observed with the Sn-chlorin e6 precursor indicating that negligible aggregation or structural modification of the chromophores occurred during the synthesis process. In vitro cell killing experiments demonstrated that all conjugates possessed significant cytotoxic activity. Biodistribution studies in mice showed that conjugates prepared with axial ligands had significant serum retention 24 h after injection while conjugates prepared without the triethanolamine ligand were much more rapidly cleared. In vivo specificity was demonstrated using rats infected with Fisher immunotype I P. aeruginosa at a site in the left posterior thigh muscle. Target to background ratios exceeded 60 at 120 h after conjugate injection of the specific immunoconjugate, compared to a ratio of only 6 for a non-specific mouse IgG conjugate. Biodistribution patterns at 120 h post injection indicate that the conjugates were both biologically active and structurally intact.

Animals↗
PubMed1993

Efficacy of an anti-CD5-ricin A chain immunoconjugate in an improved human peripheral blood lymphocyte--reconstituted severe combined immunodeficient mouse model.

Severe combined immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID mice) were used to evaluate in vivo efficacy of a mouse IgG1 monoclonal antibody (mAb)-ricin toxin A chain immunoconjugate (H65-RTA) directed against the CD5 cell surface antigen present on human T-cells. Initial studies demonstrated that plasma levels of human soluble interleukin-2 receptor (sIL-2R) are predictive of human T-cell engraftment in spleens and blood of SCID mice transplanted with human PBL. Therefore, chimeric mice with detectable plasma levels of human sIL-2R were used in subsequent studies. Systemic injection of such mice with H65-RTA resulted in a significant depletion of human T-cells from spleens, blood and bone marrow, and a decrease in plasma levels of human sIL-2R as compared to vehicle-treated control animals. The effect of H65-RTA was dose-dependent, treatment schedule-dependent, and mAb-specific, as an isotype-, linker- and toxin-matched immunoconjugate of irrelevant binding specificity was not efficacious. Moreover, human T-cells remained depleted from SCID tissues for at least 10 days after cessation of H65-RTA treatment, indicating that the cells were killed by the immunoconjugate. Unconjugated H65 mAb and an H65-derived F(ab')2-RTA conjugate, but not unconjugated F(ab')2, were also efficacious, suggesting that the Fc portion of the mAb and the toxin moiety may both play a role in the mechanism of human T-cell depletion by H65-RTA in this model. Results indicate that the hu-PBL-SCID mouse model can be used to compare in vivo efficacy of immunosuppressive agents specifically directed against human T-cells.

Animals↗
PubMedDate not supplied

Immunoconjugate design: a predictive approach for coupling of daunomycin to monoclonal antibodies.

There is increasing interest in the development of daunomycin-antibody immunoconjugates for the targeting of drug to specific cells or tissues. To this end, we have examined the factors influencing the synthesis of daunomycin-monoclonal antibody conjugates linked covalently by an acid-labile cis-aconitic spacer (which is considered to aid drug release from immunoconjugates in the lysosomes and thus enhance their cytotoxic potential). A rapid and efficient procedure for the purification of drug from contaminants and stabilizers was first developed; conditions for the optimal preparation of cis-aconityldaunomycin were established; products were analyzed and identified by TLC and HPLC. The coupling of cis-aconityldaunomycin to antibody was accomplished by activating the modified drug with a carbodiimide before addition to antibody. Several factors were identified which influenced the efficiency of the conjugation; in particular, the compositional features of the antibody which determine its electrophoretic charge characteristics were of profound effect. However, by appropriate choice and control of buffer pH during conjugation, it was possible to define conditions resulting in the controlled substitution of antibody with drug. The consequent effects upon the cell-binding activity of immunoconjugates were established and related to the extent of substitution. The procedures described enable appropriate reaction conditions to be selected for the linkage of daunomycin to antibody (at set drug/antibody molar ratios) and in good yield, based upon consideration of the compositional and charge properties of the antibody.

Antibodies, Monoclonal↗
PubMed1993

Phase I/II study of murine monoclonal antibody-ricin A chain (XOMAZYME-Mel) immunoconjugate plus cyclosporine A in patients with metastatic melanoma.

XOMAZYME-Mel (XMMME-001-RTA) is an immunoconjugate comprised of ricin A chain conjugated to a murine monoclonal antibody directed against high molecular weight melanoma antigens. Although not necessarily related to increased toxicity or decreased efficacy, the development of anti-immunoconjugate antibodies may limit repetitive dosing with an immunoconjugate. We evaluated the role of cyclosporine A in blocking the antibody response in patients with melanoma treated with XMMME-001-RTA. Patients received cyclosporine in divided daily doses to achieve serum levels by HPLC of 150-200 ng/ml on days 1-22. On day 3, XMMME-001-RTA was begun at dosages 0.2-0.6 mg/kg daily for 5 days. Treatment was repeated every 35 days. Three patients were treated in each dosage tier (0.2, 0.4, 0.6 mg/kg). Nine patients were entered and all nine were evaluable. Patients had histologically confirmed melanoma. Metastatic sites included skin, soft tissue, and lymph nodes (seven), lung (two), liver (one), and spleen (one). There were four men and five women aged 46-75 years. Toxicities included myalgia, arthralgia, hypoalbuminemia, fatigue, elevations in liver function tests, and increased peripheral edema. Four patients received two to five repeated dosages of XMMME-001-RTA. One wheal-and-flare reaction from an immunotoxin test dose of XMMME-001-RTA was noted after five cycles. After a test dose subsequent to one cycle, two patients experienced chest tightness without ECG changes and were removed from the study. All toxicities resolved without sequelae. One patient experienced partial lymph node remission for 9 months. A second patient had stable mediastinal disease for 20 months. XMMME-001-RTA is safe when given repeatedly with cyclosporine.

Aged↗
PubMed1991

Monoclonal antibody 44-3A6 doxorubicin immunoconjugates: comparative in vitro anti-tumor efficacy of different conjugation methods.

Doxorubicin (Dox) was coupled by four published methods to a murine monoclonal antibody (MAb) developed against human pulmonary adenocarcinoma. Dox immunoconjugates made with this murine IgG1 MAb, 44-3A6, were evaluated for anti-tumor activity against the human lung cancer cell line, A549. Dox was attached to the MAb (1) by an oxidized dextran T40 intermediate, (2) using dilute glutaraldehyde cross-linking, (3) with an acid-sensitive linker using cis-aconitic anhydride and EDCI, a water-soluble carbodiimide, and (4) using EDCI alone. The biological activity of the different conjugates was compared in vitro by antigen binding (whole-cell RIA) versus serial dilutions of unconjugated MAb cytotoxicity (dye exclusion/viability) versus long dilutions of the various Dox conjugates, Dox and mixtures of Dox and MAb. Preincubation of antigen-expressing tumor cells (A549) for 2 h with excess (250 micrograms/ml) unconjugated MAb prior to conjugate exposure was attempted in order to block the cytotoxic effect. The number of Dox molecules conjugated to 44-3A6 (molar incorporation ratio or MIR) ranged from 3 to 10/1 for carbodiimide linkage and up to 63/1 using the dextran intermediate. Cis-aconityl-derivatized Dox conjugates contained an average of 22 mol Dox/mol immunoglobulin, but drug incorporation was quite variable from experiment to experiment. Dilute glutaraldehyde cross-linking produced an average MIR of 10/1. After repeated attempts to minimize drug and/or MAb precipitation, the percentage decrease (versus MAb) in immunoreactivity of the drug conjugates ranged from 2 to 42% and was dependent on the coupling method and extent of aggregate formation in the preparation. Loss of biological activity (antigen binding and cytotoxicity) was significant when aggregation and precipitation occurred. There were additional losses (17-25%) after sterile filtration through low protein-binding (0.22 microns) filters. Immunoconjugates produced by glutaraldehyde cross-linking were reproducibly 5-10 times more potent against antigen-bearing tumor cells than Dox, and showed selectivity for inhibiting the viability of antigen-positive A549 cell line. Noncovalent mixtures of 44-3A6 and Dox were slightly more potent than Dox. Immunoconjugates produced by the aconityl method and the dextran intermediates were less effective than Dox, the glutaraldehyde-mediated conjugates or Dox and 44-3A6 mixtures. The unconjugated MAb was not cytotoxic when tested at concentrations up to 500 micrograms/ml. Blocking studies using 'cold', unlabeled MAb were of limited success.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1996

Absence of lysosomal cleavage in the cytotoxicity mechanism of an immunoconjugate composed of anti-alpha-fetoprotein monoclonal antibody and vindesine analog.

The effect of lysosomal enzyme inhibition on the cytotoxic activity of an immunoconjugate composed of anti-alpha-fetoprotein monoclonal antibody and vindesine analog (VDS) was studied in vitro using human tumor clonogenic assay (HTCA). Addition of the lysosome enzyme inhibitors, leupeptin and ammonium chloride, to the HTCA system had little influence on the cytotoxicity of this immunoconjugate. In separate experiments, no released VDS was detected by HPLC after incubation with the supernatant of rat liver homogenate without inhibitor. These results show that the immunoconjugate may bypass the lysosomal process and exert its activity as an intact or similar form.

Ammonium Chloride↗
PubMedDate not supplied

Selective cytotoxicity of adriamycin immunoconjugate of monoclonal antibody MSN-1 to endometrial adenocarcinoma in vitro and in vivo.

Missile therapy, which destroys cancer cells specifically, has been regarded as an effective treatment modality for carcinoma. The monoclonal antibody MSN-1 (IgM), which reacts strongly with endometrial adenocarcinomas, was combined with adriamycin (ADM) by a disulfide bond using N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) and 2-iminothiolane. Its selective cytotoxicity against SNG-II was examined in a colony formation in vitro, and on athymic mice in vivo. The results of our study suggest that the or IC50, of the MSN-1-ADM immunoconjugate against SNG-II to be 57 times that of ADM alone in vitro. The reductions in resected weights of target tumor cells, at the local site of the MSN-1-ADM immunoconjugate treatment, were 25% with caudal vein administration, and 38% with local administration, as compared with the untreated group, in vivo. There was no weight loss in treated mice. Our results suggest that this MSN-1-ADM immunoconjugate has potential clinical application in the treatment of endometrial adenocarcinomas.

Adenocarcinoma↗
PubMed1990

Immunohistochemical and pharmacokinetic characterization of the site-specific immunoconjugate CYT-356 derived from antiprostate monoclonal antibody 7E11-C5.

In this study, a site-specific immunoconjugate, designated CYT-356, of the prostate-reactive monoclonal antibody 7E11-C5 was characterized by immunohistological methods for reactivity with normal and neoplastic human tissues. In addition, CYT-356 labeled with 111In was assessed by in vivo imaging and pharmacokinetic studies for localization to human tumor xenografts in nude mice. The native antibody and the site-specific immunoconjugate exhibited similar patterns of reactivity with normal human tissues. Although the majority of tissues tested were negative, weak reactivity with cardiac muscle, proximal kidney tubules, and sweat glands was observed. Positive staining of normal prostate epithelial cells and glandular lumina and strong reactivity with a subset of skeletal muscle cells were also observed. CYT-356 reacted with 100% of prostate tumors examined but was negative on a variety of other neoplasms. Following i.v. administration, CYT-356-111In rapidly localized to and imaged LNCaP human prostate adenocarcinoma xenografts in nude mice, reaching maximal levels of about 30% of injected dose/g of tumor within 3 days. No unusual localization was seen to any nontumor tissue or organ; the level of radioactivity in the normal tissues and organs was at or below that seen in the blood. The localization to xenografts was antigen specific and the accessible binding sites in 100-200-mg tumors appeared to be saturated at an antibody dose between 10 and 100 micrograms. These findings suggest that the CYT-356 immunoconjugate may be useful in the diagnosis and therapy of prostate cancer.

Animals↗
PubMed1991

Epidermal growth factor receptor-reactive monoclonal antibodies: xenograft antitumor activity alone and as drug immunoconjugates.

Antibodies reactive with human epidermal growth factor receptor (EGFr), such as 225 IgG1 (Masui et al., Cancer Res., 44: 1002-1007, 1984), are effective tumor-suppressive agents in xenograft models. In the present study an additional antibody reactive with EGFr was made and compared to 225 IgG1 for antitumor activity as an unmodified antibody or as a drug immunoconjugate. This IgG1 clone, designated EGFrL11, competed with EGF and immunoprecipitated a Mr 178,000 protein identical to that immunoprecipitated with 225 IgG1. Cross-competition and immunodepletion studies indicated that the two antibodies bound to distinct epitopes on the same molecule. Immunofluorescence studies confirmed that the EGFrL11 epitope was expressed on the surface of viable human squamous cell carcinoma lines including T222. Unmodified EGFrL11 and 225 IgG1 were tested for antitumor activity in T222 xenografts. At a dose of 81 mg/kg given twice weekly for 3 weeks, tumor suppression, but not regression, occurred with EGFrL11. A similar result was obtained with 225 IgG1. To gauge the potential of these antibodies as immunoconjugates, both were tested for antitumor activity in the T222 model after conjugation to the Vinca derivative 4-desacetylvinblastine-3-carboxhydrazide. Both immunoconjugates completely regressed established tumors. These data suggest that Vinca conjugates with EGFr-reactive monoclonal antibodies warrant further investigation as possible clinical candidates.

Animals↗
PubMed1990

In vivo selection of human tumor cells resistant to monoclonal antibody-Vinca alkaloid immunoconjugates.

UCLA-P3 human lung adenocarcinoma cells were grown in nude mice and given repetitive treatments of a monoclonal antibody-Vinca alkaloid immunoconjugate. Although this therapy resulted in a greater than 4-fold reduction in mean tumor mass of the established tumors, some animals experienced a reinitiation of tumor growth after cessation of conjugate treatment. Two such animals were treated again with high doses of monoclonal antibody-Vinca but one of the tumors was no longer regressed by the drug conjugate. The tumor was excised, enzymatically dissociated, and grown in tissue culture. Cultured cells were reimplanted in nude mice and subjected to further therapy with a monoclonal antibody-Vinca conjugate. The resulting tumors were also refractory to the immunoconjugate therapy. This cycle was repeated for a total of three times and resulted in the serial in vivo selection of three conjugate resistant variants. The mechanism responsible for the in vivo resistance of human tumor cells to the monoclonal antibody-Vinca immunoconjugate is unknown but does not appear to involve antigen modulation, altered tumor cell growth rate, or an apparent decrease in tumor targeting in vivo. The resistance was also not accompanied by any detectable elevation in multidrug resistance 1 mRNA or P-glycoprotein expression. Significantly, the resistance pattern was observed only in vivo and was not maintained by cells grown in vitro.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Immunoconjugates containing ricin A chain and either human anti-gp41 or CD4 kill H9 cells infected with different isolates of HIV, but do not inhibit normal T or B cell function.

We have previously reported that immunoconjugates composed of deglycosylated ricin A chain coupled to either recombinant (r) CD4 or two different monoclonal human anti-gp41 antibodies (rCD4-dgA and anti-gp41-dgA, respectively) are specifically toxic to HIV-infected lines of human T cells (H9) and monocytes (U937). In order to further evaluate these immunoconjugates as potential therapeutic reagents for killing HIV-infected cells, H9 cells infected with five different isolates of HIV were used as target cells in vitro. All three HIV-specific immunoconjugates were toxic to H9 cells infected with each HIV isolate, but were virtually nontoxic to uninfected cells. Chloroquine markedly potentiated the specific toxicity of all three conjugates, particularly the anti-gp41-dgAs. None of the conjugates affected the ability of normal peripheral blood B cells to respond to mitogen or the ability of normal T cells to respond to alloantigens.

Antibodies, Monoclonal↗
PubMed1990

Antitumor activity of the monoclonal antibody-Vinca alkaloid immunoconjugate LY203725 (KS1/4-4-desacetylvinblastine-3-carboxhydrazide) in a nude mouse model of human ovarian cancer.

The activity of the conjugate of monoclonal antibody KS1/4 with 4-desacetylvinblastine-3-carboxhydrazide (KS1/4-DAVLB-HY) was explored in the OVCAR-3 human ovarian xenograft tumor model. Multiple schedules of KS1/4-DAVLB-HY administration were employed, including a comparison of i.p. and i.v. routes of treatment. When inoculates of 6 x 10(7) OVCAR-3 cells were injected i.p. into female athymic nude mice, untreated control animals had a mean survival of 18-34 days, with the development of massive ascites and large intraabdominal tumors. Significant increases in survival were observed in KS1/4-DAVLB-HY conjugate-treated animals with all schedules utilized. Parallel therapy with equivalent doses of free DAVLB-HY or a non-antigen-binding immunoconjugate did not significantly increase the survival of the animals. These data demonstrate that the immunoconjugate KS1/4-DAVLB-HY significantly increases the survival of OVCAR-3 tumor-bearing mice and indicates that this immunoconjugate may be useful in the treatment of human ovarian cancer.

Animals↗
PubMed1994

Gelonin analogs with engineered cysteine residues form antibody immunoconjugates with unique properties.

We engineered the ribosome inactivating-protein gelonin (Gel) to generate a family of Gel analogs, each with a single unpaired cysteine residue. The cysteine sites coincide with surface-accessible loops in the probable three-dimensional structure of Gel, or with the positions of endogenous cysteine residues. In most cases, enzymatic activity in vitro was unaltered by this modification. The rGel analogs were conjugated via their unpaired cysteine residue to the anti-CD5 antibody H65, or to H65 Fab and F(ab')2. Several rGel analogs formed immunoconjugates that were up to 6-fold more cytotoxic to antigen-bearing cells than those made with linker-modified rGel, whereas others were less potent. In the rat, the in vivo clearance rates of whole antibody conjugates correlated with their relative in vitro disulfide bond stability, and deconjugation to intact antibody and rGel was the predominant clearance mechanism. Fab conjugates to rGel analogs which differed in their in vitro disulfide bond stability had similar serum clearance rates, suggesting that clearance occurs mainly by removal of intact immunoconjugate from the serum, and is less dependent on deconjugation. Our results demonstrate that rGel analogs with a single cysteine at various positions on the solvent exposed surface are produced efficiently in Escherichia coli (>1 g/liter), and that the position of the cysteine greatly influences the potency and stability of the resulting immunoconjugates.

Amino Acid Sequence↗
PubMed1997

Biodistribution of iodine-125 labeled monoclonal antibody/interleukin-2 immunoconjugate in athymic mice bearing human tumor xenografts.

BACKGROUND: Some vasoactive drugs have been studied in the hope of altering the vascular permeability and/or blood of tumors to enhance monoclonal antibody (MoAb) uptake. The pretreatment of interleukin-2 (IL-2), one of the vasoactive reagents, produced a generalized vascular permeability, but its function was not tumor specific. Conversely, MoAb/IL-2 immunoconjugates were developed that selectively alter the vasopermeability of tumors. In the current study the authors evaluated whether radiolabeled anti-carcinoembryonic antigen (CEA) MoAb, ZCE025/IL-2 immunoconjugate, specifically can enhance delivery of iodine-125 (I-125) to tumor sites. METHODS: ZCE025 was conjugated with IL-2, and the conjugate then labeled with I-125. Biodistribution studies were performed in athymic mice bearing CEA-producing human tumor (MKN45) xenografts. Mice were injected with I-125-ZCE025/IL-2 conjugate, and I-125 activities in the organs, including blood and tumor, were investigated at 1, 3, and 5 days after injection. Vascular permeability of the organs, including tumors, also was studied by using I-131 labeled mouse serum albumin in three groups. RESULTS: I-125 labeled ZCE025/IL-2 conjugate destroyed its lymphokine-activated killer cell (LAK) activation, but retained a minimum of 75% of the antibody binding reactivity. Biodistribution of I-125-ZCE025/IL-2 conjugate showed increased uptake of I-125 in tumor by a factor of 1.5, 4.2, and 4.1 compared with I-125-ZCE025 on Days 1, 3, and 5, respectively. In contrast, I-125 distribution was not enhanced in any organs except the tumor. Vascular permeability studies demonstrated that the physiologic effect of IL-2 was tumor specific in the mice that received the I-125-ZCE025/IL-2 conjugate. CONCLUSIONS: These studies indicate that the administration of radiolabeled MoAb/IL-2 double conjugate may enhance the therapeutic potential of radiolabeled MoAb without any pretreatment with IL-2 or repeated injection of MoAb.

Animals↗