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PubMed1997

Preparation and biodistribution of copper-67-labeled porphyrins and porphyrin-A6H immunoconjugates.

The synthetic porphyrins, N-benzyl-5,10,15,20-tetrakis (4-carboxyphenyl) porphine (N-bzHTCPP) and N-4-nitrobenzyl-5-(4-carboxyphenyl)-10,15,20-tris(4-sulfophenyl) porphine (N-bzHCS3P), represent excellent radiocopper chelating agents that may find utility in antibody-mediated diagnosis and/or therapy. N-bzHCS3P was conjugated to an anti-renal cell carcinoma (RCC) antibody, A6H, and labeled with copper-67. 67CuCS3P-A6H was studied for its biodistribution in human RCC xenograft-bearing nude mice, along with the radiolabeled free porphyrins. The porphyrins resulted in tumor:blood ratios in the range of 3 to 4 after 48 h. The radiolabeled antibody achieved a tumor:blood ratio of over 16 after 45 h, indicating accumulation at the desired site. However, unwanted localization also occurred in the liver and spleen, which will have to be rectified before realizing the full potential of this approach.

Animals↗
PubMed1997

Tissue distribution and radiation dosimetry of astatine-211-labeled chimeric 81C6, an alpha-particle-emitting immunoconjugate.

A paired-label study was performed in athymic mice bearing subcutaneous D-54 MG human glioma xenografts to compare the localization of human/mouse anti-tenascin chimeric antibody 81C6 labeled by reaction with N-succinimidyl 3-[211At]astatobenzoate and N-succinimidyl 3-[131I]iodobenzoate. Over the 48-h observation period, the distribution of 211At- and 131I-labeled antibody were quite similar in tumor and normal tissues except stomach. These data were used to calculate human radiation doses for both intravenously and intrathecal administered 211At-labeled chimeric 81C6 using a quality factor of 5 for alpha-emissions.

Animals↗
PubMedDate not supplied

New hydrazone derivatives of adriamycin and their immunoconjugates--a correlation between acid stability and cytotoxicity.

New N-substituted hydrazine linkers were synthesized and their hydrazone derivatives of adriamycin were prepared. These functionalized adriamycin derivatives were conjugated with a monoclonal antibody, 5E9. The release rate of adriamycin from the hydrazones and from some of the conjugates was studied, and their relationship to the IC50's of the conjugate against 5E9-positive Daudi cells was investigated.

Antibodies, Monoclonal↗
PubMedDate not supplied

Preparation and properties of the immunoconjugate composed of anti-human colon cancer monoclonal antibody and mitomycin C-dextran conjugate.

Monoclonal antibody (mAb) A7, produced against human colon cancer, was conjugated with a polymeric prodrug of mitomycin C (MMC), the MMC-dextran conjugate with an anionic charge (MMCDan) and a molecular weight of 70,000. The amino groups were introduced into the MMCDan by reacting ethylenediamine with the carboxyl group in the spacer arm of the dextran bridge by a carbodiimide-catalyzed reaction. The coupling to mAb A7 was performed using SPDP. A 15 M excess of ethylenediamine produced an optimal MMCDan with amino groups, which resulted in a homogenous conjugate (A7-MMCD) with minimal formation of high-molecular-weight aggregates in about a 30% yield of both IgG and MMC. The molar binding ratio of IgG:dextran:MMC in A7-MMCD was estimated to be 1:1.2:40. A7-MMCD, having MMC prodrug properties, released active MMC with a half-life of 29.1 h and had an almost neutral electric charge under physiological conditions. A competitive binding assay using 125I-labeled A7 revealed that the A7-MMCD almost fully retained its antibody-binding activity. The cytotoxicity of A7-MMCD was assayed by determining the degree of inhibition of [3H]-thymidine in corporation in two different ways using the human colon cancer cell line SW1116. A 48-h continuous exposure test revealed that the pharmacological activity of MMC in A7-MMCD was completely preserved. In addition, A7-MMCD exhibited about a 14-fold greater cytotoxicity than MMCDan when the IC50 values determined using a 2-h pretreatment exposure system were compared. These results suggest that A7-MMCD could be useful in immunotargeting chemotherapy for colorectal cancer.

Antibodies, Monoclonal↗
PubMedDate not supplied

Application of monoclonal antibodies against cytosine deaminase for the in vivo clearance of a cytosine deaminase immunoconjugate.

The selective delivery of anticancer drugs to tumors vs normal tissue using targeted antibody-enzyme conjugates for prodrug activation is limited by the amount of drug generated by blood-borne enzyme. Clearance of non-tumor-associated conjugate would increase the tumor/blood conjugate ratio, and enable larger amounts of prodrugs to be administered. A method for clearing the monoclonal antibody (mAb) conjugate L6-cytosine deaminase (L6-CD) was established by using an antibody raised against CD. The mAb 102-26 was obtained by immunizing BALB/C mice with CD conjugated to keyhole limpet hemocyanin. 102-26 was able to precipitate purified CD from solution as assessed by radioimmune precipitation and recognized CD in Western blot analyses. Similar studies were used to establish that 102-26 also recognized CD when conjugated to the L6 and 1F5 mAbs. Selective removal of L6-CD from the circulation of nude mice bearing H2981 human lung adenocarcinoma (L6-antigen positive) was achieved by injecting 102-26 24 h after L6-CD administration. High T/B ratios were obtained by clearance of a L6-CD (38:1 compared to 1.3:1 without clearance).

Adenocarcinoma↗
PubMedDate not supplied

(6-Maleimidocaproyl)hydrazone of doxorubicin--a new derivative for the preparation of immunoconjugates of doxorubicin.

The (6-maleimidocaproyl)hydrazone of doxorubicin was synthesized and conjugated to several mAbs, including chimeric BR96, via a Michael addition reaction to thiol-containing mAbs. DTT reduction of disulfides present in the mAb was a reliable and general method for generating a consistent number of reactive SH groups. The conjugates, after purification by Bio-Beads, were free of unreacted linker and/or doxorubicin. All conjugates released doxorubicin under acidic conditions that mimic the lysosomal environment, while they were relatively stable at neutral pH. BR96 conjugates showed antigen-specific cytotoxicity.

Adenocarcinoma↗
PubMed1991

Xenogeneic monoclonal antibodies in the management of cancer: control of their in vivo immunogenicity and induction of specific unresponsiveness using an antibody-drug immunoconjugate.

A bispecific mouse monoclonal antibody (mAb) that recognises carcinoembryonic antigen (CEA) with one binding site and vinblastine (VLB) with the other was used, and its in vivo immunosuppressive effect specific for anti-mouse immunoglobulin (Ig) was studied. The antibody was incubated with VLB at a molar ratio (MR) of 1:1, and administered i.v. to rabbits. Control animals received either the MAb alone, or the MAb with VLB covalently linked (MR 1:1), or the parental anti-CEA with equimolar amount of VLB. Seven days later, the rabbit anti-mouse Ig primary response was measured, and found to be almost 55% reduced in the animals that received the VLB 'loaded' MAb. In vivo kinetics and stability experiments revealed that the T1/2 of the MAb was 68 +/- 5 h, whereas free VLB disappeared within minutes. It was concluded that as soon as the drug dissociates from the antibody's binding site, it is rapidly removed. This problem was overcome by subcutaneously implanting osmotic mini-pumps containing VLB. The pumps released the drug at a constant rate for a period greater than 1 week, saturating the antibody's binding site. Under these conditions rabbits developed 80% less anti-mouse Ig antibodies when the bispecific antibody was administered (compared with the parental anti-CEA). The immunosuppression observed was specific for the mouse Ig, under conditions compatible with the full clinical therapeutic potential of the MAb. In conclusion, these experiments show, that it is possible to develop hybrid antibodies that can act as a 'lethal bait' to any specific lymphocyte in vivo, thus preventing undesirable responses against the xenogeneic MAb.

Animals↗
PubMedDate not supplied

In vivo studies of whole ricin monoclonal antibody immunoconjugates for the treatment of murine tumours.

Ricin is a highly potent toxin which binds to cells via galactose binding sites on the B chain; the toxicity is manifest by the A chain and most studies with immunotoxins have used ricin A chain-antibody conjugates. We have previously described a method for the coupling of whole ricin to monoclonal antibody (MoAb) so that the galactose binding sites on the B chain are blocked; these conjugates are not non-specifically toxic. Whole ricin-MoAb conjugates were examined in vivo for their stability, clearance rates and toxicity, and these were compared with modified ricin-MoAb conjugates produced by periodate treatment of ricin. First, the biological half-life of whole ricin or modified ricin was determined and indicated that while ricin was rapidly cleared from the circulation (t 1/2 = 4.5 +/- 0.5 min) compared with modified ricin (t 1/2 = 17 +/- 1 min), covalent linkage of native ricin to MoAb increased the blood circulation time of the toxin (t 1/2 = 22 +/- 1 min). Immunotoxins synthesized with the Ly-2.1 MoAb using native or modified (deglycosylated) ricin were compared in vivo. In two different models anti-Ly-2.1 immunotoxins could be shown to be effective in vivo: (i) intraperitoneal tumours, thymomas grown in the peritoneal cavity could be completely eradicated by ricin-MoAb; (ii) subcutaneous tumours, mice with tumours approximately 0.75 cm in diameter received intravenous doses of the whole ricin-MoAb and a substantial reduction in tumour size was achieved. Thus whole ricin-antibody conjugates made with the galactose binding site blocked combine the advantage of high potency with high specificity (which was previously lacking in intact ricin conjugates) and can be successfully used in vivo to treat tumours.

Animals↗
PubMed1989

Cerebral distribution of immunoconjugate after treatment for neoplastic meningitis using an intrathecal radiolabeled monoclonal antibody.

A detailed autopsy and autoradiographic study was performed after the death of a patient undergoing intrathecal, antibody-guided irradiation for carcinomatous meningitis. The results demonstrated tumor cells infiltrating the surface meninges and a severe astrocytic reaction associated with oedema in the periventricular and brain stem subpial white matter. This was not seen in cortical or other gray matter structures. Autoradiographic examination correlated well, demonstrating isotope within the oedematous areas of the white matter in addition to the expected concentration in the leptomeningeal layers. These findings are discussed in the context of antibody binding to tumor tissue and the possible benefits conferred in the treatment of infiltrating tumor cells.

Antibodies, Monoclonal↗
PubMed1991

Tumor localization and in vivo antitumor activity of the immunoconjugate composed of anti-human colon cancer monoclonal antibody and mitomycin C-dextran conjugate.

The tissue distribution and in vivo antitumor activity of a novel monoclonal antibody-mitomycin C conjugate (A7-MMCD) composed of anti-human MAb A7 and MMC-dextran conjugate were investigated using tumor-bearing mice. A7-MMCD was prepared via an anionic dextran intermediate for the purpose of keeping the non-specific uptake by the reticuloendothelial system to a minimum. 111In-labeled A7-MMCD showed about a 5-times-greater accumulation in SW1116 (targeted tumor) than in S180 (non-targeted tumor) 48 h after injection, and produced a tumor-to-blood ratio which was 3 times higher in SW1116-bearing mice than in S180-bearing mice 96 h after injection. Accumulations in the liver, spleen, and kidney were also observed to some extent. Pharmacokinetic analysis revealed that A7-MMCD had nearly the same properties in the body as MMCDan (MMCD with an anionic charge), i.e., those of a negatively charged macromolecule. Both A7-MMCD and MMCDan had relatively similar tissue uptake rate indices for the liver and spleen. The tumor uptake rate index for SW1116 was about 2.5 times greater than that for S180, and the total amount of 111In-A7-MMCD accumulated in SW1116 was calculated to be approximately 5 times greater than the amount in S180. These results indicated that A7-MMCD could achieve site-specific targeting in the body. Furthermore, in the therapeutic experiment using SW1116 implanted subcutaneously, A7-MMCD suppressed tumor growth significantly, compared to free MMC and MMCDan. These results suggest that in designing an monoclonal antibody-drug conjugate via an intermediary, the physicochemical properties of intermediate macromolecules must also be taken into consideration to obtain a high degree of efficacy in vivo.

Animals↗
PubMed2004

In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells.

HuN901 is a humanized monoclonal antibody that binds with high affinity to CD56, the neuronal cell adhesion molecule. HuN901 conjugated with the maytansinoid N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), a potent antimicrotubular cytotoxic agent, may provide targeted delivery of the drug to CD56 expressing tumors. Based on gene expression profiles of primary multiple myeloma (MM) cells showing expression of CD56 in 10 out of 15 patients (66.6%) and flow cytometric profiles of MM (CD38(bright)CD45(lo)) cells showing CD56 expression in 22 out of 28 patients (79%), we assessed the efficacy of huN901-DM1 for the treatment of MM. We first examined the in vitro cytotoxicity and specificity of huN901-DM1 on a panel of CD56(+) and CD56(-) MM cell lines, as well as a CD56(-) Waldenstrom's macroglobulinemia cell line. HuN901-DM1 treatment selectively decreased survival of CD56(+) MM cell lines and depleted CD56(+) MM cells from mixed cultures with a CD56(-) cell line or adherent bone marrow stromal cells. In vivo antitumor activity of huN901-DM1 was then studied in a tumor xenograft model using a CD56(+) OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.

Animals↗
PubMed1993

A comparison of the detection sensitivity of lymphocyte membrane antigens using fluorescein and phosphor immunoconjugates.

In this study we compared the sensitivity of immunocytochemical procedures, using conventional and time-resolved fluorescent dyes, in a model system consisting of paraformaldehyde-fixed human lymphocytes. The lymphocytes were stained for the presence of the CD4 epitope by indirect immunofluorescence using FITC as label or by using time-resolved luminescent immunophosphors. These immunophosphors were primarily developed for use under time-resolved fluorescence conditions, but they are also very well suited for use in conventional fluorescence microscopes. The differently labeled cells were first examined visually with a conventional fluorescence microscope in a double-blind study. The fluorescence was also measured with a CCD camera mounted on a specially constructed time-resolved fluorescence microscope which allows the suppression of the fast decaying fluorescence, thereby permitting visualization of the specific, slowing decaying luminescence of the phosphor label. With this microscope FITC and immunophosphor labeled lymphocytes were compared under normal conditions (i.e., continuous excitation) and under conditions of time-resolved registration. Conventional fluorescence microscopy revealed a better sensitivity in favor of the phosphor conjugates. This difference became more prominent when the preparations were quantitatively assessed with the CCD-time-resolved microscope. Time-resolved microscopy permitted a suppression of fast decaying fluorescence better than 1 to 10(6).

CD4 Antigens↗
PubMed2001

Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells.

Antibody-targeted chemotherapy is a promising therapy in patients with acute myeloid leukemia (AML). In a phase II study of Mylotarg (CMA-676, gemtuzumab ozogamicin), which consists of a CD33 antibody linked to calicheamicin, saturation and internalization by leukemic and normal myeloid cells were analyzed in 122 patients with relapsed AML. Peripheral blood samples were obtained just before and 3 and 6 hours after the start of the first and second Mylotarg treatment cycles. Within 3 to 6 hours after infusion, near complete saturation of CD33 antigenic sites by Mylotarg was reached for AML blasts, monocytes, and granulocytes, whereas Mylotarg did not bind to lymphocytes. Saturation levels prior to the start of the second Mylotarg treatment cycle were significantly increased compared with background levels before the start of the first cycle. This apparently was caused by remaining circulating Mylotarg from the first treatment cycle (approximately 2 weeks earlier). On binding of Mylotarg to the CD33 antigen, Mylotarg was rapidly internalized, as determined by the decrease in maximal surface membrane Mylotarg binding. Internalization of Mylotarg was also demonstrated in myeloid cells in vitro and was confirmed by confocal laser microscopy. In vitro studies using pulse labeling with Mylotarg showed a continuous renewed membrane expression of CD33 antigens, which can significantly increase the internalization process and thereby the intracellular accumulation of the drug. Finally, Mylotarg induced dose-dependent apoptosis in myeloid cells in vitro. These data indicate that Mylotarg is rapidly and specifically targeted to CD33(+) cells, followed by internalization and subsequent induction of cell death.

Adult↗
PubMed1991

Clinical evaluation of intraperitoneal Pseudomonas exotoxin immunoconjugate OVB3-PE in patients with ovarian cancer.

OVB3-PE is an immunotoxin composed of a murine monoclonal antibody reactive with human ovarian cancer and conjugated to Pseudomonas exotoxin (PE). Twenty-three patients with refractory ovarian cancer were treated intraperitoneally (IP) with escalating doses of OVB3-PE to study toxicity, pharmacokinetics, antiimmunotoxin antibody formation, and antitumor response. Dose-limiting CNS toxicity occurred after repeated doses at 5 and 10 micrograms/kg. Other non-dose-limiting toxicities included transient elevation of liver enzymes, fever, and gastrointestinal toxicity. Pharmacokinetics of IP and serum OVB3-PE were determined in 16 patients. Peak peritoneal fluid levels exceeded the in vitro median effective dose at all doses tested. At doses of 1 to 2 micrograms/kg, the immunotoxin concentration in the peritoneal fluid remained constant for up to 8 hours and dropped to negligible levels after 12 hours. At the 5 and 10 micrograms/kg doses, levels remained high for up to 24 hours (greater than 100 ng/mL) and then gradually decreased and became undetectable (less than 4 ng/mL) after 72 hours. Serum levels of OVB3-PE were also analyzed in 16 patients. At doses of 1 micrograms/kg and 2 micrograms/kg, serum levels were not detectable (less than 5 ng/mL). However, after doses of 5 or 10 micrograms/kg, peak serum level occurred at 24 hours after each dose and dropped to negligible levels by 72 hours. Sera from 12 patients were analyzed for anti-PE antibodies and antibodies to mouse immunoglobulin (HAMA). All patients developed antibodies against PE within 14 days of therapy. Domain II of PE appeared to be the most immunogenic portion of the PE molecule. HAMA was detected on day 14 of therapy in nine patients, on day 21 in two, and on day 28 in one patient. No clinical antitumor responses were observed. We conclude that IP OVB3-PE at dose levels of 5 micrograms/kg (x 3) and 10 micrograms/kg (x 2) is accompanied by dose-limiting toxic encephalopathy. Neurologic toxicity is likely to be due to crossreactivity of OVB3 to normal human brain tissue, which was not appreciated during preclinical screening.

ADP Ribose Transferases↗
PubMed2000

Phase I trial of the anti-Lewis Y drug immunoconjugate BR96-doxorubicin in patients with lewis Y-expressing epithelial tumors.

PURPOSE: We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Dox), a chimeric anti-Lewis Y (Le(Y)) monoclonal antibody conjugated to doxorubicin, in patients whose tumors expressed the Le(Y) antigen. The study aimed to determine the toxicity, maximum-tolerated dose, pharmacokinetics, and immunogenicity of BR96-Dox. PATIENTS AND METHODS: This was a phase I dose escalation study. BR96-Dox was initially administered alone as a 2-hour infusion every 3 weeks. The occurrence of gastrointestinal (GI) toxicity necessitated the administration of BR96-Dox as a continuous infusion over 24 hours and use of antiemetics and antigastritis premedication. Patients experiencing severe GI toxicity underwent GI endoscopy. All patients underwent restaging after two cycles. RESULTS: A total of 66 patients predominantly with metastatic colon and breast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a maximum dose of 875 mg/m(2) (doxorubicin equivalent, 25 mg/m(2)) administered every 3 weeks. Toxicity was reversible and generally of short duration. Premedication with the antiemetic Kytril (granisetron hydrochloride; SmithKline Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m(2) BR96-Dox (doxorubicin equivalent, 19 mg/m(2)) every 3 weeks was determined to be the optimal phase II dose when administered with antiemetic and antigastritis prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohistochemically and by confocal microscopy. At the 550-mg/m(2) dose, the half-life (mean +/- SD) of BR96 and doxorubicin was 300 +/- 95 hours and 43 +/- 4 hours, respectively. BR96-Dox elicited a weak immune response in 37% of patients. Objective clinical responses were seen in two patients. CONCLUSION: BR96-Dox provides a unique strategy to deliver doxorubicin to Le(Y)-expressing tumor and was well tolerated at doses of 700 mg/m(2) every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.

Adult↗
PubMed1992

New application of human tumor clonogenic assay to in vitro evaluation of tumor-targeting efficiency of immunoconjugates.

This report proposes an efficient in vitro method for the evaluation of drug targeting with monoclonal antibody as a carrier to tumor cells. Monoclonal antibody (35G; IgG2a) selectively binding to alpha-fetoprotein (AFP) from human hepatoma cells (HuH-7) was conjugated with an anticancer drug, vindesine (VDS). Human tumor clonogenic assay (HTCA) with some modifications was applied to estimate the targeting efficiency of a conjugate (VDS-35G) for the first time. In this assay, VDS-35G was cytotoxically active against HuH-7 cells at a lower concentration (0.5 ng/ml) and for a shorter contact time than VDS (50 ng/ml), while 35G and VDS-normal mouse immunoglobulin conjugate (VDS-n-IgG) were not active against the cells. Both VDS-35G and VDS-n-IgG were inactive against HuH-13 cells established from a human hepatocellular carcinoma producing no AFP. In the conventional monolayer culture assay (MCA), VDS-35G showed little effect on HuH-7 cells at the concentration effective in HTCA. The cytotoxic activity of VDS in MCA was similar to that in HTCA but the cytotoxic activity of VDS-35G in MCA was considerably different from that in HTCA. This discrepancy could be explained by the hypothesis that VDS-35G was directed at stem cells of the HuH-7 cell population sensitively and selectively. HTCA was shown to be a useful in vitro evaluation method for drug targeting.

Animals↗