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At least 271 records · Page 15Linked to original sources
PubMed1997

Effect of linker variation on the stability, potency, and efficacy of carcinoma-reactive BR64-doxorubicin immunoconjugates.

The internalizing anti-Le(y) monoclonal antibody (MAb) BR64 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to the DOX and either a disulfide or thioether bond to the MAb. The resulting disulfide (BR64-SS-DOX) and thioether (BR64-S-DOX) conjugates were evaluated for stability, potency, and antigen-specific activity in both in vitro and in vivo model systems. The BR64-SS-DOX conjugates demonstrated antigen-specific activity both in vitro and when evaluated against antigen-expressing, DOX-sensitive human carcinoma xenografts. However, the stability and potency of disulfide conjugates were poor, and in vivo activity superior to unconjugated DOX was seen only at doses approaching the maximum tolerated dose. Furthermore, BR64-SS-DOX conjugates were not active against antigen-expressing, DOX-insensitive colon tumor xenografts. In contrast, the BR64-S-DOX conjugates demonstrated good stability both in vitro and in vivo. The increased stability of the BR64-S-DOX conjugates resulted in the delivery of more biologically active DOX to tumors with a concomitant increase in potency and efficacy over that which could be achieved with either unconjugated DOX or BR64-SS-DOX conjugates. Delivery of DOX by BR64-SS-DOX conjugates resulted in complete regressions and cures of both DOX-sensitive lung xenografts and DOX-intensitive colon tumor xenografts. These results demonstrate the importance of linker stability when delivering drugs such as DOX to carcinomas via internalizing antibodies and are likely to have direct relevance to the clinical utility of MAb-directed delivery.

Animals↗
PubMed1998

Prospects for the management of non-Hodgkin's lymphomas with monoclonal antibodies and immunoconjugates.

PURPOSE: To review the role of monoclonal antibody constructs in the treatment of B-cell malignancies. PATIENTS AND METHODS: The efficacy and tolerability of unmodified monoclonal antibodies, immunotoxins, and radioimmunoconjugates have been investigated in patients with hematologic B-cell malignancies. Response rates, durability of responses, and tolerability were the principal measures of treatment outcome. RESULTS: Investigators from several institutions have documented response rates ranging from 25% to 95% in lymphoma patients suffering relapses who were treated with antibody constructs targeting the CD19, CD20, CD22, DR, or idiotypic immunoglobulin epitopes on malignant B-cell lymphomas. Chimeric anti-CD20 antibodies and 131I-labeled anti-CD20 antibodies appear particularly promising, producing response rates of 50% to 95%. Complete remissions (CRs) appear to be more frequent and durable with radiolabeled anti-CD20 antibodies (33% to 85% CR rate) than with unmodified chimeric anti-CD20 antibodies (6% to 10% CR rate), although a randomized comparison has not yet been made. CONCLUSION: Monoclonal antibodies provide promising new reagents for the treatment of patients with B-cell non-Hodgkin's lymphomas. Impressive response rates have been achieved in clinical trials using unmodified monoclonal antibodies, immunotoxins, and radioimmunoconjugates, although the durability of responses is still under scrutiny. Durability may be improved when the antibodies are used in conjunction with chemotherapy or stem cell transplantation.

Antibodies, Monoclonal↗
PubMed1998

Phase II clinical trial of bolus infusion anti-B4 blocked ricin immunoconjugate in patients with relapsed B-cell non-Hodgkin's lymphoma.

Immunotoxins, composed of a monoclonal antibody conjugated to a protein toxin, mediate cell death through novel cytotoxic mechanisms. Anti-B4-blocked ricin (anti-B4-bR) recognizes CD19-positive cells, which includes most B-cell non-Hodgkin's lymphomas (NHLs). Previous Phase I clinical studies of anti-B4-bR, using both bolus and continuous dosing regimens, demonstrated no safety or efficacy advantage to the continuous infusion regimen. This Phase II trial in 16 patients with relapsed CD19-positive NHL was conducted to evaluate the efficacy of anti-B4-bR when administered at the previously established maximum tolerated dose using a daily bolus for a 5 consecutive days schedule. Serum pharmacokinetics were measured in selected patients. Tissue samples of involved lymph nodes and bone marrow were also obtained from a portion of patients for determination of anti-B4-bR penetration into tissues. Toxicity was similar to what has been described previously for anti-B4-bR and consisted mainly of reversible elevations of hepatic transaminases and mild to moderate thrombocytopenia. No sustained clinical responses were documented. Pharmacokinetic measurements demonstrated that serum levels compatible with 3 logs of cell kill in vitro could be sustained for several hours in most patients. Immunohistochemical analysis of tissue samples provided some insight into the low efficacy. The immunotoxin could be detected in three of the four bone marrow aspirate samples but in only two of the seven lymph node specimens. Thus, anti-B4-bR, using a single daily bolus for a 5 consecutive day schedule, is not an active agent in relapsed NHL. Poor penetration into certain sites of disease may be one explanation for its lack of efficacy.

Adult↗
PubMed1994

A mouse model for calculating cross-organ beta doses from yttrium-90-labeled immunoconjugates.

BACKGROUND: The organs of laboratory mice used in radioimmunotherapy experiments are relatively small compared to the ranges of high-energy yttrium-90 (Y-90) beta particles. Current Medical Internal Radiation Dose (MIRD) dosimetry methods do not account for beta energy that escapes an organ. A dosimetry model was developed to provide more realistic dose estimates for organs in mice who received Y-90-labeled antibodies by accounting for physical and geometric factors, loss of beta dose due to small organ sizes, and cross-organ doses. METHODS: The dimensions, masses, surface areas, and overlapping areas of different organs of 10 athymic nude mice, each weighing approximately 25 g, were measured to form a realistic geometric model. Major organs in this model include the liver, spleen, kidneys, lungs, heart, stomach, small intestine, large intestine, thyroid, pancreas, bone, marrow, and carcass. A subcutaneous tumor mass also was included in the model. By accounting for small organ absorbed fractions and cross-organ beta doses, the MIRD methodology was extended from humans to mice for beta dose calculations. RESULTS: Absorbed fractions of beta energy were calculated using the Berger's point kernels and the electron transport code EGS4. Except for the tumor and carcass, the self-organ absorbed fractions ranged from 15% to 20% in smaller organs (the marrow and thyroid) to 65%-70% in larger organs (the liver and small intestine). Cross-organ absorbed fractions also were calculated from estimates of the overlapping surface areas between organs. CONCLUSION: The mathematic mouse model presented here provides more realistic organ dosimetry of radiolabeled monoclonal antibodies in the nude mouse, which should, in turn, contribute to a better understanding of the correlation of biodistribution study results and organ-tumor toxicity information.

Animals↗
PubMed1994

Application of the cross-organ beta dose method for tissue dosimetry in tumor-bearing mice treated with a 90Y-labeled immunoconjugate.

BACKGROUND: Radioimmunotherapy of nude mice bearing human tumor xenografts using 90Y-labeled monoclonal antibodies has resulted in slower tumor growth, decreased tumor burden, and increased survival times. Dosimetry estimates in the murine model usually were based on biodistribution data and standard Medical Internal Radiation Dose approaches. A new dosimetric model for the mouse that takes into consideration the small dimensions, mass, and proximity of murine organs has been developed based on self-organ absorbed and cross-organ doses. METHODS: Nude mice bearing carcinoembryonic antigen-expressing WiDr human colon cancer xenografts were injected with 240 microCi 90Y-anti-carcinoembryonic-antigen monoclonal antibodies and then killed at 12, 24, 72, 120, and 168 hours. Tumors and major organs were removed, weighed, and counted on a gamma counter. Using the resulting biodistribution data, the radiation doses to tumor and normal organs were calculated using the new dosimetric model for the mouse. RESULTS: Three organs (the liver, kidneys, and large bowel) directly received > 50% of the total absorbed beta dose from radioactivity. Lungs, stomach, and marrow received the highest percentage (70-75%) of the total absorbed dose from adjacent organs. Tumor absorbed dose, estimated with the new dosimetric model, was three times less than that obtained with a MIRD-style calculation without correction for self-absorbed and cross-organ doses. CONCLUSIONS: The new dosimetric model, which accounts more accurately for self-organ absorbed and cross-organ beta dose fraction, allows the calculation of tumor and organ doses in the murine model. Accurate estimation of radiation doses to tumor and critical organs, such as the marrow, spleen and kidneys, is important in determining the efficacy and toxicity of radioimmunotherapy regimens in animals and in subsequent human applications.

Animals↗
PubMed1988

Immunoconjugate generation between the ribosome inactivating protein restrictocin and an anti-human breast carcinoma MAB.

In the perspective of therapeutic approaches the monoclonal antibody, MBrl, with a quite restricted spectrum of reactivity for human breast carcinoma, was coupled to restrictocin (Res), a ribosome inactivating protein produced by Aspergillus restrictus. In a cell-free system this toxin was found to have an activity comparable to that of other plant toxins, but its in vitro toxicity was shown to be low on different cell lines. Three batches of MBr1-Res conjugate were prepared and their specificity, efficiency, and maximum level of cytotoxicity were analyzed on the cell line MCF-7 expressing the relevant antigen, on several irrelevant tumor cell lines, and on normal cells. Conjugates were from 600 to 1500 times more efficient than the uncoupled derivatized Res towards MCF-7 cells and were completely ineffective on the other target cells. The antigen-driven cytotoxicity was confirmed by the nontoxicity of an irrelevant conjugate on MCF-7 cells. The cytotoxic efficiency of MBr1-Res was low when compared to the binding level of MBr1 at the same concentration and a portion of treated cells (from 10% to 30%) survived the treatment. The heterogeneity of expression of the relevant antigen, together with its only partial internalization, could account for these limitations. The lysosomotropic agent ammonium chloride and the carboxylic ionophore monensin were tested as potentiating agents but in both cases the cytotoxicity remained unmodified. A neutralization assay performed on a xenogenic model indicated that the MBr1-Res conjugate was capable of reducing the tumor take. These data indicate the possibility of using the Res to prepare a reproducible and highly selective breast cancer conjugate. However, there are still a number of problems which must first be solved before we can consider its clinical application.

Allergens↗
PubMed2000

Targeted therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates.

Traditional chemotherapy for acute leukemia often causes life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target cell surface antigens on leukemic blasts are being evaluated for their cytotoxic effects and as a means of delivering chemotherapeutic agents or radiation directly to malignant cells. It is hoped that this strategy might selectively ablate malignant cells without many of the toxic effects commonly associated with conventional chemotherapy. In acute myeloid leukemia (AML), the cell surface antigens CD33 and CD45 are especially suitable targets. Although CD33 is expressed on AML blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all nonhematopoietic tissues. For that reason, anti-CD33 antibodies have been created to target malignant myeloid and immature normal cells selectively while sparing normal stem cells. Anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. Since the vast majority of leukemias and normal stem cells express the cell surface antigen CD45, another targeting approach allows the delivery of myeloablative radiation to bone marrow and spleen, common sites of leukemic involvement. Consequently, 131I-labeled anti-CD45 antibody has been combined with traditional preparative regimens for patients receiving bone marrow transplantation for acute leukemia. Finally, fusion proteins such as those combining diphtheria toxin with granulocyte-macrophage colony-stimulating factor (GM-CSF) to target the GM-CSF receptor are now being evaluated in clinical trials. Both unconjugated and conjugated antibodies have shown promise in early clinical trials, and may represent appealing therapeutic alternatives for patients with AML.

Acute Disease↗
PubMed1991

A carbohydrate-directed heterobifunctional cross-linking reagent for the synthesis of immunoconjugates.

A novel, highly water-soluble, heterobifunctional cross-linking reagent, S-(2-thiopyridyl)-L-cysteine hydrazide (TPCH), was synthesized which contains a hydrazide moiety for coupling to aldehyde groups generated in the carbohydrate residues of antibodies by mild periodate oxidation, and a pyridyl disulfide moiety for coupling to molecules with a free sulfhydryl group. Since the carbohydrate moieties are distal to the antigen binding region of antibodies, derivatization with this cross-linker minimizes impairment of the antigen binding function. Derivatization of the human monoclonal IgM antibody 16-88 against human colon carcinoma cells with as many as 16 TPCH cross-linker molecules did not impair its antigen binding capability. Using mild oxidation conditions for antibody derivatization, sialic acid residues were identified as attachment sites for the cross-linker molecules, since after desialylation of antibody 16-88 by neuraminidase virtually no cross-linker molecules could be incorporated. Comparison of TPCH with S-(2-thiopyridyl)mercaptopropionic acid hydrazide and S-(2-thiopyridyl)-L-cysteine, two related cross-linking reagents, revealed that TPCH is most efficiently incorporated into periodate-treated antibody. Based on the structural differences of the cross-linkers, the more efficient incorporation of TPCH appears to be a function of the presence of a hydrazide moiety with an adjacent amino group. When three to four molecules of pyridyl disulfide-derivatized barley toxin were coupled to TPCH-derivatized antibody 16-88, the antigen binding capability remained uncompromised. In addition, no significant impairment of toxin activity upon coupling to the antibody was observed. Based on these data, TPCH may be very useful for the synthesis of immuno-conjugates with no or only minimal impairment of the antigen binding function.

Antibodies, Monoclonal↗
PubMed1990

Large scale preparation of an immunoconjugate constructed with human recombinant CD4 and deglycosylated ricin A chain.

A method for the preparation and purification of large amounts (grams) of a conjugate containing recombinant CD4 antigen (rCD4) and chemically deglycosylated ricin A chain (dgA) is described. The cross-linking of rCD4 and dgA molecules was accomplished with N-succinimidyl-oxycarbonyl-alpha-methyl-(2-pyridyldithio)toluene (SMPT). The rCD4-dgA conjugate was purified by an automatic liquid chromatography system consisting of Blue-Sepharose CL-4B and Sephacryl S-200HR Pharmacia Bioprocess columns. The purified, endotoxin-free rCD4-dgA conjugate had a stable (hindered) disfulfide bond between rCD4 and dgA and was able to efficiently kill a human T cell line infected with HIV-1.

CD4 Antigens↗
PubMed1992

In vitro stability of EDTA and DTPA immunoconjugates of monoclonal antibody 2G3 labeled with indium-111.

Monoclonal antibody 2G3 directed against a high molecular weight glycoprotein on breast and ovarian cancer cells was conjugated with bicyclic DTPA (or EDTA) anhydride or benzyl isothiocyanate DTPA (benzyl DTPA) and labeled with 111In. DTPA anhydride was more reactive with the antibody than benzyl DTPA, and kinetics of labeling with 111In were more rapid for DTPA substituted 2G3 than for benzyl DTPA substituted 2G3. On the other hand, 111In-2G3 conjugates prepared using DTPA anhydride were subject to more extensive dimerization and higher losses in immunoreactivity than those prepared using benzyl DTPA. On the basis of measurement of transchelation to transferrin, the stability of 111In-2G3 prepared using DTPA anhydride or benzyl DTPA did not differ during incubation in human plasma for 6 days at 37 degrees C. These results suggest that an important advantage of benzyl DTPA over DTPA anhydride for preparing 111In-labeled antibodies is the prevention of intermolecular (and intramolecular) crosslinking during conjugation which ultimately leads to alterations in conformation and losses in immunoreactivity of the radioimmunoconjugate.

Antibodies, Monoclonal↗
PubMed1990

Radioactive gold cluster immunoconjugates: potential agents for cancer therapy.

An 11 gold atom (undecagold) cluster was covalently attached to specific sites on Fab', F(ab')2 and whole IgG molecules such that each carried 11-33 gold atoms without significant loss of native immunospecificity. Gold cluster labeled 17-1A monoclonal F(ab')2 antibody fragments showed 80% immunoreactivity compared to native antibody fragments in binding to human colon carcinoma cells in vitro. Radioactive gold in vivo biodistributions in nude mice with human tumors are also reported. By using clusters, potentially a larger destructive payload can be carried per antibody.

Animals↗
PubMed1993

Fractionated intravenous administration of 90Y-labeled B72.3 GYK-DTPA immunoconjugate in beagle dogs.

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas, was coupled with linker-chelator GYK-DTPA using carbohydrate mediated conjugation chemistry and radiolabeled with yttrium-90. Single and double intravenous injections of radioimmunoconjugate were compared for acute and late normal tissue toxicity in 15 beagle dogs. The second injection was given 4 or 8 days after the first. Pharmacokinetics of the radioimmunoconjugate in blood, bone marrow and urine were similar for first and second injections. Only bone marrow (acute) and liver (late) toxicity were observed. Both liver and bone marrow toxicity were decreased by fractionation of the injections. After double injections, the total equitoxic dose was 15 and 60% higher for bone marrow and liver toxicity, respectively. The mechanisms of normal tissue protection offered by fractionated radioimmunoglobulin therapy (RIT) remain to be defined. Fractionated RIT will have a better therapeutic ratio than single injection RIT, if antitumor effects appear to be less susceptible to fractionation than normal tissues.

Animals↗
PubMed1988

Biodistribution studies of anti-Thy 1.2 IgM immunoconjugates: implications for radioimmunotherapy.

We have prepared 111In radioimmunoconjugates (RICs) of the IgM isotype with specificity for the murine T cell/neuroectodermal surface antigen, Thy 1.2. Using gamma camera immunoscintigraphy, we have analyzed the biodistribution patterns of the RICs after intravenous and intraperitoneal injection into normal Thy 1.2+ and Thy 1.2- mice. Both routes of administration show antigen-specific uptake by the splenic T lymphocyte population. A high degree of nonspecific uptake by the reticuloendothelial system is also observed. Analysis of the specific activity of various segments of spleens from RIC-injected animals shows inhomogeneous uptake of the RIC not readily apparent by immunoscintigraphy. Animals injected with the RIC and then given high dose total body irradiation showed rapid shifts in radionuclide distribution away from the target cell population and into the general reticuloendothelial system, suggesting that death of the target cell can alter RIC biodistribution. Analyses of RIC biodistribution patterns will contribute to optimization of treatment by radioimmunotherapy.

Animals↗
PubMed1997

Inhibition of cell proliferation on lens capsules by 4197X-ricin A immunoconjugate.

PURPOSE: To evaluate the cytotoxicity of immunotoxin 4197X-ricin A (4197X-RA) and its ability to inhibit protein synthesis and human lens epithelial cell (LEC) proliferation on the inner surface of the lens capsule. SETTING: Houston Biotechnology, Inc., The Woodlands, Texas. METHODS: A cell culture system was established using human LECs as a model for the proliferation of remnant LECs that occurs during posterior capsule opacification (PCO) after extracapsular cataract extraction. The LEC culture system was also used in vitro for testing compounds that might inhibit this process in vivo. Human LECs were cultured on the surface of the original lens capsule fixed to collagen. Variability was reduced by dissecting each lens capsule into equivalent halves and exposing the segments to immunotoxin 4197X-RA. RESULTS: Protein synthesis and LEC proliferation were almost completely inhibited at relatively low 4197X-RA concentrations after short exposure. The inhibitory effects persisted up to 3 weeks after withdrawal of the immunotoxin and after several media exchanges. CONCLUSION: Immunotoxin 4197X-RA may help prevent PCO after primary cataract surgery.

Antibodies, Monoclonal↗