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At least 829 records · Page 46Linked to original sources
PubMed1991

Development of a large-animal human brain tumor xenograft model in immunosuppressed cats.

A large-animal model was developed to facilitate the noninvasive investigation of the effect on the human glioma-derived D-54 MG (glioblastoma multiforme) continuous cell line of a variety of therapeutic regimens. Twenty random-bred male cats were inoculated intracerebrally with 1 x 10(7) D-54 MG tumor cells after being initiated on one of three preparatory regimens of cyclosporin A p.o. Reproducible success of D-54 MG xenotransplantation (100%, 6 of 6 cats) was achieved only after pretreatment with 120 mg cyclosporin A p.o. (24-30 mg/kg) daily for greater than or equal to 10 days prior to tumor implantation. High-performance liquid chromatography-derived whole blood cyclosporin A 12-h trough levels of greater than or equal to 640 ng/ml were seen in successful implants. Lesions ranging from 2 to 20 mm in diameter were seen in cats sacrificed 27-44 days after implantation with no growth seen in control animals. Histopathological examination revealed the tumors to be well-circumscribed anaplastic intracerebral tumors with some invasion into surrounding host parenchyma. Perivascular lymphocytic cuffing was observed, but intratumoral lymphocytic infiltration was minimal. Gadolinium-EDTA-enhanced nuclear magnetic resonance imaging provided accurate tumor localization in T1-weighted images (TE 26 ms; TR 600 ms). Biochemical tests of kidney, liver, and hematological function were within normal limits, although 10% (2 of 20) of the animals developed gingival hyperplasia, and 5% (1 of 20) developed intussusception. The reproducible growth of the D-54 MG human glioblastoma cell line in a large-animal model eliminates many of the limitations associated with the standard nude mouse/rat model, thereby providing a novel test bed for a variety of imaging modalities as well as for drug immunoconjugate localization and toxicity studies.

Animals↗
PubMed1990

Natural serum antibodies which bind to damaged erythroblasts: isotypes and light-chain composition.

Dimethyl-sulphoxide-induced Friend leukaemia erythroblasts (IFLE) which had been damaged by treatment with inhibitors of protein synthesis (cycloheximide, puromycin) were incubated with normal mouse serum or with doubling dilutions of it. The erythroblasts were subsequently tested for their binding of natural antibodies of all the major immunoglobulin (Ig) isotypes and both light-chain types, using Fc- and light-chain-specific FITC-immunoconjugates, and flow cytometry. After short-term (4-h) exposure of IFLE to puromycin, some binding of IgG but not of IgM or IgA could be demonstrated. By contrast, prolonged (17-h) exposure of IFLE to cycloheximide or puromycin resulted in their reaction with antibodies of all major isotypes (IgM, IgG1, IgG2a, IgG2b, IgG3, IgA) containing kappa-light chains. Under these conditions of damage the percentage of IgM- or IgG-binding IFLE significantly exceeded that of IgA-reactive cells. Moreover, the percentage of damaged IFLE which bound IgG2a or IgG3 was greater than that of cells which bound IgG1 or IgG2b. The percentage of damaged IFLE which bound a certain Ig-isotype did not correlate with the concentration of that Ig-isotype in normal mouse serum. The results suggest that natural antibodies of all major isotypes containing kappa-light chains bind specifically to severely damaged IFLE and could facilitate their interaction with macrophages in a concerted manner.

Animals↗
PubMed1990

[Host factors that changes the distribution of immunotoxin].

Mouse monoclonal antibody A 7, which was raised against human colon cancer, was used for preparing the conjugates with neocarzinostatin, mitomycin C and adriamycin. The tissue distribution of these three conjugates were examined in athymic nude mice transplanted with human colon cancer. The distribution in tumor was different in these three conjugates. The route of administration of the conjugate affected its distribution in tumor tissues. In the case of tumor transplanted in the back of mice, intravenous administration seemed to superior to intraperitoneal one. In clinical trials of immunoconjugate composed of A 7 and polypeptide anticancer drug neocarzinostatin (A 7-NCS), human anti-mouse antibody (HAMA) was observed in most cases without serious immune response such as anaphylactic shock. Human antibody against neocarzinostatin could not be detected in any case receiving A 7-NCS.

Animals↗
PubMed1990

Purging of small cell lung cancer-contaminated bone marrow by monoclonal antibodies and magnetic beads.

At diagnosis, most patients with small cell lung cancer (SCLC) have bone marrow involvement detected by immunological techniques. As preparative regimens become more effective in the elimination of systemic disease, bone marrow purging may become a significant intervention, even more so with the trend toward use of greater numbers of stem cells for reconstitution (such as peripheral blood stem cells). The optimal conditions for removal of SCLC cell lines from bone marrow mixtures with magnetic bead immunoconjugates are described. Metabolically labelled SCLC cells (SW2, OC2, NCI-H82) were incubated with mouse monoclonal antibodies reactive with SCLC membrane antigens (SM1, LAM2, LS1) alone or in combination. Magnetic beads conjugated with secondary goat anti-mouse-IgG or IgM antibody were added and the unpurged cells decanted off. Tumor removal was evaluated by residual radioactive counts in the decanted cell mixture as well as by clonogenic assay. The log removal was compared to controls performed without primary or secondary antibody. All assays were performed in triplicate. Bone marrow toxicity was similarly evaluated. In a simulation of bone marrow purging, a bead to total cell ratio of greater than or equal to 10:1 provided maximal tumor removal regardless of the degree of contamination. However, when the bead to total cell ratio dropped lower than 10:1, purging efficiency lessened despite maintenance of bead: tumor cell ratio of 100:1. A concentration of primary antibody ten-fold greater than saturation by indirect immunofluorescence provided optimal elimination. Using single exposures of antibody and beads, a mixture of all 3 MoAbs resulted in 2.4-2.6 log removal for SW2 and OC2. However, with NCI-H82, a cell line with low expression of these antibodies on the cell surface, maximal elimination was only 1.6 logs. Double bead exposure for 30 minutes each was more effective than single treatments for 30-60 minutes. No significant toxicity to bone marrow function was observed in parallel studies. Magnetic bead separation appears to be an efficient and nontoxic method to purge bone marrow of tumor contamination with SCLC.

Animals↗
PubMed1990

Phase I clinical comparative study of monoclonal antibody KS1/4 and KS1/4-methotrexate immunconjugate in patients with non-small cell lung carcinoma.

A Phase Ia clinical trial was undertaken to evaluate and compare murine monoclonal antibody KS1/4 and KS1/4-methotrexate immunoconjugate in patients with Stage IIIB or IV non-small cell carcinoma of the lung. Six patients received KS1/4 alone and five patients received KS1/4-methotrexate conjugate. The maximal total dose received per patient in both groups was 1661 mg. Mild to moderate side effects in both groups included fever, chills, anorexia, nausea, vomiting, diarrhea, anemia, and brief transaminasemia. One patient who received antibody alone had an apparent acute immune complex-mediated reaction. Ten of 11 patients had a human anti-mouse response. Posttreatment carcinoma biopsies revealed binding of monoclonal antibody KS1/4 and deposition of C3d and C4c complement fragments. Monoclonal antibody binding and complement deposition correlated with increasing doses of infused antibody. There was one possible clinical response.

Adult↗
PubMed1990

Selective inhibition of growing pigment epithelial cells by a receptor-directed immunotoxin.

An immunotoxin conjugate of a murine monoclonal antibody against human transferrin receptors and the A chain of ricin was examined for its potential to inhibit selectively the growth of retinal pigment epithelial (RPE) cells which grow in an uncontrolled manner in proliferative vitreoretinopathy. The probable efficacy of such an agent in vivo stems from the observation that actively proliferating cells possess many more transferrin receptors than normal quiescent cells. The authors showed in vitro that the immunoconjugate (454A12 MAB-rRA) inhibits protein synthesis in actively dividing RPE cells but has a smaller or no effect on protein synthesis by confluent, nondividing RPE cells. The effect was specific in that neither the free ricin A chain (rRA) nor the monoclonal antibody (454A12 MAB) alone has any inhibitory effect. Furthermore, the antibody competes with the immunotoxin and suppresses the latter's toxicity. This immunotoxin has applications for therapy in conditions in which the pathologic proliferation of RPE cells occurs.

Antibodies, Monoclonal↗
PubMed1990

Intraperitoneally administered 90Y-labelled monoclonal antibodies as a third line of treatment in ovarian cancer. A phase 1-2 trial: problems encountered and possible solutions.

A phase 1-2 trial of 90Y-labelled monoclonal antibody, HMFG1 administered intraperitoneally to 30 patients with ovarian carcinoma is presented. The problems encountered with myelotoxicity are described, and the steps which have so far been taken to overcome this and to increase the dose of 90Y to an estimated tumouricidal level. Bone deposition of free 90Y limits the dose which can be administered without severe bone marrow toxicity. The intravenous use of a chelating agent, Ledclair (EDTA) has allowed the dose to be increased from 18 to 30 mCi without causing severe myelotoxicity. 90Y-DTPA MAb is an unstable immunoconjugate in vivo and in vitro. The use of a more stable linkage such as a macrocycle should enable the administered dose to be increased without increasing the amount of free 90Y which becomes available to be deposited in bone. This would be expected to reduce toxicity and increase therapeutic efficacy.

Antibodies, Monoclonal↗
PubMed1988

Potentiation of anti-carcinoembryonic antigen immunotoxin cytotoxicity by monoclonal antibodies reacting with co-expressed carcinoembryonic antigen epitopes.

The initial step in ricin A-chain (RTA)-immunotoxin-mediated cell cytotoxicity involves binding to the target cell Ag through the antibody moiety. One of the factors influencing this is the affinity of the antibody component for the target cell Ag. Multiple epitopes on carcinoembryonic Ag have been mapped providing a range of mAb of known specificity. These have been used to show that the cytotoxicity of an immunotoxin containing RTA conjugated to an anti-carcinoembryonic Ag mAb (228-RTA) is potentiated by mAb recognizing different epitopes. The potentiating antibodies also increased the level of target cell binding of antibody 228. Cross-linking of cell bound antibody was not involved because monovalent fragments of a potentiating antibody were effective. The potentiating antibodies modified the binding affinity of 228 antibody increasing the t1/2 of antibody at the tumor cell surface. This increased the dwell time of cell bound antibody and using conjugates of 228 linked to albumin-tetramethylrhodamine it was shown to enhance conjugate endocytosis. These investigations indicate that enhanced antibody affinity leads to increased endocytosis of bound immunoconjugate and potentiates cytotoxicity.

Adjuvants, Immunologic↗
PubMed1988

Ricin A-chain containing immunotoxins directed against different epitopes on the CD2 molecule differ in their ability to kill normal and malignant T cells.

Immunoconjugates consisting of mAb covalently coupled to plant or bacterial toxins or to cytotoxic drugs have provided novel experimental reagents for the treatment of malignancies and autoimmune diseases. In this report, we analyzed the efficacy of three ricin A chain-containing immunotoxins (IT-A) which recognize different epitopes on the CD2 molecule (E rosette receptor) on human T cells. Although all IT-A had similar binding avidities and A-chain activities, one (RFT11-A) was 100-1000-fold more effective in killing normal and malignant T cells than the others (35.1-A, 9.6-A). Immunoprecipitation experiments confirmed that all IT-A bound to the CD2 molecule. However, cross-blocking experiments, differential proteolysis with trypsin, and T cell co-activation experiments showed that the less effective IT-A, 35.1-A and 9.6-A, bound to an epitope far from the cell membrane (region I), whereas the more effective IT-A, RFT11-A bound to an epitope closer to the membrane (region II). Using cellular RIA and immunoelectron microscopy, it was shown that both RFT11-A and 35.1-A were rapidly internalized by T cells, but that their intracellular fates differed. The more toxic IT-A, RFT11-A, was retained for longer periods of time inside the cells and was more slowly degraded than the less effective IT-A, 35.1-A, which was rapidly transported to lysosomes, digested, and expelled. These results demonstrate that different IT-A targeting the same surface molecule can differ markedly in potency, and that the epitope recognized by an IT-A may have a significant impact on the ability of the IT-A to insert into cell membranes, translocate to the cytosol, and kill cells.

Antibodies, Monoclonal↗
PubMed1989

Interleukin receptors in lymphoid lesions. Relevance to diagnosis, biology, and therapy.

Interleukin 2 and its receptor have emerged as a central control system in the regulation of the immune response and the proliferation of T cells, B cells, and macrophage. IL-2 receptor expression is strongly associated with several forms of human lymphoproliferative disease including adult T-cell leukemia-lymphoma, hairy cell leukemia, Hodgkin's disease, and peripheral T-cell lymphoma in which it may play a pathogenetic role. IL-2 receptor expression may also play a role in some B-cell non-Hodgkin's lymphomas and histiocytic proliferations. Recent discoveries in immunology and advances in biotechnology have opened therapeutic possibilities for IL-2 including the use of anti-Tac monoclonal antibodies and immunoconjugates for the therapy of Tac-positive lymphoproliferative disease, the use of anti-Tac monoclonal antibodies as novel immunosuppressants, and the use of genetically engineered recombinant IL-2 and activated autologous lymphocytes in the adoptive immunotherapy of cancer. Therapeutic and diagnostic applications of IL-2 continue to be defined.

Antibodies, Monoclonal↗
PubMed1989

Phase I clinical trial of drug-monoclonal antibody conjugates in patients with advanced colorectal carcinoma: a preliminary report.

Melphalan (MEL), an alkylating agent, has been modified to a derivative, N-acetylmelphalan (N-AcMEL), which can be conjugated to anticolon cancer monoclonal antibodies (MoAbs 30.6, I-1, and JGT) and used for immunochemotherapy. The final immunoconjugates possess potent cytotoxicity and specificity in preclinical studies. In a phase I clinical study, N-AcMEL-MoAb conjugates were administered via the hepatic artery to 10 patients, nine of whom had disseminated colorectal cancer (including the liver) and one of whom had Dukes' C colon cancer that had been resected. The selection of MoAb was based on the immunoperoxidase staining of the primary colon cancer tissue. Thus far doses of 1000 mg/m2 MoAb conjugated to 20 mg/m2 of N-AcMEL have been administered with no significant side effects, whereas MEL unconjugated to monoclonal antibodies would have caused myelosuppression in a proportion of patients at the same dosage. Serum antimouse antibody responses were noted in all of the patients; febrile reactions were noted with higher doses but were easily controlled with antipyretics, antihistamines and, if necessary, steroids. Serum sickness developed in one patient who was given a second course of treatment in the presence of human antimouse antibody, but the episode was self-limiting. Eight of the 10 patients had evaluable disease. Subjective improvement was noted in almost all of the patients examined, and 33%, or 3 of 9, of the treatments (nine courses of treatment in eight patients with evaluable disease; one of the patients had two courses of treatment) led to antitumor responses (minor response) by objective assessment with computed tomography of the liver. It is important to note that treatment with N-AcMEL-MoAb conjugates was safe at a dose of 20 mg/m2 of N-AcMEL, whereas the efficacy of such a form of treatment remains to be determined.

Adult↗
PubMed1989

Improved radiolabeled monoclonal antibody uptake by lavage of intraperitoneal carcinomatosis in mice.

The effect of peritoneal lavage with saline on tumor and systemic uptake of intraperitoneally administered tumor-specific (131I-5G6.4) and nonspecific (125I-UPC-10) radiolabeled monoclonal antibodies was evaluated in a nude mouse model of human intraperitoneal ovarian carcinomatosis (IP3 model). Peritoneal lavage at 2 or 6 hr postintraperitoneal antibody injection significantly improves intraperitoneal tumor/nontumor uptake ratios of specific antibody apparently by limiting systemic exposure to antibody. This enhancement tends to be more dramatic if lavage is performed within 2 hr, rather than 6 hr, of intraperitoneal antibody administration, though both times result in significant improvements in target/background ratios over no lavage. Twenty-four-hour tumor/nontumor ratios for specific antibody 5G6.4 generally are 1.5-fourfold higher following lavage than those achieved in control animals, without decreasing absolute tumor uptake of specific radiolabeled antibody. By contrast, nonspecific antibody UPC-10 binding is lower in tumor and normal tissues following lavage, with no lavage-induced improvement in tumor/nontumor ratios seen. Peritoneal lavage is a simple method to allow for specific antibody binding to accessible intraperitoneal tumors yet to limit systemic exposure thus increasing the therapeutic margin. This method may have considerable applicability in the enhancement of intraperitoneal immunoconjugate delivery to intraperitoneal tumors.

Animals↗
PubMed1988

Serotherapy of ovarian cancer.

The development of monoclonal antibodies has permitted the identification of several ovarian-tumor-associated antigens which might serve as targets for serotherapy in vivo. With the exception of antibodies directed against growth factor receptors, unmodified monoclonal reagents must activate complement (C') components or bind effector cells to destroy tumor targets. Antibody-dependent cell-mediated cytotoxicity (ADCC) may be particularly important for eliminating tumor cells in vivo. A shortage of functionally active effector cells can limit the efficacy of serotherapy with heteroantisera or monoclonal reagents. The use of immunostimulants such as Corynebacterium parvum has increased the number and activity of effector cells for ADCC within the peritoneal compartment of mice and of patients with ovarian cancer. Intraperitoneal serotherapy can achieve direct contact between antibody and microscopic deposits of ovarian tumor cells which persist following cytoreductive operations and cytotoxic chemotherapy. Conjugation of monoclonal antibodies with radionuclides, drugs or toxins might increase the potency of serotherapy and circumvent the effector shortage. Clinical studies to date have evaluated radionuclide conjugates for imaging and for therapy. Patients with a small volume of disease have responded to treatment. Preclinical models suggest that drug and toxin conjugates might also prove active. Recent studies have demonstrated a synergistic interaction between different immunotoxins. Ovarian carcinoma is likely to be a valuable clinical model for evaluating immunoconjugates which react with epithelial tumor cells.

Animals↗
PubMed1987

Establishment of a human B-cell tumor in athymic mice.

Human B-cell tumors have been established in athymic, BALB/c mice using the EBV-positive Burkitt lymphoma cell line Namalwa. One-hundred-one of 104 animals (97%) developed tumors 10-14 days following s.c. injection of a mixture of 20 x 10(6) Namalwa and 5 X 10(6) irradiated human fibrosarcoma (HT-1080) cells. Tumors developed at the site of injection and reached approximately 300 mm2 (product of cross-sectional diameters) after 21 days; no metastases were found. Histological analysis showed that tumors consisted solely of lymphoid cells. Immunofluorescence assays demonstrated that while 85% of the tumor cells retained reactivity with the monoclonal B-cell antibody BA-1, 96% retained reactivity with antibody BA-2 and 43% with BA-3. A similar reactivity profile was observed with cultured Namalwa cells. Tumors were passaged serially 10 times without significant change in BA-1, BA-2, or BA-3 reactivity. Indirect immunofluorescence demonstrated that antibody BA-2 reached tumor cells within 2 h following i.p. injection; antigen modulation was not observed. These results demonstrate the suitability of this B-cell model for testing the in vivo efficacy and stability of anti-B-cell immunoconjugates.

Animals↗
PubMed1988

[Countercurrent immunoblotting].

Urinary proteins, concentrated and separated on cellulose-acetate membranes by counterflow isotachophoresis (ITP), were transferred by direct contact onto a strip of nitrocellulose membrane (NCM). ITP in the system of electrolytes: tris-HCl, pH 6.7 (the leading one) and tris-beta-alanine, pH 8.6 (the terminal one) gives rise to a strong electroendo-osmotic flow (EEF) in NCM, directed to the cathode. The rate of the counterflow in the zone, occupied by the leading electrolyte, exceeds the migration rate of any protein possessing anode mobility and present in the zone. Under these circumstances EEF serves as a "conveyer belt" transferring immunological reagents (antibodies, immunoconjugates, peroxidase) through the protein bands, "printed" on NCM. The immunoblots were developed in a standard way with 4-ethyl-1-naphthol as a substrate for antibody-bound peroxidase. The counterflow immunoblotting makes it possible to reveal and characterize light chains of immunoglobulins when they are present in the urine in the range of 20 ng/ml.

Counterimmunoelectrophoresis↗
PubMed1988

Radioimmunoimaging of metastatic medullary carcinoma of the thyroid gland using an indium-111-labeled monoclonal antibody to CEA.

Elevated levels of carcinoembryonic antigen (CEA) or calcitonin after surgical therapy for medullary carcinoma of the thyroid gland (MCT) indicate the presence of residual or metastatic disease. CEA elevations appear to be prognostically more reliable in patients with metastatic disease and suggest a more virulent tumor. Attempts to stage the disease with use of conventional imaging techniques are usually inadequate, as is the therapy for disseminated or recurrent MCT. An indium-111-labeled anti-CEA monoclonal antibody (ZCE-025) was used to image metastases in a patient with MCT. Potential applications of monoclonal antibody technology in the management of MCT would include (1) preoperative differentiation of unicentric from multicentric thyroid gland involvement, (2) detection of regional or distant metastases or both, (3) measurement of response to systemic therapy, and (4) the facilitation of radionuclide immunoconjugate therapy.

Antibodies, Monoclonal↗
PubMed1988

Inhibition of human T-cell tumor growth by T101-ricin A-chain in an athymic mouse model.

An immunotoxin prepared with the pan-T-cell, anti-CD5, antibody T101, and purified ricin A-chain (RTA) was selectively cytotoxic in vitro, inactivating protein synthesis in the human T-cell line MOLT-4 but not in the human B-cell line 8392. Modulation studies showed that the immunoconjugate was more rapidly cleared from the cell surface than unconjugated T101. Preclinical evaluation of T101-RTA was conducted in a human T-cell, athymic mouse model (Dillman et al., Cancer Res., 45:5632-5336, 1985). Tumor-bearing mice received single i.p. injections of saline, T101, UPC-10 (irrelevant IgG2a), unconjugated RTA, an irrelevant conjugate, UPC-10-RTA, a mixture of T101 plus RTA, or T101-RTA. T101-RTA was the most effective reagent. Thirty animals given injections of 33 micrograms of T101 showed reductions in tumor growth (compared to tumor growth in animals receiving phosphate-buffered saline) but no complete regressions. No decrease in tumor growth was observed with UPC-10. Animals given 12 micrograms of free RTA exhibited reduced tumor growth but only one complete regression was observed; similar results were obtained with mice given 45 micrograms of UPC-10-RTA or a mixture of 33 micrograms of T101 plus 12 micrograms of RTA. Eleven complete regressions and 18 partial regressions were produced in the 46 animals given injections of 45 micrograms of T101-RTA and tumor growth was almost completely blocked. No toxicity was observed in any experimental arm. These results suggest that T101-RTA may be administered safely and with significant antitumor effect.

Animals↗
PubMed1988

[Immunoscintigraphy of colorectal cancers and specific immunotherapy of pancreatic cancers using monoclonal antibodies].

The routine application of immunoscintigraphy for the detection of colorectal carcinomas is now possible thanks to the development of the BW 431/31-F(ab')2-DTPA-In-111 or the BW 431/26-Tc-99m kits. The quick tumor localization (6 hours p.i.), the specificity and sensitivity (approximately equal to 90%) as well as the lack of side reactions argue for the quality of the reagents. The change from I-131 labelled murine monoclonal antibodies (MAbs) to In-111 or Tc-99m immunoconjugates in kit form resulted in a reduction of radiation dose for the patient down to 20% (In-111) or to 5% (Tc-99m) of the dose applied using I-131 labelled MAbs. The BW 250/183-Tc-99m conjugate suited for the immunoscintigraphic detection of inflammatory processes by in vivo labelling of granulocytes possesses the same favourable characteristics. The specific tumor immunotherapy of pancreatic carcinoma using MAb BW 494 points to interesting effects which have to be statistically confirmed in future clinical trials.

Antibodies, Monoclonal↗