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At least 307 records · Page 17Linked to original sources
PubMed1997

Large scale manufacturing of TXU(anti-CD7)-pokeweed antiviral protein (PAP) immunoconjugate for clinical trials.

We have conjugated the murine monoclonal anti-CD7 antibody TXU to the plant hemitoxin pokeweed antiviral protein (PAP) to construct an effective immunotoxin against CD7 antigen positive hematologic malignancies. The scaled-up production and purification of TXU antibody, PAP toxin, and TXU-PAP immunotoxin permitted the manufacturing of a highly purified clinical-grade TXU-PAP preparation. In clonogenic assays, TXU-PAP elicited selective and potent cytotoxicity against CD7 antigen positive human leukemia cells and killed primary clonogenic leukemic cells from T-lineage acute lymphoblastic leukemia (ALL) patients. To our knowledge, this pre-IND work represents the first effort of producing a clinical-grade PAP immunotoxin for treatment of T-lineage ALL. Since the CD7 antigen is also expressed on AML cells, TXU-PAP could also be useful for the treatment of CD7 positive acute myeloid leukemia (AML) patients.

Antibodies, Monoclonal↗
PubMed2002

Prostate stem cell antigen as therapy target: tissue expression and in vivo efficacy of an immunoconjugate.

We conducted an expression analysis of prostate stem cell antigen (PSCA)in normal urogenital tissues, benign prostatic hyperplasia (n = 21), prostatic intraepithelial neoplasia (n = 33), and primary (n = 137) and metastatic (n = 42) prostate adenocarcinoma, using isotopic in situ hybridization on tissue microarrays. In normal prostate, we observe PSCA expression in the terminally differentiated, secretory epithelium; strong expression was also seen in normal urothelium. Forty-eight percent of primary and 64% of metastatic prostatic adenocarcinomas expressed PSCA RNA. Our studies did not confirm a positive correlation between level of PSCA RNA expression and high Gleason grade. We characterized monoclonal anti-PSCA antibodies that recognize PSCA expressed on the surface of live cells, are efficiently internalized after antigen recognition, and kill tumor cells in vitro in an antigen-specific fashion upon conjugation with maytansinoid. Unconjugated anti-PSCA antibodies demonstrated efficacy against PSCA-positive tumors by delaying progressive tumor growth in vivo. Maytansinoid-conjugated antibodies caused complete regression of established tumors in a large proportion of animals. Our results strongly suggest that maytansinoid-conjugated anti-PSCA monoclonal antibodies should be evaluated as a therapeutic modality for patients with advanced prostate cancer.

Adenocarcinoma↗
PubMed1992

[Preparation and biological activities of monoclonal antibody-streptonigrin immunoconjugates].

The clinic use of streptonigrin (114B), a highly active antitumor antibiotic, is limited by its detrimental effects on normal tissues. In an attempt to improve its specificity streptonigrin was conjugated to anti-human hepatoma monoclonal antibody 3A5 by four different chemical linkage methods. The first method was via water-soluble carbodiimide (EDCI) to create conjugates (1); in the second, an active ester of streptonigrin was applied as a reactive intermediate (2); and in the other two, spacers were put to use for coupling streptonigrin to McAb 3A5-Dextran T-40 (3) or McAb 3A5-bovin serum albumin (BSA) (4). The conjugates showed biological activities and UV spectral characteristics of streptonigrin and 3A5. As determined by clonogenic assay with human hepatoma BEL-7402 cells for 1 hour exposure, the IC50 for conjugate (2), conjugate (3) and streptonigrin were 0.355 ng/ml, 1.23 ng/ml and 22.4 ng/ml, respectively. The potency of conjugates (2) and (3) were 63-fold and 18-fold stronger than that of free streptonigrin. Clonogenic assay with KB cells which weakly react with 3A5 by Elisa showed that the potency of conjugate (2) and (3) were 11-fold and 13-fold weaker than free streptonigrin, respectively. The results suggest that the conjugates of McAb 3A5 and streptonigrin show specific cytotoxicity to target liver cancer cails. The linkage groups of streptonigrin were also discussed.

Antibodies, Monoclonal↗
PubMed1991

Immunoconjugates of Pseudomonas exotoxin A: evaluation in mice, monkeys, and man.

Immunotoxins of PE were constructed with stable thioether linkages using two monoclonal antibodies to ovarian cancer, OVB-3 and NR-LU-10. Antigens recognized by both antibodies have limited normal tissue distribution and are expressed on virtually all ovarian cancers. Both antibodies form highly potent conjugates (ID50 = 100 pg/ml) with high selectivity (greater than or equal to 4 logs) and can eliminate greater than or equal to 5 logs of tumor cells in vitro. The conjugates have been evaluated for efficacy in both ovarian and colon carcinoma ascites xenografts. In the ovarian model, the conjugates produce an increase in life span (ILS) of 200 to 300 with some cures against established but low tumor burden ascites. Increasing the tumor burden decreases efficacy and duration of responses. A lower ILS of 150 to 200 is achieved in the more aggressive colon model. However, the combination of immunotoxin with chemotherapy, which is ineffective on its own, demonstrated enhanced activity (ILS = 300). Toxicity of the conjugates is hepatic and easily monitored by liver function tests (LDH). Antitoxin responses are highly variable, but typically have a rapid onset and appear to be predicted by preexisting levels. Pilot clinical evaluation in ovarian cancer (intraperitoneal) is ongoing.

ADP Ribose Transferases↗
PubMed1990

Preclinical evaluation of immunoconjugates consisting of doxorubicin linked to complement-fixing monoclonal antibody DLC-48 for bone marrow purging of B-cell lymphomas.

Complement-fixing monoclonal antibody DLC-48 was linked covalently to doxorubicin using two methodologies, and the resulting conjugates were evaluated for their usefulness in purging B-cell lymphomas from human bone marrow autografts using a clonogenic assay for the large cell lymphoma cell line SU-DHL-4. Conjugation did not impair the reactivity of the antibodies. The resultant molar ratios provided for maximal immunoreactivity at doxorubicin concentrations that would permit the growth of CFU-GM. Conjugate DLC-48D-G retained its complement-fixing capacity, and was more cytotoxic to SU-DHL-4 cells, even in the absence of complement, than equivalent doses of doxorubicin. This effect appeared to be non-specific, in that CFU-GM were eliminated, even at low concentrations. DLC-48D-G was no more effective than equivalent doses of doxorubicin, and equally cytotoxic to CFU-GM. Mixtures of unconjugated DLC-48 and doxorubicin, however, were more effective than doxorubicin alone. The mechanism of action of these conjugates is under study. Alternative methods of conjugation will be investigated.

Animals↗
PubMed1989

Phase I trial of mitomycin C immunoconjugates cocktails in human malignancies.

Nineteen patients with refractory solid malignancies received individualized combinations of mitomycin C conjugated murine monoclonal antibodies selected by immunohistochemical and flow cytometric screening of tumor specimens. There were no responses in this Phase I study. Thrombocytopenia precluded escalation above a mitomycin C dose of 60 mg per treatment cycle. Preclinical, clinical, and toxicity experiences with this investigational approach to the treatment of cancer are discussed.

Adult↗