Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been demonstrated previously that the degree of glycosylation of a molecule may alter its pharmacokinetic properties and, in the case of an antibody, its metabolism and other biological properties. Transfectomas producing aglycosylated chimeric B72.3(gamma 1) pancarcinoma monoclonal antibody (mAb) were developed by introduction of the eukaryotic expression construct pECMgpB72.3 HuG1-agly, into SP2/0 murine myeloma cells producing the chimeric kappa chain of mAb B72.3. After cell cloning, one subclone with the highest binding to the TAG-72-positive human colon carcinoma was designated mAb aGcB72.3, and its biological and biochemical properties were compared with those of the chimeric B72.3(gamma 1), designated mAb cB72.3. Polyacrylamide gel electrophoresis showed that under non-reducing conditions, the molecular masses of the aGcB72.3 and cB72.3 mAbs were 162 kDa and 166 kDa respectively. The heavy chain of mAb aGcB72.3 had a slightly faster mobility than that of cB72.3, while the mobility of the light chains of the two chimeric mAbs was similar. No difference was observed in the isoelectric points of either chimeric mAb. Liquid competition radioimmunoassays demonstrated that the aGcB72.3 and cB72.3 mAbs have comparable binding properties to TAG-72. These studies demonstrate that aglycosylation of the chimeric IgG1 mAb B72.3 at the CH2 domain, as has been shown for other mAbs [Dorai H., Mueller B., Reisfeld R. A., Gillies S. D. (1991) Hybridoma 10:211; Morrison S. L., Oi V. T. (1989) Adv Immunol 44:65], eliminates antibody-dependent cell-mediated cytotoxicity activity, but does not substantially alter affinity or plasma clearance in mice. These studies also demonstrate for the first time (a) no difference in plasma clearance of an aglycosylated and a chimeric mAb in a primate after i.v. inoculation; (b) a difference (P less than or equal to 0.05) in mice in the more rapid peritoneal clearance of a chimeric mAb versus an aglycosylated chimeric mAb; (c) higher (0.05 less than or equal to P less than or equal to 0.1) tumor: liver ratios at 24, 72 and 168 h using 111In-labeled aglycosylated chimeric mAb versus chimeric mAb. Since the liver is the major site of metastatic spread for most carcinomas, slight differences in tumor to normal liver ratios may be important in diagnostic applications. These studies thus indicate that comparative analyses of a novel recombinant construct (i.e., aglycosylated) and its standard chimeric counterpart require documentation in more than one system and are necessary if one is ultimately to define optimal recombinant/chimeric constructs for diagnosis and therapy in humans.
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PMID:Comparative biological properties of a recombinant chimeric anti-carcinoma mAb and a recombinant aglycosylated variant. 163 52

Hybridoma technology has made the production of antigen-specific monoclonal antibodies feasible and almost routine, but the production of certain biologically desirable antibody isotypes has remained difficult. Three strains of autoimmune mice (MRL/l, NZB, and BXSB) were compared to a normal strain (BALB/c), in fusions with a BALB/c myeloma (NS-1) in order to study the rescue of relevant isotypes with the desired antigenic specificities. Mice from these four strains were immunized with colon carcinoma cells, and the hybridoma supernatants from thirty fusions were analyzed for (1) reactivity with cell surface determinants on the immunizing cell line; and (2) Ig class and subclass isotypes. We found that compared to BALB/c mice, MRL/l mice produced greater numbers, and NZB and BXSB mice comparable numbers, of cell surface-reactive hybridoma clones per fusion. MRL/l mice produced the largest number and highest percentage of cell-surface reactive IgG2a (22.4%) and IgG3 (10.6%) producing clones, followed by NZB mice which produced predominantly IgG2a clones (12.3%). BXSB mice, which have latent autoimmune disease, showed no significant difference from normal BALB/c controls (IgG2a:0.7% and IgG3:1.9% vs. IgG2a:4.8% and IgG3:4.8%). The increase in IgG2a and IgG3 clones derived from MRL/l mice was age-dependent, correlating with the age at which abnormal proliferation of T cell and splenic enlargement occurs (2-4 months). We conclude that MRL/l mice are useful for generating monoclonal antibodies of the IgG2a or IgG3 isotype, provided fusions are performed at the time of maximal lymphoproliferation.
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PMID:Increased yields of IgG2a- and IgG3-secreting hybridomas after fusion of B cells from mice with autoimmune diseases. 196 Apr 13

To avoid the exclusive use of rodent monoclonal antibodies (MAbs) in patients for the detection of tumors by immunoscintigraphy and for radioimmunotherapy, swine MAbs were produced that are directed against carcinoembryonic antigen (CEA). Spleen cells from 2 pigs immunized with purified colon carcinoma CEA were fused with a nonsecreting mouse myeloma cell line by conventional methods, except that a particularly long immunization protocol and large amounts of spleen and myeloma cells were used. Of 1,200 growing hybrids tested, 20 were found initially to produce antibodies binding to radiolabeled CEA. Seven stable clones producing anti-CEA MAbs for more than 6 months were derived from these hybrids by repeated subcloning. The pig origin of the seven MAbs was demonstrated in a solid-phase CEA enzyme immunoassay where anti-pig immunoglobin (Ig) antibodies coupled to peroxidase gave a positive reaction while anti-mouse Ig antibodies were entirely negative. All swine MAbs were of the IgG isotype. Three anti-CEA MAbs showed no cross-reactivity with granulocytes, while four others gave various degrees of reactivity with different granulocyte glycoproteins. Competitive binding to CEA performed for two purified swine MAbs showed that they recognized two different epitopes. The affinity constants measured for these two MAbs by Scatchard plot on purified CEA were high (1.2 X 10(9) and 1.2 X 10(10) liter/mol). One of the MAbs was tested in vivo for tumor localization by injection, after radiolabeling, in nude mice bearing human colon carcinoma xenograft. High ratios of tumor to normal tissue were obtained with mean values of 10.5 for intact MAbs and of 26.8 for F(ab')2 fragments of the porcine MAb. The results showed that heterofusion with this particular protocol can be used to produce swine MAbs of high affinity and specificity for a well-defined tumor marker. These reagents may have an important clinical utility, particularly in patients who became sensitized to mouse immunoglobulins.
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PMID:Swine monoclonal antibodies of high affinity and specificity to carcinoembryonic antigen. 243 34

By fusion of mouse NS1 myeloma cells with splenocytes from a BALB/c mouse immunized with human melanoma cells, an IgG1 monoclonal antibody, designated as 140.72, was produced. By the mixed hemadsorption antibody binding assay, 140.72 was shown to react with 17 of 20 melanoma cell lines and with 5 of 14 carcinoma cell lines. This antibody also reacted with 3 of 3 normal melanocyte cultures in much lower titers. It did not react with any of 35 other normal and malignant lines, including neuroblastoma, glioblastoma, sarcoma, teratoma, fibroblast, and lymphoid cell lines. Absorption with fresh melanoma and carcinoma homogenates confirmed the results of direct tests. Fetal reactivity of antibody 140.72 was determined by positive absorption with 10 of 11 tissue homogenates derived from different fetuses of 10-16 weeks' gestation. The reactivity of this antibody was completely removed by absorption with a highly purified preparation of carcinoembryonic antigen (CEA) derived from a colon carcinoma. The antigenic activity was detected in the culture medium of reactive cell lines. Immunoprecipitation analyses of melanoma and carcinoma cells indicated that the antigenic determinant recognized by antibody 140.72 is on a glycoprotein with an apparent molecular weight of 95,000-150,000 common to both serologically reactive cell types. Additionally, a 200,000-molecular-weight glycoprotein corresponding to the CEA molecule was detected only on the reactive carcinoma cells. These data confirmed previous findings obtained with polyclonal anti-CEA antisera for the existence of shared CEA-related antigenic determinants on human carcinomas and melanomas and provided additional molecular characterization of these glycoproteins. Further characterization of the molecules bearing the antigenic determinant recognized by antibody 140.72 should be performed with a view to exploring its potential in the immunodiagnosis and immunotherapy of patients with melanoma.
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PMID:Monoclonal antibody recognizing human melanoma-carcinoma cross-reacting oncofetal antigen epitopically associated with carcinoembryonic antigen. 258 73

A chimeric antibody was constructed in which the murine H- and L-chain variable regions of mAb 17-1A, raised against human colorectal cancer cells, were joined with the human constant mu and kappa regions. Transfection of these constructs into the murine myeloma Sp2/0 resulted in the expression and secretion of a pentameric Ig, designated chimeric 17-1A IgM. The chimeric 17-1A IgM was subsequently compared to a previously described chimeric 17-1A IgG1 for biological activities. Both chimeric mAbs were equally effective (weight basis) in competing against the binding of murine 125I-17-1A to cultures of HT-29 colon carcinoma cells. The calculated association constants for the chimeric 17-1A IgM and IgG1 were 1.63 x 10(8) l/mol and 3.41 x 10(7) l/mol, respectively. Unlike chimeric 17-1A IgG1, the chimeric 17-1A IgM was able to render colon carcinoma target cells susceptible to lysis by both xenogeneic (rabbit) and human complement. The extent of complement-mediated lysis dependent upon chimeric 17-1A IgM was correlated to 17-1A antigen expression on target cells. HT-29 colon carcinoma cells treated with chimeric 17-1A IgM did not directly result in antibody-dependent cellular cytotoxicity by human peripheral blood monocytes. However, chimeric 17-1A IgM greatly enhanced the deposition of C3 on complement-treated HT-29 cells, and concomitant incubation with monocytes resulted in heightened lysis of the tumor cells. The feasibility of enhancing host defense against gastrointestinal malignancies by the administration of this chimeric 17-1A IgM may have certain clinical advantages.
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PMID:Biological characterization of a chimeric mouse-human IgM antibody directed against the 17-1A antigen. 259 74

A monoclonal rat IgM (kappa) antibody (MAb) is produced by a hybridoma obtained by fusion of the rat myeloma Y3 Ag 1.2.3 with spleen cells from a female W/Fu rat bearing a yolk-sac carcinoma isograft. In the rat this antibody (4D7) shows strong selective binding to all tested yolk-sac carcinomas, but no binding to cultured cells of a number of other tumor types or to cells of normal tissues. Immunohistochemical analysis of the specificity of the antibody confirmed the strong binding to yolk-sac carcinomas and also revealed binding to some other rat tissues. These include one colon carcinoma, the embryonic ectoderm and the primitive visceral endoderm of 8.5-day-old embryos, the central nervous system and the oviduct epithelium and some cells in the seminal tubules, the gastrointestinal epithelium and associated mucus and also the distal tubuli and collecting ducts of the kidney. The MAb binds strongly to purified SSEA-1 but not to purified Lewis A glycolipid. It is concluded that the 4D7 MAb recognizes a determinant which is identical to or includes Gal beta 1-4(Fuc alpha 1-3) GlcNAc. The immunogenicity of the SSEA-1 determinant is further confirmed by the demonstration that antibodies binding to purified SSEA-1 but not to Lewis A appear in the sera of some of the rats developing primary yolk-sac carcinoma.
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PMID:A rat monoclonal antibody 4D7 produced by a hybridoma established from a yolk-sac tumor-bearing rat binds selectively to the stage-specific embryonic antigen SSEA-1. 288 79

Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of the breast and ovary, as well as multiple myeloma. Although commercially available in Europe and Canada, intravenous (IV) melphalan remains investigational in the United States. The role of IV melphalan in cancer chemotherapy is not well defined, despite its manageable toxicity and higher and more predictable blood levels following IV administration compared with oral administration. In addition, unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken. At lower doses (eg, 30 to 70 mg/m2), both as a single agent and in combination, the activity of IV melphalan has been evaluated in only a limited number of diseases. However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma, a disease not generally considered responsive to alkylating agents. When administered at high doses (greater than 140 mg/m2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no improvement in survival) in a variety of nonhematologic tumor types, including resistant tumors such as melanoma and colon carcinoma. In contrast, in poor-prognosis patients with non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity. Additional clinical trials will be necessary to define the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan.
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PMID:The systemic administration of intravenous melphalan. 305 5

Chessboard vaccination (i.d. injection of various mixtures of mitomycin-treated fresh cells of the DE-TA colon carcinoma cell line and Vibrio cholerae neuraminidase (VCN] had a beneficial effect on recurrence and survival in Duke C patients. To standardize this kind of immunotherapy the following parameters of the DE-TA cell have been evaluated:--Karyotype (46 chromosomes, deletions in chromosome 8; 17); doubling time 24 hr; expression of CEA.--Stability of membrane antigens characterized by 9 different monoclonal antibodies over more than 40 cell culture passages.--Homogeneity of cell culture as evaluated by limiting dilution cloning at different culture passages and evaluation of expression of membrane antigens. Immunogenicity of lyophilized cells compared to cultured fresh cells by counting the number of specific antibody secreting clones after fusing spleen cells of immunized mice with SP-2/0-Ag14 mouse myeloma. As this characterization as well as safety tests (lack of infectious particles, tumorigenicity in nude mice) revealed no apparent risks, lyophilized DE-TA cells will be used as a standardized stable cell preparation for clinical trials.
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PMID:Characterization of a colon carcinoma cell line for tumor immunotherapy. 318 Jan 40

The effects of recombinant human interferon-alpha A/D (rIFN-alpha A/D, a subtype of recombinant human leukocyte interferon with biological activities against murine tumor cells) on the growth of murine tumors were studied. rIFN-alpha A/D significantly inhibited the growth of mouse M5076 reticulum cell sarcoma, MOPC-104E myeloma, colon carcinoma 26 and Meth A fibrosarcoma by dose-dependent fashion. rIFN-alpha A/D also inhibited the metastases and growth of Lewis lung carcinoma and showed a synergistic effect with combination of cyclophosphamide. The antitumor activity of rIFN-alpha A/D was observed by intra-muscular, intravenous, subcutaneous, intraperitoneal injections or by the injection at the site of the tumors.
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PMID:[Effects of recombinant human interferon-alpha A/D on the growth of experimental tumors in mice]. 330 69

We studied the pharmacokinetic properties of two human monoclonal antibodies to colon carcinoma cells and their ability to detect tumors in nude mice bearing primary human colon carcinoma xenografts. The 16-88 and 28A32 monoclonal antibodies are immunoglobulin M class human antibodies produced by cell lines derived from peripheral blood lymphocytes from patients with colon carcinoma. The patients received an autologous tumor cell vaccine as part of an active specific immunotherapy protocol. The 125I-labeled antibodies were cleared from the circulation of non-tumor-bearing and tumor-bearing nude mice with a 6-8-h half-life. The half-life of the antibodies in tumor tissue was 48 to 72 h compared to 8 to 12 h for normal tissues. Tumor:normal tissue ratios were highest 4 to 7 days postinjection with tumor:blood ratios of 12:1 for 16-88 and 10:1 for 28A32 antibody. Experiments with a control human immunoglobulin M myeloma protein confirmed the specificity of the human monoclonal antibodies. Radioimmunoscintigraphic studies using nude mice bearing contralateral antibody-reactive and nonreactive colon tumor xenografts further confirmed that the antibodies specifically localized in tumor tissues. The antibody-reactive tumors were clearly visible by radioimmunoscintigraphy within 4 days of injection. These experiments, undertaken as a preliminary step to clinical trials, demonstrated for the first time that i.v. administered human immunoglobulin M monoclonal antibodies could be taken up by human colon tumor tissue and retained to a sufficient extent to easily permit tumor detection by external radioimmunoscintigraphy. These studies also demonstrated that the nude mouse human colon tumor xenograft model is a useful in vivo system for comparison studies of human monoclonal antibodies as part of a selection process for clinical trials and for evaluating immunoconjugates containing these antibodies for relative pharmacokinetic properties and potential diagnostic or therapeutic efficacy.
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PMID:Preclinical studies on the pharmacokinetic properties of human monoclonal antibodies to colorectal cancer and their use for detection of tumors. 339 Aug 31


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