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)

CC49 is a second-generation monoclonal antibody (MAb) that has high affinity for the tumor-associated pancarcinoma antigen tumor-associated glycoprotein-72. In clinical trials using gamma scanning, radiolabeled CC49 has facilitated the detection of more than 90% of carcinomas. We report here the development of a constant heavy-chain 2 (CH2) domain-deleted chimeric (c) CC49 MAb by transfecting an expression construct consisting of the CC49 murine variable region and a CH2 domain-deleted human IgG1 constant region into cCC49 kappa producing SP2/0 murine myeloma cells. As determined by SDS-PAGE, the intact cCC49 delta CH2 has a molecular weight of 153,000 and, under reducing conditions, molecular weights of 43,000 and 27,000. The plasma clearance and tumor-targeting properties of cCC49 delta CH2 were evaluated and compared with those of mouse/human chimeric forms cCC49 delta CH1 and intact cCC49. Previous studies have shown that the in vitro antigen-binding properties of cCC49 delta CH1 are similar to those of cCC49. Biodistribution studies reported here, using 131I-labeled cCC49 delta CH1 and 125I-labeled cCC49 in athymic mice bearing human colon carcinoma xenografts, demonstrated that both cMAbs localized to the tumor and cleared from the normal tissues similarly. However, in comparison with 125I-labeled cCC49, 131I-labeled cCC49 delta CH2 localized to tumors earlier and had a significantly lower percentage of the injected dose of cMAb/g (%ID/g) in normal tissues than cCC49. Immunoscintigraphy of 131I-labeled cCC49 delta CH2 and 125I-labeled cCC49 in athymic mice bearing human tumor xenografts demonstrated a clear image of the tumor by 24 h after i.v. administration of the delta CH2 cMAb versus the 72 h required for cCC49. Biodistribution studies using 177Lu-conjugated cCC49 delta CH1 and cCC49 showed no significant difference between the radiolocalization indices (% ID/g in tumor divided by % ID/g in normal tissue). 177Lu-conjugated cCC49 delta CH2, however, had lower % ID/g values in tumor xenografts and lower radiolocalization indices than either 177Lu-conjugated cCC49 delta CH1 or 177Lu-conjugated cCC49. Pharmacokinetic studies in non-tumor-bearing athymic mice using cCC49 delta CH1 and cCC49 revealed no significant difference between these cMAbs. However, the plasma clearance of cCC49 delta CH2 in non-tumor-bearing mice was significantly faster than that of cCC49. These results were similar when the cMAbs were labeled with either iodine or lutetium. In nonhuman primates, 131I-labeled cCC49 delta CH2 cleared significantly faster than 125I-labeled cCC49. The similar plasma clearance and tumor localization of cCC49 and cCC49 delta CH1 suggest that these two cMAbs may be used in similar clinical settings. However, because of the unique pharmacokinetics and tumor targeting of cCC49 delta CH2 versus cCC49 or cCC49 delta CH1, this chimeric immunoglobulin form may be useful in clinical settings that require efficient tumor targeting and rapid serum and whole-body clearance.
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PMID:Biological properties of chimeric domain-deleted anticarcinoma immunoglobulins. 749 77

27 engineered chimeric antibodies possessing human gamma, epsilon, mu or alpha constant regions and V region specificity for nitrophenyl or dansyl were used to study the isotype specificity of 29 murine monoclonal antibodies (MAbs) specific for human immunoglobulins (IgG1-4, IgE, IgM, IgA or secretory piece). The isotype-restricted immunoreactivity observed with wild-type chimeric antibodies paralleled the pattern of each MAb's reactivity with purified human myeloma proteins. 16 mutant IgG anti-dansyl chimeric antibodies with genetically engineered domain switches, deletions or point-mutations were used as antigens to further characterize the epitopes recognized by the human IgG subclass-specific MAbs. The binding of three human IgG1-specific MAbs (HP6069, HP6070 and HP6091) was mapped to similar epitopes on the CH2 domain of human IgG1. Of the two anti-human IgG2 MAbs tested, HP6002 reacted with the CH2 of IgG2 while HP6014 bound to the CH1 domain. Both anti-human IgG3 MAbs (HP6047, HP6050) reacted with different regions of the IgG3 hinge. The anti-human IgG4 MAbs (HP6023, HP6025) bound to a similar epitope on the carboxyl terminus of CH2 or the CH3 of human IgG4. The three exclusion antibodies (HP6019, HP6030 and HP6058) bound to different epitopes in the CH2 domain of three of four IgG subclasses. The domain mapping was confirmed by competitive inhibition experiments. These results were used to select a group of IgG-reactive MAbs for construction of a poly-monoclonal anti-IgG capture and detection reagent that uniformly bound all four subclasses of human IgG. This study provides support for the use of engineered chimeric human chimeric antibodies as replacements for increasingly rare, purified human paraproteins in the specificity analysis of immunochemical reagents used in clinical and research laboratories for the detection and quantitation of human antibodies. Moreover, these studies demonstrate how the MAbs can serve as effective probes for examining conformational differences among the four human IgG subclasses.
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PMID:Epitope mapping of human immunoglobulin-specific murine monoclonal antibodies with domain-switched, deleted and point-mutated chimeric antibodies. 767 28

A human monoclonal IgA1-IgA2 lambda hybrid molecule was detected in a myeloma patient homozygous for the A2m(1) allotype during a systematic study of monoclonal IgA with subclass-specific monoclonal antibodies (mAb) and the lectin jacalin. This monoclonal immunoglobulin (GAU) reacted with both, although not with all, anti-alpha 1 and anti-alpha 2 mAb. Its heavy (H) chain contained an alpha 1 hinge region as shown by jacalin reactivity, the presence of disulfide-linked H and light chains in spite of its belonging to the IgA2m(1) allotype and amino acid composition of the isolated hinge region. The complete sequence of the H chain was deduced from that of complementary DNA clones from bone marrow cells. The CH1 domain, hinge region and beginning of the CH2 domain and the membrane peptide were encoded by the alpha 1 gene, with an insertion of an alpha 2m(1) gene sequence accounting for the end of the CH2 and part or all of the CH3 domain (sequence identity between the two normal genes precludes a precise definition of breakpoints). The region of the 5' recombination site included a repeat of a six base pair sequence which might play a role in the genetic exchange. The GAU hybrid alpha gene was undetectable in the patient's genomic DNA from polymorphonuclear cells. The genetic event which occurred at the level of the proliferating plasma cell clone is most likely to be a gene conversion.
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PMID:A human myeloma IgA with a hybrid heavy chain resulting from putative somatic gene conversion. 843 72

The proliferating plasma cells of patient COM with nonsecretory myeloma synthesized truncated 42 kDa gamma 1 chains made of a complete constant region but devoid of variable domain. In the absence of light chain expression, the shortened gamma chains were retained intracellularly and were subsequently degraded within 12 h. COM neoplastic plasma cells contained short gamma 1 heavy chain transcripts in which the leader peptide exon was directly joined to the CH1 exon using the regular splice sites. However, study of the productive gamma gene showed that the skipped variable exon was bounded by normal splicing signals and that the adjacent intron organization was not altered. Since this unusual splicing pattern was maintained when COM gamma gene was transfected in murine plasmocytoma cells, exon skipping possibly relates to the modified structure of COM variable region. The latter showed a 2-base pair deletion introducing a translation frameshift in the VH region and a DNA insertion at the VH-DJH junction consisting in a perfect duplication of the first 54 nucleotides of the recombined DJH segment. The lack of light chain production by COM cells was explained by alterations of the variable region of the rearranged kappa gene leading to abnormally spliced transcripts.
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PMID:Exon skipping without splice site mutation accounting for abnormal immunoglobulin chains in nonsecretory human myeloma. 850 May 24

Mc5, a murine monoclonal antibody that binds to human breast epithelial mucin (BEM), has been shown to be a promising reagent in the diagnosis of breast cancer. We have cloned cDNAs encoding both variable regions of Mc5 (VL and VH) as well as the CL and CH1 constant regions. Mc5 is an IgG1, kappa antibody. We have constructed an IgG1, kappa human/mouse chimeric antibody (by inserting the murine VH and VL-encoding cDNAs into plasmids encoding human constant domains), and expressed it in SP2/0-Ag14 mouse myeloma cells. The affinity of chimeric Mc5 (chMc5) for BEM is 4.4 x 10(8) M-1. Mc5 binds BEM with an affinity constant of 2.8 x 10(8) M-1. Purified chMc5 and purified Mc5 gave similar competition curves when tested against either 125I-labeled Mc5 or 125I-labeled chMc5 for binding to BEM in a competition radioimmunodetection format. Additionally, chMc5 used in breast carcinoma tissue staining stained as well as the original Mc5.
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PMID:Cloning and expression of cDNAs encoding the variable domains of the antibreast carcinoma antibody Mc5. 874 96

The construction, synthesis and expression of a genetically engineered bifunctional antibody/cytokine fusion protein is described. To target IFN-tau to tumor cells, recombinant antibody techniques were used to construct a RM4/IFN-tau fusion protein containing the chimeric anti-tumor F(ab')2 (RM4) and the IFN-tau moiety. The recombinant cDNA of IFN-tau was linked to 3 prime end of the chimeric heavy-chain gene fragment (M4) containing the VH, the CH1 and the hinge region to form the fused heavy-chain gene fragment M4-IFN-tau. Transfection of the M4-IFN-tau gene fragment into a myeloma derived cell line VKCK which produced the chimeric light-chain of the same antibody, allowed the transfectant secreting the bifunctional fusion protein RM4/IFN-tau. The RM4/IFN-tau was purified by the affinity chromatography. Our data showed that the RM4/IFN-tau retained the TAG72 antigen-binding reactivity as well as the IFN-tau activity as measured in ELISA, FACS analysis of cell-surface TAG72 expression, immunohistochemical study, and up-regulation of cell-surface expression of CEA, HLA class I and class II antigens. Therefore, the bifunctional fusion protein RM4/IFN-tau may prove to be useful in targeting biological effects of the IFN-tau to tumor cells and in this way to stimulate the immune destruction of tumor cells.
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PMID:Targeting gamma interferon to tumor cells by a genetically engineered fusion protein secreted from myeloma cells. 888 31

A method of obtaining mutants defective in the regulatory function of Ig mu gene expression was developed. Such mutants are useful for discovering the functions of transcription factors and isolating their genes, especially those of DNA-unbinding factors. Cells expressing Ig mu and Eco-GPT simultaneously under control of each mu enhancer were prepared as follows: myeloma X63Ag8.653 cells were transfected with pSV-V mu Me delta CH1 encoding a mu gene modified for cell surface mu expression without light chains, selected by neomycin resistance, transfected with Eco-GPT gene connected to the mu enhancer, and selected with mycophenolic acid in a medium containing xanthine. The mu(m)/Eco-GPT cells were mutated with ethane methyl sulfonate (EMS), and selected with toxin-conjugated anti-mu antibody, and then with 6-thioguanine. The mu(M)-/Eco-GPT- mutants obtained were fused with X63Ag8.653 cells. Fusion caused the mutant to recover mu(M) expression, suggesting that some trans-acting transcription factor other than the mu-encoding gene itself was probably mutated.
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PMID:Method of obtaining mutants defective in immunoglobulin mu transcription factors. 898 61

Nonspecific IgE binding to allergens was observed in testing myeloma IgEs, namely, IgE-VL and IgE-PS, chimeric IgE (IgE-JW8), and the recombinant IgE Fc epsilon peptide CH1-CH4, in two different immunoassays. This binding was concentration-dependent but detectable only at higher IgE concentration. In RAST inhibition, IgE-allergen interactions could be reduced by using either matching or nonmatching allergens. In order to test whether the nonspecific binding of IgE to allergens was due to carbohydrate interaction, myeloma IgEs and the chimeric IgE were desialized with neuraminidase. Desialized samples were equally well recognized by xenogenic antibodies as native IgEs, but binding of IgE to Fc epsilon receptors on basophils was affected by the treatment, as shown in the histamine-release assay. Desialization of IgE affected also its binding capacity to allergens in RAST: binding of chimeric IgE was reduced, but nonspecific binding of myeloma IgE-VL was enhanced. Hence, nonspecific allergen-IgE binding may be partly due to a lectin-like interaction, but may depend mostly on the tertiary structure of IgE. Thus, nonspecific IgE-allergen interactions might present a problem 1) at high IgE concentration, and 2) depend on the grade of sialization of IgE, which might affect its conformation. This may explain why patients with elevated total IgE levels often have multiple weak positive RASTs with non-cross-reactive allergens.
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PMID:Nonspecific binding of IgE to allergens. 928 84

A 45-year-old white woman was found to have microscopic hematuria during her annual physical examination. After a negative urologic workup, she returned 5 months later with nephrotic syndrome, renal insufficiency, and hypocomplementemia. Renal biopsy showed a nodular sclerosing glomerulopathy that could not be further characterized because of inadequate tissue for immunofluorescence. The patient returned 8 months later with chronic renal failure. A repeat renal biopsy showed deposits composed of immunoglobulin G (IgG) heavy chain and complement components C3 and C1 along glomerular, tubular, and vascular basement membranes, with negativity for kappa and lambda light chains, findings consistent with heavy chain deposition disease (HCDD). The heavy chain subclass was exclusively IgG3. Staining with monoclonal antibodies to epitopes of the constant domains of IgG heavy chain showed a CH1 deletion, indicating a truncated heavy chain. On review of the previously reported cases of HCDD, common clinical presentations include nephrotic syndrome, renal insufficiency, hematuria, and, in some cases, hypocomplementemia. In most patients, the hematologic disorder is mild, without overt myeloma. Light microscopy shows a nodular sclerosing glomerulopathy, and heavy chain deposits are detectable within basement membranes throughout the kidney by immunofluorescence and electron microscopy. There is no effective treatment for this condition, and virtually all patients progress to chronic renal failure.
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PMID:Heavy chain deposition disease: the disease spectrum. 1021 55

This study reports the clinicopathologic findings and outcome in 34 patients with renal monoclonal immunoglobulin deposition disease (MIDD), which included 23 light-chain DD (LCDD), 5 light- and heavy-chain DD (LHCDD), and 6 heavy-chain DD (HCDD). A total of 23 patients had pure MIDD, whereas 11 patients had LCDD with coexistent myeloma cast nephropathy (LCDD & MCN). Renal biopsy diagnosis preceded clinical evidence of dysproteinemia in 68% of all cases. By immunofluorescence, the composition of deposits included 11kappa/1lambda (LCDD), 3IgGkappa/2IgGlambda (LHCDD), 5gamma/1alpha (HCDD), and 10kappa/1lambda (LCDD & MCN). Patients with pure MIDD presented with mean serum creatinine of 4.2 mg/dl, nephrotic proteinuria, and hypertension. Cases of HCDD were associated with a CH1 deletion and frequently had hypocomplementemia and a positive hepatitis C virus antibody but negative hepatitis C virus PCR. LCDD & MCN is a morphologically and clinically distinct entity from pure MIDD, presenting with higher creatinine (mean, 7.8 mg/dl; P = 0.01), greater dialysis dependence (64 versus 26%; P = 0.053), subnephrotic proteinuria, and less nodular glomerulopathy (18 versus 100%; P < 0.0001). Multiple myeloma was more frequently diagnosed in LCDD & MCN than in pure MIDD (91 versus 31%; P = 0.025). Renal and patient survivals were significantly worse in patients with LCDD & MCN (mean, 4 and 22 mo, respectively), compared with patients with pure MIDD (mean, 22 and 54 mo). Chemotherapy stabilized or improved renal function in 10 of 15 patients (67%) with pure MIDD who presented with creatinine of <5.0 mg/dl, emphasizing the importance of early detection. On multivariate analysis, initial creatinine was the only predictor of renal and patient survival in pure MIDD, underscoring the prognostic significance of the renal involvement.
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PMID:Renal monoclonal immunoglobulin deposition disease: the disease spectrum. 1142 77


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