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)

We have determined the variable region sequences of four heavy chains from beta(1-6)D-galactan-binding myeloma proteins. Two of these proteins are identical to position 100 which is located in the third complementarity-determining region (CDR-3). The remaining two differ at a total of 8 positions over the first 100 amino acids, and all of the differences can be explained by single-base mutations at the DNA level. When an assessment is made of the protein segment following CDR-3, which has been termed "J segment" or "FR4," a completely different pattern of variation is observed. The J segments from the four proteins can be divided into two sets. Members of each set share a series of linked amino acids not found in members of the alternative set. The two proteins identical to position 100 have J segments from the two different sets, suggesting that recombination has occurred between V and J genes. An examination of the CDR-3 sequences from the four heavy chains reveals substitutions at positions 100 and 105. Gly is found at 100 in two of the proteins and His in the remaining two. In the two proteins with Gly-100, the following J sequence is limited to one of the two sets of J segments defined by linked amino acids. Similarly, the two heavy chains with His-100 have J segments from the second set. Thus, at the protein level an apparent association is seen between CDR-3 and J segment. If CDR-3 should be found linked to J segment at the DNA level, a new mechanism would be introduced for increasing antibody diversity by recombining various CDR-3 plus J genes with genes coding for the remainder of the variable region. Alternatively, if CDR-3 were coded for by the V gene, then the recombination of V with J may provide an opportunity to introduce mutations in CDR-3. In this case the linkage of amino acids in CDR-3 and the J segments would suggest that recognition signals are used such that certain V genes only pair with a given J gene.
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PMID:Structural evidence for independent joining region gene in immunoglobulin heavy chains from anti-galactan myeloma proteins and its potential role in generating diversity in complementarity-determining regions. 11 Dec 45

Myeloma M 104E (IgM, lambda 1) with specificity for the alpha(1----3) glucosidic linkage of dextran B 1355 S (Dex) carries two idiotopes (Id) as defined by isogenic anti-idiotype mAb. The public Id is not influenced by two amino acid replacements in CDR 2 nor by an alternative D region sequence. It is shared by all or nearly all humoral antibodies in the primary immune response against Dex of mice carrying haplotype Igha. The private Id-5' appears to depend on the integrity of the VH germ-line sequence and on the particular M 104E D region sequence. It is present on a highly fluctuating but usually small fraction of primary anti-Dex antibody. We report here that this situation is changed when mice are treated with Cobra venom anti-complement factor (CVF), after birth and thereby were deprived of complement for the first two weeks of life. When immunized with Dex as adults the majority of anti-Dex Ab carried the M 104E Id-5. Thus, humoral antibody in CVF-treated animals resembled the Ly-1+ anti-Dex precursor B cell population in the peritoneal cavity, while anti-Dex Ab in animals not treated with CVF more closely corresponded to the Ly-1- precursor B cell pool in spleen (H.-P. Lehmann and G. Lehle, Eur. J. Immunol. 1991. 21: 1201).
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PMID:Neonatal complement depletion results in predominant expression of a myeloma M 104E private idiotope among anti-dextran antibodies. 170 69

Amyloid subunit proteins related to the lambda IV subgroup of immunoglobulin light chains have not been previously reported. We have determined the amino acid sequence of an AL amyloid protein BAK and shown that it has the structure typical of lambda IV light chain proteins. This protein, which was isolated from the spleen of a patient with AL amyloidosis, has 111 residues in the variable domain and also includes the first tryptic peptide of the constant domain for a total of 130 residues. Comparison of the primary structure of this protein with the only other completely characterized lambda IV protein (SH) reveals that they are highly homologous with only one amino acid change in FR1, two changes in FR2, and one change in FR3. The CDR regions also show few changes, with only three in CDR1, one in CDR2, and five in CDR3. To test the hypothesis that the formation of AL amyloid is related to changes in the FR regions which could affect molecular aggregation, the structure of BAK was compared with the myeloma protein SH with respect to the presumed tertiary structure. Only limited amino acid substitution was found in the surface positions that might affect intradimer and interdimer aggregation. These included an isoleucine for leucine change at position 43 and phenylalanine for valine at 45, which may affect intradimer interaction and a change of histidine to asparagine at position 67.
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PMID:Amyloidosis related to a lambda IV immunoglobulin light chain protein. 249 77

We have cloned a rearranged immunoglobulin heavy chain variable (VH) region gene (NL-1-H-5) from the cells of a mouse hybridoma, NL-1, which produce a monoclonal antibody against the common acute lymphocytic leukemia (cALL) antigen. The DNA base sequence of NL-1-H-5 clone revealed that the VH region gene of NL-1 cells used the identical or closely related leader (L) and VH gene to those of the myeloma cell line MOPC-21. There were seven base differences, and six of them were found in the second complementary-determining hypervariable region (CDR-2). The five nucleotide differences in CDR-2 resulted in the variation of amino acid residues of positions 54, 56, 58, and 59. In particular, nucleotide changes at position 56 and 59 yielded tyrosine residues which might be involved in a part of the antibody-combining site structure for cALL antigen.
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PMID:The antibody molecule to common acute lymphocytic leukemia (cALL) antigen used the identical or closely related VH gene segment as that of MOPC-21 immunoglobulin heavy chain. 315 8

The variable domains of an antibody consist of a beta-sheet framework with hypervariable regions (or complementarity-determining regions--CDRs) which fashion the antigen-binding site. Here we attempted to determine whether the antigen-binding site could be transplanted from one framework to another by grafting the CDRs. We substituted the CDRs from the heavy-chain variable region of mouse antibody B1-8, which binds the hapten NP-cap (4-hydroxy-3-nitrophenacetyl caproic acid; KNP-cap = 1.2 microM), for the corresponding CDRs of a human myeloma protein. We report that in combination with the B1-8 mouse light chain, the new antibody has acquired the hapten affinity of the B1-8 antibody (KNP-cap = 1.9 microM). Such 'CDR replacement' may offer a means of constructing human monoclonal antibodies from the corresponding mouse monoclonal antibodies.
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PMID:Replacing the complementarity-determining regions in a human antibody with those from a mouse. 371 31

The variable domain (V) sequence of the lambda-light chain of the Gar IgG2 human myeloma protein was determined from enzymatically generated peptides that were isolated, characterized, and ordered by overlap and/or by subgroup homology. The sequence consisted of the amino terminal 107 residues of the light chain, and shared subgroup V lambda III-specific residues as well as a pattern of CDR deletions unique to most V lambda III sequences. The structural role of the light V region in the high affinity for flavins and the low affinity for 2,4-dinitrophenyl haptens characteristic of the intact IgG molecule was coarsely assessed by way of model building and by comparison with the refined combining site model of MOPC 315, an Ig with relative affinity values for DNP and riboflavin the converse of those observed in Gar.
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PMID:The modeled structure of the IgG Gar VL region and its implications for anti-flavin and anti-DNP fine specificities. 641 82

Multiple myeloma is a malignancy of plasma cells for which there is no effective treatment. To develop an immunotherapeutic agent, we have raised a high affinity mAb (AT13/5) against CD38, one of the few well-characterized surface Ags present on myeloma cells. Since murine monoclonals have many disadvantages as human therapeutics, we prepared two engineered forms of the Ab: a CDR-grafted humanized IgG1 and a chimeric FabFc2 (mouse Fab cross-linked to two human gamma 1 Fc). To retain affinity in the humanized Ab, a number of changes were required to the human framework regions of the heavy chain. In particular, through systematic mutagenesis and computer modeling, we identified a critical interaction between the side chains of residues 29 and 78, which may be important for the humanization of other Abs. The properties of the humanized IgG1 and FabFc2 constructs were compared in a series of in vitro tests. Both constructs efficiently directed Ab-dependent cellular cytotoxicity against CD38-positive cell lines, but C was activated only poorly. Neither construct caused down-modulation of CD38, nor did they affect the NADase activity of CD38. Despite their differing structures, both Abs showed similar activity in most assays, although the humanized IgG1 was more potent at inducing monocyte cytotoxicity. These data represent the first direct comparison of CDR-grafted and chimeric FabFc2 forms of the same Ab, and offer no support for the perceived advantages of the FabFc2. These Abs show promise for therapy of multiple myeloma and other diseases involving CD38-positive cells.
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PMID:Engineered anti-CD38 monoclonal antibodies for immunotherapy of multiple myeloma. 760 68

BrE-3 is an IgG1,kappa murine monoclonal antibody that binds to human breast epithelial mucin and that has been shown to be promising for imaging and treatment of breast cancer. We have cloned and sequenced cDNAs encoding the variable regions of the light (VL) and heavy (VH) chains of BrE-3. VL belongs to group II and resulted from a V kappa-J kappa 1 fusion. VH belongs to group IIIc and arose from a V-D-JH3 non-conservative fusion which left little or nothing of the original D minigene. Thus, the third VH CDR contains only 4 amino-acids. We constructed an IgG1,kappa human/mouse chimeric antibody (by joining the murine variable domains to human constant domains) and expressed it in SP2/0 myeloma cells. This chimeric monoclonal antibody stains breast carcinoma tissue sections by the ABC immunoperoxidase method. Its affinity for the BrE-3 antigen is 2.68 x 10(8) M-1, which, considering the experimental error, is indistinguishable from the affinity of the original murine antibody (3.75 x 10(8) M-1). The VL and VH domains alone are respectively 73%, and 63% identical to the human V kappa II and VHIII consensus sequences. If the CDRs are excluded, these numbers become respectively 82% and 80%. Therefore, we expect the reported chimeric BrE-3 to be considerably less immunogenic to humans than the original murine antibody, while retaining the original binding properties.
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PMID:Cloning of cDNAs encoding the variable domains of antibody BrE-3 and construction of a chimeric antibody. 845 2

One advantage of the use of peripheral blood stem cells (PBSCs) over autologous bone marrow would be a reduced risk of tumor cell contamination. However, the level of neoplastic cells in the PB of multiple myeloma (MM) patients after mobilization protocols is poorly investigated. In this study, we evaluated PB samples from 27 pretreated MM patients after the administration of high dose cyclophosphamide (7 g/m2 or 4 g/m2) and granulocyte-colony stimulating factor for the detection of myeloma cells as well as hematopoietic progenitors. Plasma cells containing intracytoplasmic lg were counted by microscope immunofluorescence after incubation with appropriate antisera directed against light- and heavy-chain lg. Moreover, flow cytometry studies were performed to determine the presence of malignant B-lineage elements by using monoclonal antibodies against the CD19 antigen and the monotypic light chain. Before initiation of PBSC mobilization, circulating plasma cells were detected in all MM patients in a percentage ranging from 0.1% to 1.8% of the mononuclear cell fraction (mean value, 0.7% +/- 0.4% SD). In these patients, a higher absolute number of PB neoplastic cells was detected after chemotherapy and granulocyte colony-stimulating factor. Kinetic analysis showed a pattern of tumor cell mobilization similar to that of normal hematopoietic progenitors with a maximum peak falling within the optimal time period for the collection of PBSCs. The absolute number of plasma cells showed a 10 to 50-fold increase as compared with the baseline value. Apheresis products contained 0.7% +/- 0.2% SD of myeloma cells (range, 0.2% to 2.7%). Twenty-three MM patients were submitted to PBSC collection. In 10 patients, circulating hematopoietic CD34+ cells were highly enriched by avidin-biotin immunoabsorption, were cryopreserved, and used to reconstitute bone marrow function after myeloablative therapy. The median purity of the enriched CD34+ cell population was 89.5% (range, 51% to 94%), with a 75-fold increase as compared with the pretreatment samples. The median overall recovery of CD34+ cells and colony-forming unit-granulocyte-macrophage was 58% (range, 33% to 95%) and 45% (range, 7% to 100%), respectively. Positive selection of CD34+ cells resulted in 2.5- to 3-log depletion of plasma cells and CD19+ B-lineage cells as determined by immunofluorescence studies, although DNA analysis of CDR III region of IgH gene showed the persistence of minimal residual disease in 5 of 6 patient samples studied. Myeloma patients were reinfused with enriched CD34+ cells after myeloablative therapy consisting of total body irradiation (1,000 cGy) and highdose melphalan (140 mg/m2). They received a median of 4 x 10(6) CD34+ cells/kg and showed a rapid reconstitution of hematopoiesis; the median time to 0.5 x 10(9) neutrophils and to 20 and 50 x 10(9) platelets per liter of PB was 10, 11, and 12 days, respectively. These results, as well as other clinically significant parameters, did not significantly differ from those of patients (n = 13) receiving unmanipulated PBSCs after the same pretransplant conditioning regimen. In summary, our data show the concomitant mobilization of tumor cells and hematopoietic progenitors in the PB of MM patients. Positive selection of CD34+ cells reduces the contamination of myeloma cells from the apheresis products up to 3-log and provides a cell suspension capable of restoring a normal hematopoiesis after a total body irradiation-containing conditioning regimen.
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PMID:Concomitant mobilization of plasma cells and hematopoietic progenitors into peripheral blood of multiple myeloma patients: positive selection and transplantation of enriched CD34+ cells to remove circulating tumor cells. 860 57

In this article, we review neoplastic contamination in the peripheral blood (PB) of patients with multiple myeloma (MM) upon stem cell mobilization. We first evaluated PB samples from pretreated MM patients following administration of high-dose cyclophosphamide (Cy, 7 g/m2 or 4 g/m2) and granulocyte colony-stimulating factor (G-CSF) for the presence of myeloma cells as well as hematopoietic progenitors. Plasma cells containing intracytoplasmic immunoglobulin (cIg) were counted by immunofluorescence microscopy after incubation with appropriate antisera against light and heavy chain Ig. Flow cytometry studies were performed to determine the presence of malignant B lineage elements, using monoclonal antibodies against the CD19 antigen and the monotypic light chain. Prior to PBSC mobilization, circulating plasma cells were detected in all MM patients at 0.1%-1.8% of the mononuclear cell (MNC) fraction (mean value 0.7 +/- 0.4% SD). In these patients, a higher absolute number of PB neoplastic cells was detected after administration of chemotherapy and G-CSF. Kinetic analysis showed a pattern of tumor cell mobilization similar to that of normal hematopoietic progenitors, with the peak coinciding with the optimal period for the collection of PBSC. The absolute number of plasma cells showed a 10-50-fold increase over the baseline value. Apheresis products contained 0.7 +/- 0.2% SD myeloma cells (range 0.2%-2.7%), which demonstrated the capacity of plasma cells to proliferate, differentiate, and mature in response to c-kit ligand (SCF), IL-3, IL-6, and a combination of IL-3 and IL-6. Subsequently, in an attempt to reduce tumor cell contamination prior to autologous transplantation, circulating hematopoietic CD34+ cells were highly enriched by avidin-biotin immunoabsorption, cryopreserved, and used to reconstitute bone marrow (BM) function after myeloablative therapy in 13 patients. The median purity of the enriched CD34+ cell population was 89.5% (range 51%-94%), with a 75-fold enrichment compared with the pretreatment samples. The median overall recovery of CD34+ cells and CFU-GM was 58% (range 33%-95%) and 45% (range 7%-100%), respectively. Positive selection of CD34+ cells resulted in 2.5-3 log depletion of plasma cells and CD 19+ B lineage cells as determined by immunofluorescence studies, although DNA analysis of the CDR III region of the IgH gene demonstrated the persistence of minimal residual disease (MRD) in 5 of 6 patient samples studied. Myeloma patients were reinfused with enriched CD34+ cells after myeloablative therapy consisting of total body irradiation (TBI, 1000 cGy) and high-dose melphalan (140 mg/m2) or melphalan (200 mg/m2) alone. They received a median of 5 x 10(6) CD34+ cells/kg and showed a rapid reconstitution of hematopoiesis. The median time to 0.5 x 10(9) neutrophils, 20 x 10(9) and 50 x 10(9) platelets/L of PB was 10, 11, and 12 days, respectively. These results, as well as other clinically significant parameters, did not significantly differ from those of patients (n = 13) receiving unmanipulated PBSC following the same pretransplant conditioning regimen. Our data demonstrate the concomitant mobilization of tumor cells and hematopoietic progenitors in the PB of MM patients. Positive selection of CD34+ cells reduces the contamination of myeloma cells from the apheresis products up to 3 log and provides a cell suspension capable of restoring normal hematopoiesis following a TBI-containing conditioning regimen.
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PMID:Concomitant mobilization of plasma cells and hematopoietic progenitors into peripheral blood of patients with multiple myeloma. 887 9


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