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)

Recombinant DNA techniques were utilized successfully to join the coding regions for the variable region of a mouse anti-tumor antibody (BA-Br-1) and the human IgG1 constant region for both the light and heavy chains. After insertion into a mouse myeloma host cell line, the chimeric genes were expressed successfully and the resulting antibody (ING-1) was purified. In this study, we describe biochemical, serological, immunohistochemical, and functional properties of the chimeric ING-1 antibody. Analysis of the synthesized antibody revealed that while it was similar in size to the mouse antibody, it had a different pI as determined by isoelectrofocusing. The flow cytometric binding profiles of the new molecule were found to be essentially identical to the parental mouse immunoglobulin. The specificity of the chimeric ING-1 and mouse BA-Br-1 antibodies were compared by extensive immunohistochemical analysis on human normal and tumor tissues. The chimeric antibody retained the same broad carcinoma binding activity, showing strong reactivity with greater than 90% of epithelial tumor tissues, as was previously observed for the mouse BA-Br-1 antibody. The chimeric and mouse antibodies also recognized the same selected normal tissues: primarily glandular epithelia, gastrointestinal mucosa, bile ducts, and thyroid follicles. Analysis of the biological function of the chimeric antibody revealed that it possessed ADCC activity against antigen-bearing tumor targets in vitro which was absent from the mouse form of the antibody. Competent effector cells could be either PBMCs from normal healthy donors, PBMCs from cancer patients receiving LAK/IL-2 therapy, or LAK cells prepared from cancer patients. Enhanced cytotoxicity even in the presence of LAK cell killing was noted with effector cells from the latter two sources. This contrasts sharply with the absence of activity in the same systems when the native murine antibody was used. The in vitro activation of cell-dependent cytolysis observed with the chimeric antibodies when effector cells from both normal and tumor-bearing donors were used strongly suggests that comparable activity would be observed in vivo. These results, along with the broad carcinoma binding activity and minimal normal tissue reactivity, suggest that the ING-1 chimeric antibody may be useful in cancer therapy. The application of the ING-1 chimeric antibody for treatment of tumors thus offers a promising avenue for future research.
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PMID:Binding and functional properties of a mouse-human chimeric monoclonal antibody of the human IgG1 subclass with specificity for human carcinomas. 210 54

Mouse monoclonal antibody 17-1A is specific for an antigen expressed on cells of human gastrointestinal malignancies and has been used in radioimmune imaging and therapy trials for patients with colon and pancreatic cancer. The cell line SG3/5 was generated by transfection of a nonproducing mouse myeloma line (SP2/0) with a chimeric gene construct composed of variable regions from the mouse 17-1A immunoglobulin (gamma 2a, kappa) and constant regions of human k and gamma 3 immunoglobulin genes. The secreted immunoglobulin was bound by mouse monoclonal antibodies to human IgG(Fc) and IgG3 but not by staphylococcal protein A. Gel filtration HPLC profiles of purified chimeric antibody were similar to normal human IgG3 but quite different from native 17-1A and normal human IgG1, 2, and 4. Native and chimeric 17-1A had similar patterns of reactivity with colon cancer, other adenocarcinoma, and leukemic cell lines. Competitive inhibition documented that native and chimeric 17-1A had identical capacities to inhibit radiolabeled native 17-1A binding to colon cancer cell lines. Thus, the chimeric 17-1A exhibits molecular characteristics of normal human IgG3 but retains the specificity and binding affinity of the native 17-1A murine monoclonal antibody. The native and chimeric 17-1A mediated similar modest degrees of human lymphocyte and monocyte ADCC in a 4-hr 51Cr release assay, and both failed to mediate complement lysis of colon carcinoma cell lines in the presence of human complement. This human/mouse chimeric monoclonal antibody may be a good candidate for use in clinical trials because it retains the tumor antigen specificity and human effector cell recognition of the native 17-1A, would presumably have a fivefold to 10-fold longer circulating half-life in man, and should be considerably less immunogenic as compared with native murine immunoglobulins.
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PMID:Characterization of a mouse/human chimeric monoclonal antibody (17-1A) to a colon cancer tumor-associated antigen. 358 80

To determine whether monoclonal gammopathy of undetermined significance (MGUS) resembles multiple myeloma (MM) with regard to phenotype and functional activity, 16 patients with MGUS and 16 with untreated MM were studied for surface markers and cytotoxic activities phytohemagglutinin-induced cellular cytotoxicity (PHA-ICC), antibody-dependent cellular cytotoxicity, natural killer (NK) activity. Our data showed a consistent immunological similarity between the two diseases. An increase in OKT8+ cells was evident in both patient groups and a significant reduction in the T4/T8 ratio, more pronounced in MM, was observed. Alterations in NK activity or ADCC were not found in MGUS or MM. A significant increase in PHA-ICC was demonstrated in the two diseases. The increase in PHA-ICC observed seems to be attributable to an increased frequency and/or lytic efficiency of PHA-ICC lymphoid effector cells. These data suggest that similar immunological alterations are common to the two diseases. The greater helper/suppressor ratio reduction observed in MM seems to be related to the more severe clonal proliferation in these patients.
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PMID:Surface markers and cytotoxic activities of lymphocytes in monoclonal gammopathy of undetermined significance and untreated multiple myeloma. Increased phytohemagglutinin-induced cellular cytotoxicity and inverted helper/suppressor cell ratio are features common to both diseases. 366 30

K-1-21 is a monoclonal antibody which binds to human free kappa light chains and recognises a determinant, KMA selectively expressed on kappa myeloma and lymphoma cells. KMA is absent on plasma cells and resting B cells from normal adults but can be detected on some foetal B cells and a small proportion of activated B cells. Expression of KMA is greatest on cycling cells. K-1-21 is an IgG1 antibody that elicits ADCC but will not cap the KMA determinant unless a second ligand is present. K-1-21 has potential for practical application.
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PMID:A monoclonal antibody with selectivity for human kappa myeloma and lymphoma cells which has potential as a therapeutic agent. 393 33

Studies on the identification, cloning, and biochemical characterization of natural and recombinant human and mouse low-affinity soluble Fc gamma R (sFc gamma R) have been developed using various methods. RT-PCR and/or biochemical analyses have demonstrated that low-affinity sFc gamma R (i) are generated by enzymatic cleavage of membrane-associated receptors or by an alternative splicing of the transmembrane region encoding exon and (ii) comprise only the extracellular domains or these domains plus the intracellular region of the membrane-associated molecules, respectively. Functional studies indicated that recombinant sFc gamma R bind mouse and human IgG subclasses with a binding profile identical to that of their membrane counterparts and inhibit Fc gamma R-mediated functions such as immune complex binding or ADCC. In addition, it has been demonstrated that a mouse recombinant truncated sFc gamma RII inhibits antibody responses to T-dependent antigens as well as B-cell proliferation and that a human recombinant truncated sFc gamma RIIIB blocks the Ig production by activated human peripheral blood mononuclear cells. Finally, different immunoassays devised to detect and quantitate circulating sFc gamma R showed that sFc gamma R serum levels vary in circumstances such as injections of protein antigens, in parasitic infections, in tumor-bearing mice, in patients with multiple myeloma (MM), or upon infusions of IgG or Fc gamma fragments in MM or immune thrombocytopenic purpura patients. The use of recombinant sFc gamma R, as well as the availability of monoclonal and polyclonal antibodies directed against different regions of these molecules, makes it possible to characterize further the biological effects of sFc gamma R and their biochemical and immunochemical characteristics, as well as to define their putative ligands on cell membranes.
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PMID:Natural and recombinant soluble low-affinity Fc gamma R: detection, purification, and functional activities. 806 28

HM1.24 antigen has been identified as a surface molecule preferentially expressed on terminally differentiated B cells, and its overexpression is observed in multiple myeloma cells. The HM1.24 antigen is, therefore, expected as a most potent target molecule for antibody-based immunotherapy for multiple myeloma. Here, we have identified the cDNA for human HM1.24 antigen and also analyzed its gene structure including the promoter region. The HM1.24 antigen is a type II membrane glycoprotein, which has been reported as a bone marrow stromal cell surface antigen BST2, and may exist as a homodimer on myeloma cell surface. Although a reason for the overexpression in myeloma cells is not understood, very interestingly, the promoter region of the HM1.24 gene has a tandem repeat of three cis elements for a transcription factor, STAT3, which mediates interleukin-6 (IL-6) response gene expression. Since IL-6 is a differentiation factor for B cells, and known as a paracrine/autocrine growth factor for multiple myeloma cells, the expression of HM1.24 antigen may be regulated by the activation of STAT3. Importantly, a humanized anti-HM1.24 antibody effectively lysed the CHO transformants which expressed HM1.24 antigen as high as human multiple myeloma cells, but not the cells with lower antigen expression. This evaluation shows that ADCC heavily depends on the expression level of target antigens and, therefore, the immunotherapy targeting the HM1.24 antigen should have a promising potential in clinical use.
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PMID:Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells. 1032 29

Multiple myeloma is currently considered incurable despite the use of high-dose chemotherapy with autologous hematopoietic stem cell transplantation support. Here, we show antitumor efficacy of a novel bivalent single-chain antibody fragment (scFv) against CD47 in an in vivo myeloma model. We generated two types of novel scFv molecules against CD47 having apoptosis-inducing activity for leukemic cell lines: a non-covalently linked scFv dimer (diabody) and a covalently linked bivalent scFv. Administration of these bivalent scFvs significantly prolonged the survival of mice transplanted with KPMM2 human myeloma cells. Because bivalent scFvs induced neither ADCC nor CDC, such antitumor activity by bivalent scFv is presumably attributable to cell death caused by the ligation of CD47. Thus, these apoptosis-inducing scFvs will be effective as a novel therapy for multiple myeloma which is considered incurable with conventional therapy.
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PMID:Apoptosis inducing bivalent single-chain antibody fragments against CD47 showed antitumor potency for multiple myeloma. 1572 79

The CD38 molecule is well represented on cell surfaces in many cases of a variety of lymphoid tumors, notably multiple myeloma, AIDS-associated lymphomas, and post-transplant lymphoproliferations. As such, this molecule is a promising target for antibody therapy. After early disappointments, improved anti-CD38 antibodies of strong cytolytic potential have been described by 3 groups. First, a human IgG monoclonal anti-CD38 antibody raised in mice transgenic for human Ig has been found to induce potent complement and cellular cytotoxicities against both myeloma cell lines and fresh harvests from myeloma marrow and leukemic blood. This antibody also exhibits the singular property of inhibiting the CD38 cyclase activity. Second, a series of CD38-specific human antibodies, with high affinities and high ADCC activities against cell lines and primary cultures of myeloma, has been selected from a unique phage-display library. Finally, to enhance specificity for myeloma cells, bispecific domain antibodies targeting both CD38 and CD138 have been developed. As they lack any Fc module, these constructs rely on cytotoxicity for delivering a toxin to tumor cells. The list of candidate CD38-bearing neoplasms as targets for these antibody constructs can now be expanded to include acute promyelocytic leukemia, and possibly other myeloid leukemias, in which surface CD38 can be induced by retinoid treatment. One caveat here is that evidence has been produced to suggest that CD38 promotes pulmonary manifestations of the hazardous retinoic acid syndrome.
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PMID:CD38 as a therapeutic target. 1738 Feb 3

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.
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PMID:Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. 2597 91

CS1 (also known as CD319, CRACC and SLAMF7) was identified as an NK cell receptor regulating immune functions. It is also expressed on B cells, T cells, Dendritic cells, NK-T cells, and monocytes. CS1 is overexpressed in multiple myeloma and makes it a target for immunotherapy. A humanized anti-CS1 antibody, Elotuzumab or Empliciti has shown promising results in clinical studies. This review focuses on the biology of CS1 in NK and other hematopoietic cells and multiple myeloma. Anti-CS1 mAb can activate natural cytotoxicity of NK cells as well as enhance ADCC (antibody-dependent cell-mediated cytotoxicity) and thus makes an effective target for immunotherapy of MM.
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PMID:CS1 (SLAMF7, CD319) is an effective immunotherapeutic target for multiple myeloma. 2886 20


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