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

The anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) is used to treat patients with various B-cell tumors, including patients with plasma cell dyscrasias who have CD20+ disease. Many patients with CD20+ disease have either primary unresponsive disease or progress after initially responding to rituximab; therefore, understanding how tumor cells are, or become, resistant to rituximab is of clinical relevance. In this report, we determined whether tumor cells express antigens that block complement-mediated lysis or antibody-dependent cell-mediated cytotoxicity (ADCC) and thereby contribute to rituximab resistance. We demonstrate that expression of the complement regulator CD59 is associated with resistance to rituximab-mediated complement lysis of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Moreover, neutralization of CD59 using a blocking monoclonal antibody reversed resistance to rituximab-mediated complement lysis of CD20++ CD59++ ARH-77 MM cells. In addition, we demonstrate the presence of CD59 and rituximab binding on viable tumor cells from patients with MM and Waldenstrom's macroglobulinemia with progressive disease despite rituximab therapy. Last, we also examined MM and NHL B-cell lines, as well as patient tumor cells, for the expression of other antigens that may have a role in blocking ADCC activity, such as Fas ligand (FasL), MUCI, or TRAIL. FasL, MUC1, and/or TRAIL were coexpressed with complement regulators on many of these cells. These studies therefore show that complement regulators, particularly CD59 and antigens that may block ADCC, are present on various B-cell tumors and associated with rituximab resistance in patients. A prospective, clinical study is assessing the role of these antigens in mediating rituximab resistance.
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PMID:Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. 1139 5

SUMMARY: The anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) is used to treat patients with various B-cell tumors, including patients with plasma cell dyscrasias who have CD20+ disease. Many patients with CD20+ disease have either primary unresponsive disease or progress after initially responding to rituximab; therefore, understanding how tumor cells are, or become, resistant to rituximab is of clinical relevance. In this report, we determined whether tumor cells express antigens that block complement-mediated lysis or antibody-dependent cell-mediated cytotoxicity (ADCC) and thereby contribute to rituximab resistance. We demonstrate that expression of the complement regulator CD59 is associated with resistance to rituximab-mediated complement lysis of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Moreover, neutralization of CD59 using a blocking monoclonal antibody reversed resistance to rituximab-mediated complement lysis of CD20++ CD59++ ARH-77 MM cells. In addition, we demonstrate the presence of CD59 and rituximab binding on viable tumor cells from patients with MM and Waldenstrom's macroglobulinemia with progressive disease despite rituximab therapy. Last, we also examined MM and NHL B-cell lines, as well as patient tumor cells, for the expression of other antigens that may have a role in blocking ADCC activity, such as Fas ligand (FasL), MUC1, or TRAIL. FasL, MUC1, and/or TRAIL were coexpressed with complement regulators on many of these cells. These studies therefore show that complement regulators, particularly CD59 and antigens that may block ADCC, are present on various B-cell tumors and associated with rituximab resistance in patients. A prospective, clinical study is assessing the role of these antigens in mediating rituximab resistance.
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PMID:Tumor Cell Expression of CD59 Is Associated With Resistance to CD20 Serotherapy in Patients With B-Cell Malignancies. 1139 43

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder characterized by a decrease or absence of glycosylphosphatidylinositol (GPI)-anchored molecules such as CD55 and CD59 from the surface of affected cells, resulting in intravascular hemolysis, cytopenia, and venous thrombosis. A PNH-like phenotype has been detected in various hematological disorders, mainly in aplastic anemia and myelodysplastic syndromes, but also in lymphoproliferative syndromes (LPSs). To the best of our knowledge, CD55- or CD59-deficient red cells have not been detected in plasma cell dyscrasias (PCDs). The aim of this study was the detection of CD55- and/or CD59-deficient red cell populations in patients with PCD. Seventy-seven patients were evaluated; 62 with multiple myeloma (MM), 7 with Waldenstrom macroglobulinemia (WM), 6 with monoclonal gammopathy of undetermined significance (MGUS), and 2 with heavy chain disease (HCD). The sephacryl gel microtyping system was applied; Ham and sucrose lysis tests were also performed on all samples with CD55- or CD59-negative populations. Red cells deficient in both molecules were detected in 10 (12.9%) of 77 patients with PCD: 2 (28.6%) of 7 with WM, 1 (16.6%) of 6 with MGUS, 6 (9.6%) of 62 with MM, and 1 of 2 patients with HCD. Isolated CD55 deficiency was found in 28.5% of all PCD patients, whereas isolated CD59 deficiency was not observed in any patients. These findings illustrate the existence of the PNH phenotype in the red cells of patients with PCD; further investigation is needed into the mechanisms and significance of this phenotype.
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PMID:Detection of CD55- and/or CD59-deficient red cell populations in patients with plasma cell dyscrasias. 1184 89

Human IgM antibody (Ab) to gangliosides induced cytolysis of HIV-1-infected cells by homologous human complement. We expected that any human IgM Ab reactive with HIV-1 infected cells could cause complement-mediated cytolysis. The trans-chromosome mouse (TC mouse) contains human chromosomes harboring genes responsible for immunoglobulin production. Spleen cells from TC mice immunized with recombinant Nef were fused with mouse myeloma cells to generate hybridomas, and we selected those that produced human mu-chain-positive Abs reactive with Nef fixed on an ELISA plate. However, the L-chain of the monoclonal Abs (mAbs) were murine lambda in type and were chimeric, and we could not succeed in obtaining mAb with human mu- and human kappa-chains. The chimeric mAbs reacted with the HIV-1 infected cells as seen with flow cytometric analysis, and the surface expression of Nef was also detectable on chronically infected OM10.1 cells which had no detectable gp120. However, although the reaction of the chimeric IgM mAb with HIV-1-infected MOLT4 cells induced C3 deposition on cell surfaces on incubation with fresh human serum, the cells remained unlysed, as determined by 51Cr release assay. The amount of Nef antigen on the cells might not have been high enough to overcome the function of HRF20 (CD59) that restricts formation of membrane attack complexes of homologous complement. However, combination of anti-Nef IgM mAb with other IgM mAbs reactive with the surface of HIV-1-infected cells may induce a synergistic effect in complement mediated cytolysis.
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PMID:Chimeric human/murine monoclonal IgM antibodies to HIV-1 Nef antigen expressed on chronically infected cells. 1272 96

Paroxysmal nocturnal hemoglobinuria (PNH) clones deficient in glycosylphosphatidylinositol-anchored molecules, including CD55 and CD59, have been previously described in patients with multiple myeloma (MM). The aim of this study was to investigate the possible association between existence of the PNH phenotype and myeloma bone disease. Forty-three patients with newly diagnosed MM were the subjects of the study. Radiographic evaluation of the skeleton was performed in all patients at diagnosis. The following biochemical markers were measured: bone resorption markers (tartrate-resistant acid phosphatase isoform 5b [TRACP-5b]and N-terminal cross-linking telopeptide of type-I collagen [NTX]), bone formation markers (bone alkaline phosphatase [bALP] and osteocalcin [OC]), osteoprotegerin (OPG), soluble receptor activator of nuclear factor KB ligand (sRANKL), and interleukin 6 (IL-6). Detection of CD55- and/or CD59-deficient red cell populations was performed after diagnosis. Patients with MM had elevated mean baseline NTX, TRACP-5b, sRANKL, and IL-6 levels compared with controls, whereas the mean values of bALP, OC, and OPG were significantly decreased. Four patients had no osteolytic lesions, whereas 8 patients had 1 to 3 lytic lesions, and 31 patients had more than 3 lytic lesions and/or pathologic fractures in the skeletal survey. CD55- and/or CD59-deficient red cell populations were observed in 56% of patients with MM. There was a strong correlation between the presence of PNH-like erythrocytes and increased bone resorption, as measured by NTX, TRACP-5b, and sRANKL/OPG ratio (P < .03, P < .02, and P < .02, respectively). There was also a significant correlation between PNH phenotype and severe bone disease (P < .02). These results suggest that there is a possible link between PNH phenotype and increased osteoclastic activity in MM owing to a potential effect of myeloma microenvironment on a preexisting PNH clone. Further studies are required for clarifying this phenomenon and investigating possible mechanisms of this unusual association.
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PMID:Unusual association between increased bone resorption and presence of paroxysmal nocturnal hemoglobinuria phenotype in multiple myeloma. 1468 93

The trans-chromosome (TC) mouse that we used harbors human chromosomes 2, 14 and/or 22, and has undergone knock-out of its endogeneous genes coding for mu-and kappa-chains of immunoglobulin. One of these TC mice was immunized with HIV-1-infected U937 cells, and spleen cells from the immunized animal were fused with the mouse myeloma cell line to generate hybridoma cells. We selected hybridomas that produce human IgM antibodies (Abs) reactive with HIV-1-infected MOLT4 cells but not with uninfected MOLT4 cells. Two hybridoma cell lines were established termed 9F11 and 2G9. Although 0.4 mug/ml of 9F11 was able to induce complement-mediated cytolysis of the infected cells in the presence of fresh human serum, 2G9 could not. There was no difference between the two monoclonal Abs in the base sequences of cDNAs coding for the constant regions of mu-and kappa-chains. Therefore, we speculate that the ability to activate complement on homologous cell membranes might reflect the structural presentation of antigenic molecules, which could facilitate the binding of an IgM Ab to multiple binding sites resulting in escape from restriction by species-specific inhibitors of complement such as DAF (CD55) and CD59. On the other hand, 2G9 induced apoptosis of HIV-1-infected cells, including latently infected OM10.1 cells, although the Ag for 2G9 remains to be identified. Since both of the Abs had reduced reactivity toward HIV-1-infected MOLT4 cells following cultivation in the presence of tunicamycin, the responsible antigens would involve a sugar moiety.
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PMID:Human IgM monoclonal antibodies reactive with HIV-1-infected cells generated using a trans-chromosome mouse. 1590 7

Although increased blood cell deficiency of glycosyl phosphatidylinositol-anchored membrane proteins has often been detected in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS), the clinical significance of such paroxysmal nocturnal hemoglobinuria (PNH)-type cells remains to be elucidated. We established a sensitive flow cytometric assay capable of detecting less than 0.01% of CD59-CD55- blood cells in a sample and used the assay to examine a large number of patients with bone marrow failure. An increase in the proportion of PNH-type cells was detectable in approximately 60% of all AA patients and in 20% of all refractory anemia (RA)-MDS patients. The increase was undetectable in patients with RA with an excessive number of blasts, acute myelogenous leukemia, multiple myeloma, or systemic lupus erythematosus. Our study showed that the presence of an increased number of PNH-type cells was predictive of a good response to immunosuppressive therapy and a favorable prognosis among patients with recently diagnosed AA and RA. A sensitive flow cytometric analysis for detection of a small population of PNH-type cells in peripheral blood cells is one of the most important examinations in the management of bone marrow failure.
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PMID:Clinical significance of a small population of paroxysmal nocturnal hemoglobinuria-type cells in the management of bone marrow failure. 1692 32

Many monoclonal antibodies (mAbs) have been extensively used in the clinic, such as rituximab to treat lymphoma. However, resistance and non-responsiveness to mAb treatment have been challenging for this line of therapy. Complement is one of the main mediators of antibody-based cancer therapy via the complement-dependent cytolysis (CDC) effect. CD59 plays a critical role in resistance to mAbs through the CDC effect. In this paper, we attempted to investigate whether the novel CD59 inhibitor, recombinant ILYd4, was effective in enhancing the rituximab-mediated CDC effect on rituximab-sensitive RL-7 lymphoma cells and rituximab-induced resistant RR51.2 cells. Meanwhile, the CDC effects, which were mediated by rituximab and anti-CD24 mAb, on the refractory multiple myeloma (MM) cell line ARH-77 and the solid tumor osteosarcoma cell line Saos-2, were respectively investigated. We found that rILYd4 rendered the refractory cells sensitive to the mAb-mediated CDC effect and that rILYd4 exhibited a synergistic effect with the mAb that resulted in tumor cells lysis. This effect on tumor cell lysis was apparent on both hematological tumors and solid tumors. Therefore, rILYd4 may serve as an adjuvant for mAb mediated-tumor immunotherapy.
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PMID:Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells. 2125 60

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

The anti-CD38 monoclonal antibody daratumumab is well tolerated and has high single agent activity in heavily pretreated relapsed and refractory multiple myeloma (MM). However, not all patients respond, and many patients eventually develop progressive disease to daratumumab monotherapy. We therefore examined whether pretreatment expression levels of CD38 and complement-inhibitory proteins (CIPs) are associated with response and whether changes in expression of these proteins contribute to development of resistance. In a cohort of 102 patients treated with daratumumab monotherapy (16 mg/kg), we found that pretreatment levels of CD38 expression on MM cells were significantly higher in patients who achieved at least partial response (PR) compared with patients who achieved less than PR. However, cell surface expression of the CIPs, CD46, CD55, and CD59, was not associated with clinical response. In addition, CD38 expression was reduced in both bone marrow-localized and circulating MM cells, following the first daratumumab infusion. CD38 expression levels on MM cells increased again following daratumumab discontinuation. In contrast, CD55 and CD59 levels were significantly increased on MM cells only at the time of progression. All-trans retinoic acid increased CD38 levels and decreased CD55 and CD59 expression on MM cells from patients who developed daratumumab resistance, to approximately pretreatment values. This resulted in significant enhancement of daratumumab-mediated complement-dependent cytotoxicity. Together, these data demonstrate an important role for CD38 and CIP expression levels in daratumumab sensitivity and suggest that therapeutic combinations that alter CD38 and CIP expression levels should be investigated in the treatment of MM. These trials were registered at www.clinicaltrials.gov as #NCT00574288 (GEN501) and #NCT01985126 (SIRIUS).
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PMID:CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. 2730 94


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