In vitro and in vivo evaluation of direct rhenium-188-labeled anti-CD52 monoclonal antibody alemtuzumab for radioimmunotherapy of B-cell chronic lymphocytic leukemia

2008 ◽  
Vol 35 (5) ◽  
pp. 599-604 ◽  
Author(s):  
Mario De Decker ◽  
Klaus Bacher ◽  
Hubert Thierens ◽  
Guido Slegers ◽  
Rudi A. Dierckx ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
In Vivo Evaluation ◽  
Cell Chronic Lymphocytic Leukemia

scholarly journals Effect of a thymic factor on T lymphocytes in B cell chronic lymphocytic leukemia: in vitro and in vivo studies

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 667-671 ◽  
Author(s):  
F Lauria ◽  
D Raspadori ◽  
S Tura
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
B Cell ◽  
Proliferative Response ◽  
Lymphocytic Leukemia ◽  
Before And After ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abnormalities of T lymphocytes in B cell chronic lymphocytic leukemia (B-CLL) have been extensively documented by several immunologic investigations. Following recent studies pointing to the favorable effect of TP-1, a partially purified extract of calf thymus, on the T cell-mediated immunity of several diseases, including Hodgkin's disease, we have used monoclonal antibodies and the enriched T lymphocytes of 16 untreated B-CLL patients to evaluate the proportion of T cell subsets before and after the administration of TP-1. In addition, the proliferative response to phytohemagglutinin (PHA) and the helper function in a pokeweed mitogen (PWM) system were assessed. In ten cases, the effect of TP-1 was also studied in vitro by evaluating the same parameters before and after incubation of B-CLL T cells with the drug. The study demonstrated that in vivo administration of TP-1 increases significantly (P less than .001) the proportion of the defective helper/inducer T cell population (OKT4-positive cells) in B-CLL, leading to a near normal OKT4/OKT8 ratio. Furthermore, the improved phenotypic profile was accompanied by an increased proliferative response to PHA and, in particular, by a significant increase (P less than .01) of T helper capacity; this increase was, however, insufficient to enable the normalization of the serum immunoglobulin levels. The in vitro incubation of B-CLL T lymphocytes did not succeed in producing significant modifications in distribution and function.

scholarly journals Effect of a thymic factor on T lymphocytes in B cell chronic lymphocytic leukemia: in vitro and in vivo studies

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 667-671
Author(s):  
F Lauria ◽  
D Raspadori ◽  
S Tura
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
B Cell ◽  
Proliferative Response ◽  
Lymphocytic Leukemia ◽  
Before And After ◽  
Cell Chronic Lymphocytic Leukemia

Abnormalities of T lymphocytes in B cell chronic lymphocytic leukemia (B-CLL) have been extensively documented by several immunologic investigations. Following recent studies pointing to the favorable effect of TP-1, a partially purified extract of calf thymus, on the T cell-mediated immunity of several diseases, including Hodgkin's disease, we have used monoclonal antibodies and the enriched T lymphocytes of 16 untreated B-CLL patients to evaluate the proportion of T cell subsets before and after the administration of TP-1. In addition, the proliferative response to phytohemagglutinin (PHA) and the helper function in a pokeweed mitogen (PWM) system were assessed. In ten cases, the effect of TP-1 was also studied in vitro by evaluating the same parameters before and after incubation of B-CLL T cells with the drug. The study demonstrated that in vivo administration of TP-1 increases significantly (P less than .001) the proportion of the defective helper/inducer T cell population (OKT4-positive cells) in B-CLL, leading to a near normal OKT4/OKT8 ratio. Furthermore, the improved phenotypic profile was accompanied by an increased proliferative response to PHA and, in particular, by a significant increase (P less than .01) of T helper capacity; this increase was, however, insufficient to enable the normalization of the serum immunoglobulin levels. The in vitro incubation of B-CLL T lymphocytes did not succeed in producing significant modifications in distribution and function.

A Monoclonal Antibody Specifically Targeting CD44 Inhibits B-Cell Chronic Lymphocytic Leukemia Cell Survival In Vitro and In Vivo

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 927-927
Author(s):  
Suping Zhang ◽  
Christina C.N. Wu ◽  
Jessie-Farah Fecteau ◽  
Bing Cui ◽  
Rongrong Wu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Survival ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Equity Ownership ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 927 B-cell chronic lymphocytic leukemia (CLL) with a highly variable clinical course is characterized by the clonal expansion of CD5+ B cells in blood, secondary lymphoid tissues, and marrow. Survival of CLL cells are supported by cells within the tissue microenvironment and by signals from the extracellular matrix, which in part are mediated via interactions with CD44, a surface glycoprotein that is expressed at high levels by CLL B cells. While monoclonal antibody (mAb) therapy targeting CD20 has improved the survival of patients with CLL, a large number of CLL patients do not achieve durable responses or become refractory altogether to therapy with anti-CD20 mAb. In this study we evaluated the cytotoxic activity against CLL cells of a newly developed, humanized anti-CD44 mAb (RO5429083, Roche). We found that sub-microgram concentrations of this anti-CD44 mAb were directly cytotoxic for CLL cells of different patients (n = 32), but had little or no effect on the viability of lymphocytes isolated from the blood of healthy donors (n = 4). The levels of cytotoxicity induced by this anti-CD44 mAb were significantly associated with the levels of CD44 expressed by each of the CLL samples (Spearman R-0.5785, p<0.001). Furthermore, survival and downstream signaling events of CLL cells induced by hyaluronic acid (HA), the principal ligand of CD44, were inhibited by this CD44 mAb. Of note, this CD44 mAb also was equally cytotoxic for CLL cells co-cultured with mesenchymal stromal cells (MSC), which otherwise can support CLL-cell survival in vitro. We also examined whether this anti-CD44 mAb could induce clearance of human CLL cells engrafted into immune deficient RAG-2−/−/γc−/− mice. Treatment of such xenografted animals with as little as 1 mg/kg of this mAb resulted in the complete clearance of engrafted CLL cells, an effect not observed in control treated animals. Based on these pre-clinical studies, we consider this anti-CD44 mAb has high potential for providing effective treatment for patients with this disease. Disclosures: Weigland: Roche Diagnostics GmbH: Employment. Carson:Wintherix: Equity Ownership. Kipps:Gilead Sciences: Consultancy, Research Funding; GSK: Research Funding; Genentech: Research Funding; Abbott Industries: Research Funding; Celgene: Consultancy, Research Funding; Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

A novel monoclonal antibody recognizing human thymocytes and B-cell chronic lymphocytic leukemia cells

1994 ◽  
Vol 39 (2) ◽  
pp. 137-146 ◽  
Author(s):  
P. Tassone ◽  
P. Bonelli ◽  
F. Tuccillo ◽  
H.M. Bond ◽  
M.C. Turco ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Cell Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

scholarly journals Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1012-1020 ◽  
Author(s):  
JS Moore ◽  
MB Prystowsky ◽  
RG Hoover ◽  
EC Besa ◽  
PC Nowell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Specific Immunoglobulin ◽  
Cell Chronic Lymphocytic Leukemia

The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

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