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Chien-hsing Chang - One of the best experts on this subject based on the ideXlab platform.

  • extensive crosslinking of cd22 by epratuzumab triggers bcr signaling and caspase dependent apoptosis in human lymphoma cells
    mAbs, 2015
    Co-Authors: Chien-hsing Chang, Yang Wang, Pankaj Gupta, David M Goldenberg
    Abstract:

    Epratuzumab has demonstrated therapeutic activity in patients with non-Hodgkin lymphoma, acute lymphoblastic leukemia, systemic lupus erythematosus, and Sjogren's syndrome, but its mechanism of affecting normal and malignant B cells remains incompletely understood. We reported previously that epratuzumab displayed in vitro cytotoxicity to CD22-expressing Burkitt lymphoma cell lines (Daudi and Ramos) only when immobilized on plates or combined with a crosslinking antibody plus a suboptimal amount of anti-IgM (1 μg/mL). Herein, we show that, in the absence of additional anti-IgM ligation, extensive crosslinking of CD22 by plate-immobilized epratuzumab induced intracellular changes in Daudi cells similar to ligating B-cell antigen receptor with a sufficiently high amount of anti-IgM (10 μg/mL). Specifically, either treatment led to phosphorylation of CD22, CD79a and CD79B, along with their translocation to lipid rafts, both of which were essential for effecting caspase-dependent apoptosis. Moreover, such imm...

  • Abstract 4744: CD22-targeting epratuzumab mediates trogocytosis of multiple cell-surface markers on normal, malignant, and lupus B cells.
    Cancer Research, 2013
    Co-Authors: Edmund A. Rossi, Rosana B. Michel, Diane L. Rossi, Daniel J. Wallace, David M Goldenberg, Chien-hsing Chang
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background. Epratuzumab, a humanized anti-CD22 antibody, is currently in clinical trials of B-cell lymphoma and autoimmune diseases, demonstrating therapeutic activities in non-Hodgkin lymphoma (NHL) and systemic lupus erythematosus (SLE). Thus, epratuzumab offers a promising option for CD22-targeted immunotherapy. Although epratuzumab is capable of depleting on average 35% of circulating B cells in patients, its in vivo mechanism of action (MOA) remains incompletely understood. We hypothesized that ligation of epratuzumab to CD22 could modulate other surface molecules involved in regulating B-cell antigen receptor (BCR) signaling, leading to altered B-cell functions that ultimately mitigate symptoms of the underlying diseases. Methods. Peripheral blood mononuclear cells (PBMCs) from either healthy donors or lupus patients with flares, were incubated with epratuzumab, and the relative surface levels of CD22 and selected BCR regulators, including CD19, CD21, and CD79B, were analyzed by flow cytometry. Results. Epratuzumab promptly induced a marked decrease of CD22 (>80%), CD19 (>50%), CD21 (>50%), and CD79B (>30%) on the surface of B cells in PBMCs obtained from normal donors or treatment-naive lupus patients, and of NHL cells (Daudi and Raji) spiked into normal PBMCs. Although some Fc-independent loss of CD22 is expected from its internalization by epratuzumab, the concurrent and prominent reduction of CD19, CD21, and CD79B is Fc-dependent and results from trogocytosis of epratuzumab-bound B cells to FcγR-expressing effector cells, including monocytes, NK cells, and granulocytes. Following incubation with epratuzumab, but not with an isotype control mAb, reduced staining of surface antigens on B cells coincided with positive CD19 and CD22 staining of the effector cells. In the absence of PBMCs, treatment of NHL cell lines (Daudi and Raji) with epratuzumab resulted in more than 80% reduction of CD22, with little, if any, reduction in CD19, CD21, CD79B or surface IgM observed. Inclusion of a crosslinking second antibody with epratuzumab induced only a minimal (

  • abstract 4744 cd22 targeting epratuzumab mediates trogocytosis of multiple cell surface markers on normal malignant and lupus b cells
    Cancer Research, 2013
    Co-Authors: Edmund A. Rossi, Rosana B. Michel, Diane L. Rossi, Daniel J. Wallace, David M Goldenberg, Chien-hsing Chang
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background. Epratuzumab, a humanized anti-CD22 antibody, is currently in clinical trials of B-cell lymphoma and autoimmune diseases, demonstrating therapeutic activities in non-Hodgkin lymphoma (NHL) and systemic lupus erythematosus (SLE). Thus, epratuzumab offers a promising option for CD22-targeted immunotherapy. Although epratuzumab is capable of depleting on average 35% of circulating B cells in patients, its in vivo mechanism of action (MOA) remains incompletely understood. We hypothesized that ligation of epratuzumab to CD22 could modulate other surface molecules involved in regulating B-cell antigen receptor (BCR) signaling, leading to altered B-cell functions that ultimately mitigate symptoms of the underlying diseases. Methods. Peripheral blood mononuclear cells (PBMCs) from either healthy donors or lupus patients with flares, were incubated with epratuzumab, and the relative surface levels of CD22 and selected BCR regulators, including CD19, CD21, and CD79B, were analyzed by flow cytometry. Results. Epratuzumab promptly induced a marked decrease of CD22 (>80%), CD19 (>50%), CD21 (>50%), and CD79B (>30%) on the surface of B cells in PBMCs obtained from normal donors or treatment-naive lupus patients, and of NHL cells (Daudi and Raji) spiked into normal PBMCs. Although some Fc-independent loss of CD22 is expected from its internalization by epratuzumab, the concurrent and prominent reduction of CD19, CD21, and CD79B is Fc-dependent and results from trogocytosis of epratuzumab-bound B cells to FcγR-expressing effector cells, including monocytes, NK cells, and granulocytes. Following incubation with epratuzumab, but not with an isotype control mAb, reduced staining of surface antigens on B cells coincided with positive CD19 and CD22 staining of the effector cells. In the absence of PBMCs, treatment of NHL cell lines (Daudi and Raji) with epratuzumab resulted in more than 80% reduction of CD22, with little, if any, reduction in CD19, CD21, CD79B or surface IgM observed. Inclusion of a crosslinking second antibody with epratuzumab induced only a minimal (<15%) reduction of CD19 and CD21. When these NHL cells (1 x 105 cells) were mixed with PBMCs (1 x 106 cells), epratuzumab induced a 40 to 70% reduction of CD19 and CD21, with significant down-regulation of surface IgM and CD79B also. Under the conditions examined, rituximab at 10 μg/mL reduced the B-cell count by 50%, whereas epratuzumab did not cause significant B-cell depletion, either at 10 μg/mL or 1 mg/mL. Conclusions. This study revealed a previously unknown, and potentially important, MOA of epratuzumab. Whether the observed trogocytosis could be correlated with the depletion of malignant B cells in lymphoid tissues is currently under investigation. Citation Format: Edmund A. Rossi, David M. Goldenberg, Rosana Michel, Diane L. Rossi, Daniel J. Wallace, Chien-Hsing Chang. CD22-targeting epratuzumab mediates trogocytosis of multiple cell-surface markers on normal, malignant, and lupus B cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4744. doi:10.1158/1538-7445.AM2013-4744

S T Pals - One of the best experts on this subject based on the ideXlab platform.

Michael J Keating - One of the best experts on this subject based on the ideXlab platform.

  • CD79B expression in chronic lymphocytic leukemia
    Archives of Pathology & Laboratory Medicine, 2009
    Co-Authors: Ellen J Schlette, Jeffrey L Medeiros, Michael J Keating
    Abstract:

    Abstract Context.—CD79B is a relatively newly characterized B-cell marker that is expressed in a minority of chronic lymphocytic leukemia (CLL) cases. Objective.—To systematically correlate CD79B expression with specific morphologic and immunophenotypic findings and trisomy 12. Design.—We assessed CD79B expression in 100 consecutively accrued CLL cases that were also analyzed by conventional cytogenetics. Based on the association between trisomy 12 and CD79B expression, we then assessed 43 additional CLL cases with trisomy 12. CD79B expression was correlated with morphology and expression of other immunophenotypic markers. Results.—Eighteen (18%) of 100 consecutively accrued cases were CD79B positive. No significant association was found between CD79B expression and atypical morphology. CD79B expression correlated with CD22 and FMC7 positivity. Eight (8%) cases had trisomy 12; 4 (50%) of these were CD79B positive, suggesting an association with trisomy 12. Examination of a second group of 51 CLL cases wit...

  • CD79B expression in chronic lymphocytic leukemia. Association with trisomy 12 and atypical immunophenotype.
    Archives of Pathology & Laboratory Medicine, 2003
    Co-Authors: Ellen J Schlette, L. Jeffrey Medeiros, Michael J Keating
    Abstract:

    ○ Context.-CD79B is a relatively newly characterized B-cell marker that is expressed in a minority of chronic lymphocytic leukemia (CLL) cases. Objective.-To systematically correlate CD79B expression with specific morphologic and immunophenotypic findings and trisomy 12. Design.-We assessed CD79B expression in 100 consecutively accrued CLL cases that were also analyzed by conventional cytogenetics. Based on the association between trisomy 12 and CD79B expression, we then assessed 43 additional CLL cases with trisomy 12. CD79B expression was correlated with morphology and expression of other immunophenotypic markers. Results.-Eighteen (18%) of 100 consecutively accrued cases were CD79B positive. No significant association was found between CD79B expression and atypical morphology. CD79B expression correlated with CD22 and FMC7 positivity. Eight (8%) cases had trisomy 12; 4 (50%) of these were CD79B positive, suggesting an association with trisomy 12. Examination of a second group of 51 CLL cases with trisomy 12 (including 8 cases from the initial study group) showed that CD79B was positive in 26 cases (49%), a frequency significantly higher than that of the consecutively accrued CLL cases without trisomy 12 (P

  • CD79B expression in chronic lymphocytic leukemia association with trisomy 12 and atypical immunophenotype
    Archives of Pathology & Laboratory Medicine, 2003
    Co-Authors: Ellen J Schlette, Jeffrey L Medeiros, Michael J Keating
    Abstract:

    ○ Context.-CD79B is a relatively newly characterized B-cell marker that is expressed in a minority of chronic lymphocytic leukemia (CLL) cases. Objective.-To systematically correlate CD79B expression with specific morphologic and immunophenotypic findings and trisomy 12. Design.-We assessed CD79B expression in 100 consecutively accrued CLL cases that were also analyzed by conventional cytogenetics. Based on the association between trisomy 12 and CD79B expression, we then assessed 43 additional CLL cases with trisomy 12. CD79B expression was correlated with morphology and expression of other immunophenotypic markers. Results.-Eighteen (18%) of 100 consecutively accrued cases were CD79B positive. No significant association was found between CD79B expression and atypical morphology. CD79B expression correlated with CD22 and FMC7 positivity. Eight (8%) cases had trisomy 12; 4 (50%) of these were CD79B positive, suggesting an association with trisomy 12. Examination of a second group of 51 CLL cases with trisomy 12 (including 8 cases from the initial study group) showed that CD79B was positive in 26 cases (49%), a frequency significantly higher than that of the consecutively accrued CLL cases without trisomy 12 (P <.05). Conclusions.-We conclude that CD79B immunoreactivity is positive in approximately 20% of CLL cases and that expression correlates with trisomy 12 and atypical immunophenotypic findings.

Koji Kazahari - One of the best experts on this subject based on the ideXlab platform.

  • physical linkage of the b29 ig β CD79B gene to the skeletal muscle sodium channel and growth hormone genes in rat and human
    Genomics, 1998
    Co-Authors: Satomi Nakazato, Keiko Nomoto, Koji Kazahari
    Abstract:

    Abstract In the region between the polyadenylation site of the rat skeletal muscle (SkM) Na-channel gene and the 5′ end of the growth hormone (GH) gene, a gene coding for B-cell-specific membrane protein B29/Ig-β was found and noted to have the same orientation as the Na-channel and GH genes. Rat B29/Ig-β gene was 3.1 kb in length with six exons and was separated by 3.3 and 9.3 kb from Na-channel and GH genes, respectively. Rat B29/Ig-β protein comprised 228 amino acids, and its amino acid sequence was 85 and 69% identical with the mouse and human counterparts, respectively. With the long-area PCR method, genomic DNA connecting human SkM Na-channel (SCN4A) and B29/Ig-β (CD79B) genes and CD79B and GH (GH1) genes was amplified, and the physical linkage of SCN4A/CD79B/GH1 genes in the human genome was established. The human CD79B gene was separated by 6.3 and 10.5 kb from the SCN4A and GH1 genes, respectively.

  • Physical Linkage of the B29/Ig-β (CD79B) Gene to the Skeletal Muscle, Sodium-Channel, and Growth Hormone Genes in Rat and Human
    Genomics, 1998
    Co-Authors: Satomi Nakazato, Keiko Nomoto, Koji Kazahari
    Abstract:

    Abstract In the region between the polyadenylation site of the rat skeletal muscle (SkM) Na-channel gene and the 5′ end of the growth hormone (GH) gene, a gene coding for B-cell-specific membrane protein B29/Ig-β was found and noted to have the same orientation as the Na-channel and GH genes. Rat B29/Ig-β gene was 3.1 kb in length with six exons and was separated by 3.3 and 9.3 kb from Na-channel and GH genes, respectively. Rat B29/Ig-β protein comprised 228 amino acids, and its amino acid sequence was 85 and 69% identical with the mouse and human counterparts, respectively. With the long-area PCR method, genomic DNA connecting human SkM Na-channel (SCN4A) and B29/Ig-β (CD79B) genes and CD79B and GH (GH1) genes was amplified, and the physical linkage of SCN4A/CD79B/GH1 genes in the human genome was established. The human CD79B gene was separated by 6.3 and 10.5 kb from the SCN4A and GH1 genes, respectively.

David M Goldenberg - One of the best experts on this subject based on the ideXlab platform.

  • extensive crosslinking of cd22 by epratuzumab triggers bcr signaling and caspase dependent apoptosis in human lymphoma cells
    mAbs, 2015
    Co-Authors: Chien-hsing Chang, Yang Wang, Pankaj Gupta, David M Goldenberg
    Abstract:

    Epratuzumab has demonstrated therapeutic activity in patients with non-Hodgkin lymphoma, acute lymphoblastic leukemia, systemic lupus erythematosus, and Sjogren's syndrome, but its mechanism of affecting normal and malignant B cells remains incompletely understood. We reported previously that epratuzumab displayed in vitro cytotoxicity to CD22-expressing Burkitt lymphoma cell lines (Daudi and Ramos) only when immobilized on plates or combined with a crosslinking antibody plus a suboptimal amount of anti-IgM (1 μg/mL). Herein, we show that, in the absence of additional anti-IgM ligation, extensive crosslinking of CD22 by plate-immobilized epratuzumab induced intracellular changes in Daudi cells similar to ligating B-cell antigen receptor with a sufficiently high amount of anti-IgM (10 μg/mL). Specifically, either treatment led to phosphorylation of CD22, CD79a and CD79B, along with their translocation to lipid rafts, both of which were essential for effecting caspase-dependent apoptosis. Moreover, such imm...

  • Abstract 4744: CD22-targeting epratuzumab mediates trogocytosis of multiple cell-surface markers on normal, malignant, and lupus B cells.
    Cancer Research, 2013
    Co-Authors: Edmund A. Rossi, Rosana B. Michel, Diane L. Rossi, Daniel J. Wallace, David M Goldenberg, Chien-hsing Chang
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background. Epratuzumab, a humanized anti-CD22 antibody, is currently in clinical trials of B-cell lymphoma and autoimmune diseases, demonstrating therapeutic activities in non-Hodgkin lymphoma (NHL) and systemic lupus erythematosus (SLE). Thus, epratuzumab offers a promising option for CD22-targeted immunotherapy. Although epratuzumab is capable of depleting on average 35% of circulating B cells in patients, its in vivo mechanism of action (MOA) remains incompletely understood. We hypothesized that ligation of epratuzumab to CD22 could modulate other surface molecules involved in regulating B-cell antigen receptor (BCR) signaling, leading to altered B-cell functions that ultimately mitigate symptoms of the underlying diseases. Methods. Peripheral blood mononuclear cells (PBMCs) from either healthy donors or lupus patients with flares, were incubated with epratuzumab, and the relative surface levels of CD22 and selected BCR regulators, including CD19, CD21, and CD79B, were analyzed by flow cytometry. Results. Epratuzumab promptly induced a marked decrease of CD22 (>80%), CD19 (>50%), CD21 (>50%), and CD79B (>30%) on the surface of B cells in PBMCs obtained from normal donors or treatment-naive lupus patients, and of NHL cells (Daudi and Raji) spiked into normal PBMCs. Although some Fc-independent loss of CD22 is expected from its internalization by epratuzumab, the concurrent and prominent reduction of CD19, CD21, and CD79B is Fc-dependent and results from trogocytosis of epratuzumab-bound B cells to FcγR-expressing effector cells, including monocytes, NK cells, and granulocytes. Following incubation with epratuzumab, but not with an isotype control mAb, reduced staining of surface antigens on B cells coincided with positive CD19 and CD22 staining of the effector cells. In the absence of PBMCs, treatment of NHL cell lines (Daudi and Raji) with epratuzumab resulted in more than 80% reduction of CD22, with little, if any, reduction in CD19, CD21, CD79B or surface IgM observed. Inclusion of a crosslinking second antibody with epratuzumab induced only a minimal (

  • abstract 4744 cd22 targeting epratuzumab mediates trogocytosis of multiple cell surface markers on normal malignant and lupus b cells
    Cancer Research, 2013
    Co-Authors: Edmund A. Rossi, Rosana B. Michel, Diane L. Rossi, Daniel J. Wallace, David M Goldenberg, Chien-hsing Chang
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background. Epratuzumab, a humanized anti-CD22 antibody, is currently in clinical trials of B-cell lymphoma and autoimmune diseases, demonstrating therapeutic activities in non-Hodgkin lymphoma (NHL) and systemic lupus erythematosus (SLE). Thus, epratuzumab offers a promising option for CD22-targeted immunotherapy. Although epratuzumab is capable of depleting on average 35% of circulating B cells in patients, its in vivo mechanism of action (MOA) remains incompletely understood. We hypothesized that ligation of epratuzumab to CD22 could modulate other surface molecules involved in regulating B-cell antigen receptor (BCR) signaling, leading to altered B-cell functions that ultimately mitigate symptoms of the underlying diseases. Methods. Peripheral blood mononuclear cells (PBMCs) from either healthy donors or lupus patients with flares, were incubated with epratuzumab, and the relative surface levels of CD22 and selected BCR regulators, including CD19, CD21, and CD79B, were analyzed by flow cytometry. Results. Epratuzumab promptly induced a marked decrease of CD22 (>80%), CD19 (>50%), CD21 (>50%), and CD79B (>30%) on the surface of B cells in PBMCs obtained from normal donors or treatment-naive lupus patients, and of NHL cells (Daudi and Raji) spiked into normal PBMCs. Although some Fc-independent loss of CD22 is expected from its internalization by epratuzumab, the concurrent and prominent reduction of CD19, CD21, and CD79B is Fc-dependent and results from trogocytosis of epratuzumab-bound B cells to FcγR-expressing effector cells, including monocytes, NK cells, and granulocytes. Following incubation with epratuzumab, but not with an isotype control mAb, reduced staining of surface antigens on B cells coincided with positive CD19 and CD22 staining of the effector cells. In the absence of PBMCs, treatment of NHL cell lines (Daudi and Raji) with epratuzumab resulted in more than 80% reduction of CD22, with little, if any, reduction in CD19, CD21, CD79B or surface IgM observed. Inclusion of a crosslinking second antibody with epratuzumab induced only a minimal (<15%) reduction of CD19 and CD21. When these NHL cells (1 x 105 cells) were mixed with PBMCs (1 x 106 cells), epratuzumab induced a 40 to 70% reduction of CD19 and CD21, with significant down-regulation of surface IgM and CD79B also. Under the conditions examined, rituximab at 10 μg/mL reduced the B-cell count by 50%, whereas epratuzumab did not cause significant B-cell depletion, either at 10 μg/mL or 1 mg/mL. Conclusions. This study revealed a previously unknown, and potentially important, MOA of epratuzumab. Whether the observed trogocytosis could be correlated with the depletion of malignant B cells in lymphoid tissues is currently under investigation. Citation Format: Edmund A. Rossi, David M. Goldenberg, Rosana Michel, Diane L. Rossi, Daniel J. Wallace, Chien-Hsing Chang. CD22-targeting epratuzumab mediates trogocytosis of multiple cell-surface markers on normal, malignant, and lupus B cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4744. doi:10.1158/1538-7445.AM2013-4744