Analysis of the B Cell/Leukemia Workshop Monoclonal Antibodies Using an Immunoenzymatic Staining Assay and a Radioimmunoassay on Cells

Dörken, Bernd; Moldenhauer, Gerhard; Pezzutto, Antonio; Schwartz, Reinhard; Kiesel, Sophie; Hünstein, W.

doi:10.1007/978-1-4612-4848-4_2

Cited by 6 publications

(5 citation statements)

References 9 publications

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“…B cell activation and acquisition of an anergic state reduces cell surface IgM levels, and activation is also reported to downregulate CD22 (42,43). Sia6LacNAc-deficient B cells exhibit characteristics that may reflect prior aberrant antigen-receptor signal transduction leading to an anergic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Immune regulation by the ST6Gal sialyltransferase

Hennet

Chui

Paulson

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

330

282

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The ST6Gal sialyltransferase controls production of the Sia␣2-6Gal␤1-4GlcNAc (Sia6LacNAc) trisaccharide, which is the ligand for the lectin CD22. Binding of CD22 to Sia6LacNAc is implicated in regulating lymphocyte adhesion and activation. We have investigated mice that lack ST6Gal and report that they are viable, yet exhibit hallmarks of severe immunosuppression unlike CD22-deficient mice. Notably, Sia6LacNAc-deficient mice display reduced serum IgM levels, impaired B cell proliferation in response to IgM and CD40 crosslinking, and attenuated antibody production to Tindependent and T-dependent antigens. Deficiency of ST6Gal was further found to alter phosphotyrosine accumulation during signal transduction from the B lymphocyte antigen receptor. These studies reveal that the ST6Gal sialyltransferase and corresponding production of the Sia6LacNAc oligosaccharide are essential in promoting B lymphocyte activation and immune function.Sialyltransferases are a family of glycosyltransferase enzymes that add sialic acid residues during oligosaccharide diversification (reviewed in ref. 1). Sialic acid addition occurs in the Golgi apparatus and generally terminates further oligosaccharide chain elongation. The outer position of sialic acid linkages places these residues in a location to provide key structural determinants in ligand formation for endogenous and pathogenic lectins. Three sialic acid linkage types commonly exist among vertebrates and the corresponding sialyltransferase genes have been previously isolated. The most abundant sialic acid linkage found among mammalian cell surface oligosaccharides is of the ␣2-3 variety and can be produced independently by four sialyltransferases that each, nonetheless, bear unique substrate preferences among glycolipids, asparagine (N)-linked glycans, and serine͞threonine (O)-linked glycans (2). Sialyltransferases have also been found to be developmentally regulated and differentially expressed among various cell types (1-6). For example, expression of ␣2-8 linked sialic acids is much less common than ␣2-3 linkages and appears restricted to a small subset of glycoproteins (7-10).␣2-6-linked sialic acids are also less abundant than ␣2-3-linked forms and are generated by at least four distinct gene products. However, the ST6Gal sialyltransferase appears solely responsible for producing the Sia␣2-6Gal␤1-4GlcNAc (Sia6LacNAc) terminus on various N glycans, and perhaps on some O glycans (1, 11). High levels of ST6Gal RNA have been found to preferentially accumulate in hematopoietic cells, as well as in the liver (3-5). Moreover, ST6Gal gene transcription is regulated by multiple promoters and altered by glucocorticoids and cytokines (12)(13)(14). Although the physiologic role of the ST6Gal sialyltransferase has not been defined previously by available genetic approaches, it has been shown to be unique in producing the ligand for the CD22 lectin molecule expressed on B lymphocytes.CD22 is a transmembrane glycoprotein lectin found exclusively on B lymphocytes and is known to p...

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Section: Discussionmentioning

confidence: 99%

Immune regulation by the ST6Gal sialyltransferase

Hennet

Chui

Paulson

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

330

282

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“…The murine homolog of CD22 has recently been cloned and has also been shown to mediate both homotypic and heterotypic cell adhesion [23]. In humans the protein has been detected on the surface of follicular mantle zone and marginal zone B cells [24]. Germinal center B cells were found to be negative for cell surface CD22 in this study.…”

Section: Introductionmentioning

confidence: 87%

Phosphotyrosine‐dependent association between CD22 and protein tyrosine phosphatase 1C

Campbell

1995

Eur J Immunol

111

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CD22 is a B lymphocyte-specific cell surface glycoprotein that becomes tyrosine phosphorylated upon B cell activation. To determine if tyrosine phosphorylated CD22 couples signaling through membrane immunoglobulin (mIg) to down-stream elements, we looked for molecules coprecipitating with CD22 after anti-Ig stimulation. We found that a 60-kDa molecule was stably associated with CD22 following cross-linking of mIg and have identified this molecule as protein tyrosine phosphatase 1C (PTP1C). The association between PTP1C and CD22 is dependent upon tyrosine phosphorylation of CD22, but does not appear to require tyrosine phosphorylation of PTP1C.

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“…[1][2][3] Because most siglecs are also endocytic receptors, they are ideal for a "Trojan Horse"-based strategy involving delivery of a therapeutic cargo into the cell when conjugated to antibodies or nanoparticles that target the desired siglec. [4][5][6] Of particular interest in this regard are CD33 (Siglec-3) and CD22 (Siglec-2), which were identied in the mid-80's as markers of primary acute myeloid leukaemia (AML) blasts and various non-Hodgkin's lymphomas, respectively, [7][8][9][10][11] leading to the development of anti-CD33 and anti-CD22 immunotoxins soon there-aer. 12,13 Gemtuzumab ozogamicin, a calicheamicin-conjugated anti-CD33 antibody, was approved in 2000 for treatment of acute myeloid leukaemia aer promising Phase I and Phase II data.…”

Section: Introductionmentioning

confidence: 99%

Disubstituted sialic acid ligands targeting siglecs CD33 and CD22 associated with myeloid leukaemias and B cell lymphomas

et al. 2014

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The siglec family of sialic acid-binding proteins are endocytic immune cell receptors that are recognized as potential targets for cell directed therapies. CD33 and CD22 are prototypical members and are validated candidates for targeting acute myeloid leukaemia and non-Hodgkin’s lymphomas due to their restricted expression on myeloid cells and B-cells, respectively. While nanoparticles decorated with high affinity siglec ligands represent an attractive platform for delivery of therapeutic agents to these cells, a lack of ligands with suitable affinity and/or selectivity has hampered progress. Herein we describe selective ligands for both of these siglecs, which when displayed on liposomal nanoparticles, can efficiently target the cells expressing them in peripheral human blood. Key to their identification was the development of a facile method for chemo-enzymatic synthesis of disubstituted sialic acid analogues, combined with iterative rounds of synthesis and rapid functional analysis using glycan microarrays.

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Analysis of the B Cell/Leukemia Workshop Monoclonal Antibodies Using an Immunoenzymatic Staining Assay and a Radioimmunoassay on Cells

Cited by 6 publications

References 9 publications

Immune regulation by the ST6Gal sialyltransferase

Immune regulation by the ST6Gal sialyltransferase

Phosphotyrosine‐dependent association between CD22 and protein tyrosine phosphatase 1C

Disubstituted sialic acid ligands targeting siglecs CD33 and CD22 associated with myeloid leukaemias and B cell lymphomas

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