Internalization and catabolism of radiolabelled antibodies to the MHC class-II invariant chain by B-cell lymphomas

Hansen, Hans J.; Ong, Gaik Lin; Diril, Habibe; Valdez, Anita C.; Roche, Paul A.; Griffiths, Gary L.; Goldenberg, David M.; Mattes, Jules M.

doi:10.1042/bj3200293

Cited by 74 publications

(81 citation statements)

References 33 publications

(51 reference statements)

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“…If no clear match was found, partial or total manual de novo sequencing of the peptide was conducted and the search was repeated using the MSEdman program. After sequencing and source protein identification, an affinity peptide score was calculated for each peptide using a predictive matrix obtained by Hammer et al (27), by peptide side chain scanning techniques, based on the DR4 peptide-binding motif (26). A value higher than 2 was considered a high score, theoretically corresponding to high affinity binding.…”

Section: Peptide Sequencingmentioning

confidence: 99%

Dissection of the HLA-DR4 Peptide Repertoire in Endocrine Epithelial Cells: Strong Influence of Invariant Chain and HLA-DM Expression on the Nature of Ligands

Muntasell

Carrascal

Álvarez

et al. 2004

The Journal of Immunology

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Class II MHC (MHC II) expression is restricted to professional APCs and thymic epithelium but it also occurs in the epithelial cells of autoimmune organs which are the unique targets of the CD4 autoreactive T cells in endocrine autoimmune diseases. This specificity is presumably conditioned by an epithelium-specific peptide repertoire associated to MHC II at the cell surface. MHC II expression and function is dependent on the action of two main chaperones, invariant chain (Ii) and DM, whose expression is coregulated with MHC II. However, there is limited information about the in vivo expression levels of these molecules and uncoordinated expression has been demonstrated in class II-positive epithelial cells that may influence the MHC-associated peptide repertoires and the outcome of the autoimmune response. We have examined the pool of peptides associated to DR4 molecules expressed by a neuroendocrine epithelial cell and the consequences of Ii and DM coexpression. The RINm5F rat insulinoma cell line was transfected with HLA-DRB1*0401, Ii, and DM molecules in four different combinations: RIN-DR4, -DR4Ii, -DR4DM, and -DR4IiDM. The analysis of the peptide repertoire and the identification of the DR4 naturally processed ligands in each transfected cell were achieved by mass spectrometry. The results demonstrate that 1) the expression of Ii and DM affected the DR4 peptide repertoires by producing important variations in their content and in the origin of peptides; 2) these restrictions affected the stability and sequence of the peptides of each repertoire; and 3) Ii and DM had both independent and coordinate effects on these repertoires.

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Section: Peptide Sequencingmentioning

confidence: 99%

Dissection of the HLA-DR4 Peptide Repertoire in Endocrine Epithelial Cells: Strong Influence of Invariant Chain and HLA-DM Expression on the Nature of Ligands

Muntasell

Carrascal

Álvarez

et al. 2004

The Journal of Immunology

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“…Thus, CD74 internalization is highly dynamic, with the antibody being moved quickly from the surface and unloaded inside the cell, followed by CD74 reexpression on the surface. Fab' internalization occurs just as rapidly as immunoglobulin G (IgG) binding, indicating that bivalent binding is not required (3,10). Later studies with a complementarity-determining region (CDR)-grafted version of murine LL1, milatuzumab (hLL1), found that the antibody could alter B-cell proliferation, migration, and adhesion molecule expression (8,11,12), but the exceptional internalization properties of the anti-CD74 antibody made it an efficient carrier for the intracellular delivery of cancer therapeutics (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

“…Approximately, 80% of the CD74 on the cell surface is associated with the MHC II antigen, HLA-DR (3). Using the murine anti-CD74 antibody, LL1, the Raji Burkitt lymphoma cell line was estimated to have 4.8 Â 10 4 copies per cell, but because of rapid intracellular transit, approximately 8 Â 10 6 antibody molecules were internalized and catabolized per cell per day (10). Thus, CD74 internalization is highly dynamic, with the antibody being moved quickly from the surface and unloaded inside the cell, followed by CD74 reexpression on the surface.…”

Section: Introductionmentioning

confidence: 99%

Milatuzumab–SN-38 Conjugates for the Treatment of CD74+ Cancers

Govindan

Cardillo

Sharkey

et al. 2013

Molecular Cancer Therapeutics

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112

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CD74 is an attractive target for antibody-drug conjugates (ADC), because it internalizes and recycles after antibody binding. CD74 mostly is associated with hematologic tumors but is expressed also in solid cancers. Therefore, ADCs of the humanized anti-CD74 antibody, milatuzumab, were examined for the therapy of CD74-expressing solid tumors. Milatuzumab-doxorubicin and two milatuzumab-SN-38 conjugates with cleavable linkers, differing in their stability in serum and how they release SN-38 in the lysosome, were prepared. CD74 expression was determined by flow cytometry and immunohistology. In vitro cytotoxicity and in vivo therapeutic studies were conducted in the human cancer cell lines A-375 (melanoma), HuH-7 and Hep-G2 (hepatoma), Capan-1 (pancreatic), NCI-N87 (gastric), and Raji Burkitt lymphoma. The milatuzumab-SN-38 ADC was compared with SN-38 ADCs prepared with anti-Trop-2 and anti-CEACAM6 antibodies in xenografts expressing their target antigens. Milatuzumab-doxorubicin was most effective in the lymphoma model, whereas in A-375 and Capan-1 solid tumors, only milatuzumab-SN-38 showed a therapeutic benefit. Despite much lower surface expression of CD74 than Trop-2 or CEACAM6, milatuzumab-SN-38 had similar efficacy in Capan-1 as anti-Trop-2-SN-38, but in NCI-N87, anti-CEACAM6 and anti-Trop-2 conjugates were superior. Studies in two hepatoma lines at a single dose level showed significant benefit over saline controls but not against an irrelevant immunoglobulin G conjugate. CD74 is a suitable target for ADCs in some solid tumor xenografts, with efficacy largely influenced by uniformity of CD74 expression and with SN-38 conjugates providing the best therapeutic responses; SN-38 conjugates were preferable in solid cancers, whereas doxorubicin ADC was better in lymphoma tested. Mol Cancer Ther; 12(6); 968-78. Ó2013 AACR.

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“…The RL cell line, a diffuse, large cell B-lymphoma, was described previously [7], and is available from the American Type Culture Collection (ATCC, Manassas, VA, USA). Cells were cultured as described [7,8].…”

Section: Cell Lines Abs and Ab Conjugatesmentioning

confidence: 99%

“…Cells were cultured as described [7,8]. They were tested routinely for mycoplasma by the Mycotect assay (Life Technologies, Grand Island, NY, USA), and were negative.…”

Section: Cell Lines Abs and Ab Conjugatesmentioning

confidence: 99%

Characterization of antibody-containing vesicles shed from B-lymphoma cell lines: exposure of annexin V binding sites

Michel¹,

Abu‐Asab²,

Tsokos³

et al. 2006

Leukemia & Lymphoma

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Antibodies (Abs) to CD20 or HLA-DR, after binding to the B-lymphoma cell line RL following an overnight incubation at 37°C, accumulate in the form of shed vesicles, which develop in the center of the cell clusters that are spontaneously formed by this cell line. These vesicles coalesce into fairly stable large structures, which we refer to as conglomerates of shed vesicles (CSVs). In the present study, we have extended our previous investigations into the nature of this material. Electron microscopy revealed a conglomerate of heterogeneous vesicles, which looked like pinched-off cytoplasmic projections. CSVs developed similarly either with or without Ab, demonstrating that CSV production is a spontaneous process that incorporates bound Abs if they are present. Before delivery to CSVs, the Abs capped on the cell surface. CSVs had high expression of annexin V binding sites, which are phagocytic signals that are exposed on damaged cells. For CSVs that were cell bound, which are frequently observed, the annexin V binding sites were only in the CSVs, and not on the surface of the intact cell. Although all CSVs contained both Abs and annexin V binding sites, the precise distribution of these two ligands was generally different. Annexin V binding sites were present on caps as well as on CSVs, and appear as soon as caps are formed. In cells incubated with anti-HLA-DR, CD20 was delivered to the CSVs together with HLA-DR, suggesting an association between these two molecules. CSVs prepared with anti-HLA-DR, but not CSVs prepared with anti-CD20, contained considerable numbers of nuclear fragments, identified by propidium iodide staining.

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Internalization and catabolism of radiolabelled antibodies to the MHC class-II invariant chain by B-cell lymphomas

Cited by 74 publications

References 33 publications

Dissection of the HLA-DR4 Peptide Repertoire in Endocrine Epithelial Cells: Strong Influence of Invariant Chain and HLA-DM Expression on the Nature of Ligands

Dissection of the HLA-DR4 Peptide Repertoire in Endocrine Epithelial Cells: Strong Influence of Invariant Chain and HLA-DM Expression on the Nature of Ligands

Milatuzumab–SN-38 Conjugates for the Treatment of CD74+ Cancers

Characterization of antibody-containing vesicles shed from B-lymphoma cell lines: exposure of annexin V binding sites

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