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PubMed2006

Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that has recently been implicated in carcinogenesis. Helicobacter pylori, which is closely linked to gastric cancer, induces the gastric epithelium to produce proinflammatory cytokines, including MIF. MIF can bind to CD74, which we have previously shown to be highly expressed on the surface of gastric epithelial cells (GEC) during H. pylori infection. In this study, we sought to investigate the role of the H. pylori-induced MIF on epithelial proliferation and procarcinogenic events. Upon establishing a role for the H. pylori CagA virulence factor in MIF production, MIF binding to CD74 on GEC was confirmed. rMIF and H. pylori were shown to increase GEC proliferation, which was decreased when cagA- strains were used and when CD74 was blocked by mAbs. Apoptosis was also decreased by MIF, but increased by cagA- strains that induced much lower amounts of MIF than the wild-type bacteria. Furthermore, MIF binding to CD74 was also shown to decrease p53 phosphorylation and up-regulate Bcl-2 expression. This data describes a novel system in which an H. pylori virulence factor contributes to the production of a host factor that in turn up-regulates procarcinogenic events by the gastric epithelium.

Antigens, Bacterial↗
PubMed2003

Cure of SCID mice bearing human B-lymphoma xenografts by an anti-CD74 antibody-anthracycline drug conjugate.

PURPOSE: The purpose of this research was to test the therapeutic efficacy of an anthracycline-antibody conjugate for the treatment of human B-cell lymphoma in a preclinical animal model. EXPERIMENTAL DESIGN: Doxorubicin (dox) conjugates of the murine and humanized versions of the anti B-cell antibody LL1, targeting CD74, were prepared, along with a nonspecific control dox-antibody conjugate, targeting carcinoembryonic antigen. Antibody conjugates carried approximately 8-10 drug molecules attached site-specifically at thiols of reduced interchain disulfide bonds. Conjugates were tested, initially in vitro, and then for therapeutic efficacy in a systemic model, using a lethal i.v. dose of Raji cells in SCID mice. RESULTS: Dox-LL1 conjugates were shown to be stable and 3-fold more effective in vitro against the human B-cell Burkitt's lymphoma line, Raji, compared with the nonspecific control conjugate that did not target CD74 or B cells. When SCID mice were given an i.v. dose of 2.5 million Raji cells, they would die of disseminated disease within 15-25 days postinjection. A single dose of dox-LL1 conjugate, 117-350 micro g, given 5 days to 14 (advanced disease) days after injection of the Raji cells resulted in cure of most animals out to 180 days after injection of the cells, whereas animals in treatment control groups were not cured. The dose of dox-LL1 found useful in this work corresponds with a significantly lower drug dose than reported previously with other drug-antibody conjugates CONCLUSION: CD74 appears to be a uniquely useful target antigen for delivery of drugs, effecting cures of animals with single, low doses of conjugate.

Animals↗
PubMed2001

Therapy of disseminated B-cell lymphoma xenografts in severe combined immunodeficient mice with an anti-CD74 antibody conjugated with (111)indium, (67)gallium, or (90)yttrium.

A radiolabeled antibody (Ab) to CD74 (the MHC class II invariant chain, Ii) was shown previously to effectively kill human B-lymphoma cells in vitro. Conjugates with both Auger electron and beta-particle emitters were able to kill cells, but the former displayed less nonspecific toxicity in the in vitro assay used. In this report, we have extended the studies to an in vivo model of tumor growth. The human B-cell lymphoma Raji was injected i.v. into severe combined immunodeficient mice, and radiolabeled Abs were injected at various times after tumor inoculation. The maximum tolerated dose (MTD), as well as lower doses, was tested. Tumor growth was monitored by hind-leg paralysis. With a 3-5-day interval before Ab injection, anti-CD74 conjugated to either (111)In or (67)Ga, at a dose of 240-350 microCi/mouse, produced a strong therapeutic effect, with greatly delayed tumor growth, and many of the treated mice were tumor free for >6 months. Control mice became paralyzed in 16-24 days, uniformly. Treatment at later time points (9-day interval) had little therapeutic effect. The MTD was required for optimal therapy. With the beta-particle emitter (90)Y, the MTD was much less, 25 microCi/mouse, and at this dose there was only a weak therapeutic effect. In conclusion, the data suggest that low-energy electrons are more effective than beta-particles in this model system. These results may be applicable to humans, particularly in the case of micrometastatic disease. This approach may also be effective with other Abs that accrete in large amounts.

Animals↗
PubMed2000

Localization of an antibody to CD74 (MHC class II invariant chain) to human B cell lymphoma xenografts in nude mice.

The tumor-specific localization of an anti-CD74 Ab, LL1, was demonstrated in nude mice bearing xenografts of human B-cell lymphoma. This Ab, conjugated to radionuclides emitting Auger electrons, including 125I and 111In, was previously reported to kill tumor cells in vitro effectively and specifically. The cytotoxic potency of this Ab is due to its uptake and catabolism at a very high level, which also affected the Ab biodistribution experiments. Thus, Ab localization to the tumor was only detected if a "residualizing" radiolabel was used, meaning a label that is trapped within cells, usually within lysosomes, after catabolism of the Ab to which it was conjugated. Similar results were obtained with three different residualizing labels: 111In conjugated via the chelators benzyl diethylenetriaminepentaacetic acid (DTPA) or 1.4,7,10-tetra-azacyclododecane-N, N', N", N"'-tetraacetic acid (DOTA), or 131I-dilactitol-tyramine, a residualizing form of iodine. The Ab protein dose could be high, 0.5 mg/mouse, without causing a decrease in specific tumor uptake, probably reflecting the high capacity for uptake. Moreover, tumors of moderate size were found to cause rapid, specific removal of the Ab from the blood, also a result of catabolic processes. This induced blood clearance naturally affected the Ab localization experiments, but this factor could be circumvented by increasing the Ab protein dose. Using a different Ab, anti-(mature MHC class II), the ability of Ab to penetrate relatively large solid tumors was investigated. Complete saturation of antigenic sites was observed in tumors up to 0.3 g in size, but quite high Ab protein doses were required, 5.0 mg/ mouse. These results provide a rationale for attempting therapy with radiolabeled LL1.

Animals↗
PubMed1995

Invariant chain (CD74) gene regulation: enhanced expression associated with activation of protein kinase C delta in a murine B lymphoma cell line.

The invariant chain (Ii, CD74) is a transmembrane glycoprotein that is transiently associated with the MHC class II antigens in the endoplasmic reticulum and in endocytic vesicles. An activator of protein kinase C (PKC), 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), was found to enhance expression of Ii mRNA in the murine B lymphoma cell line, A20, 6-48 hr following treatment. In contrast, TPA did not induce the Ii in NIH 3T3 fibroblasts. TPA addition to either cell line activated PKC. Pretreatment of A20 cells with the PKC inhibitors, staurosporine or chelerythrine chloride, for 5 or 20 min prior to addition of TPA, decreased Ii mRNA levels when compared to cells treated with TPA alone. A 20 min preincubation with the highly specific PKC inhibitor, calphostin C, completely blocked the TPA enhanced expression of the Ii suggesting that activation of PKC was responsible for TPA increased Ii mRNA levels. IFN-gamma also blocked the TPA increased Ii mRNA levels. Constitutive expression of Ii mRNA was decreased by treatment with staurosporine but not chelerythrine chloride or calphostin C, suggesting that non-PKC protein kinases may also be important for maintaining high levels of Ii mRNA in these cells. Western blot analysis using PKC isotype specific antibodies showed that A20 cells express PKC delta abundantly whereas NIH 3T3 cells express primarily PKC alpha. These data suggest that a PKC delta mediated signal transduction pathway plays a crucial role in up-regulation of the Ii.

3T3 Cells↗
PubMed2004

Cellular association and cytotoxicity of anti-CD74-targeted lipid drug-carriers in B lymphoma cells.

The ability to selectively target anti-cancer drugs via specific ligands against antigens expressed on malignant cells could greatly improve the therapeutic indices of the drugs. In this paper an anti-CD74 antibody (Ab), LL1, was covalently attached to the surface of sterically stabilized lipid drug-carriers (emulsions and liposomes) by use of a PEG-based heterobifunctional coupling agent. Target cells internalize LL1 very fast and that was found to be true for the LL1-lipid drug-carrier complexes as well. During a 24 h in vitro incubation with the target Raji B-lymphoma cells about 30% of the added complexes were associated with the cells. The corresponding value for drug-carrier without targeting ligand was near 0.6%. Displacement experiments showed that free LL1 competed well with LL1-complexes indicating preserved immunoreactivity. Non-target cells showed only unspecific association of LL1-complexes. A dioleoylated derivative of the anti-cancer drug 3',5'-O-dioleoyl-FUdR (FUdR) (FUdR-dO) loaded into LL1-lipid drug-carriers showed good cytotoxic activity. In vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity tests against neoplastic B-cells gave IC30 values of 0.45, 1.25, 5.30 and 7.30 microM for the prodrug FUdR-dO in LL1-emulsions, LL1-liposomes, emulsions and liposomes, respectively. The value for the parent drug FUdR was calculated to 4.35 microM. In the light of the extensive and specific delivery of LL1-lipid drug-carriers to B-cells and the selective cytotoxicity of the incorporated drug, we infer that the complexes may be useful in the selective elimination of circulating malignant B-cells in vivo.

Antibodies, Neoplasm↗
PubMed2003

Experimental therapy of disseminated B-Cell lymphoma xenografts with 213Bi-labeled anti-CD74.

A (213)Bi-labeled antibody to CD74 was evaluated as a therapeutic agent for B-cell lymphoma. The alpha-particle emission, with a half-life of 46 min, is appropriate for therapy of micrometastases. The labeled Ab retained full immunoreactivity, and was potent at single-cell kill of the Raji B-lymphoma cell line. Approximately 30 decays of cell-bound (213)Bi was required for a cell kill of 99%, and dosimetry calculations suggested that the cGy dose delivered was sufficient to produce the level of toxicity observed. A non-reactive control Ab, labeled similarly, also produced toxicity, due to decays occurring in the medium, but was approximately 3-fold less potent than the reactive Ab. In a SCID mouse xenograft micrometastatic model, Ab injection at day 2 or day 5 after tumor inoculation resulted in strong, specific suppression of tumor growth, with some apparent cures.

Animals↗
PubMed1999

Surface-expressed invariant chain (CD74) is required for internalization of human leucocyte antigen-DR molecules to early endosomal compartments.

Transport of major histocompatibility complex (MHC) class II molecules to the endocytic route is directed by the associated invariant chain (Ii). In the endocytic pathway, Ii is proteolytically cleaved and, upon removal of residual Ii fragments, class II alpha beta dimers are charged with antigenic peptide and recognized by CD4+ T cells. Although distinct peptide-loading compartments such as MIIC (MHC class II loading compartment) and CIIV (MHC class II vesicles) have been characterized in different cells, there is growing evidence of a multitude of subcellular compartments in which antigenic peptide loading takes place. We employed a physiological cellular system in which surface Ii (CD74) and surface human leucocyte antigen (HLA)-DR were induced either alone or in combination. This was achieved by transient exposure of HT-29 cells to recombinant interferon-gamma (rIFN-gamma). Using distinct cellular variants, we showed that: (i) the majority of Ii molecules physically associate on the cell membrane with class II dimers to form DR alpha beta:Ii complexes; (ii) the presence of surface Ii is a prerequisite for the rapid uptake of HLA-DR-specific monoclonal antibodies into early endosomes because only the surface DR+/Ii+ phenotype, and not the DR+/Ii- variant, efficiently internalizes; and (iii) the HLA-DR:Ii complexes are targeted to early endosomes, as indicated by co-localization with the GTPase, Rab5, and endocytosed bovine serum albumin. Internalization of HLA-DR:Ii complexes, accommodation of peptides by DR alphabeta heterodimers in early endosomes and recycling to the cell surface may be a mechanism used to increase the peptide repertoire that antigen-presenting cells display to MHC class II-restricted T cells.

Antigens, CD↗
PubMed1999

Cell surface expression and metabolism of major histocompatibility complex class II invariant chain (CD74) by diverse cell lines.

We previously described the processing of antibodies to CD74 (the major histocompatibility complex class II-associated invariant chain, Ii), by B-cell lymphoma cell lines. These cells expressed relatively low levels of Ii on the surface, but the molecules were rapidly internalized and replaced by new molecules, so that approximately 8 x 10(6) antibody molecules per cell were taken up per day. We herein report the results of similar studies with other cell types, namely a melanoma, a colon carcinoma, a T-cell lymphoma and B-lymphoblastoid cell lines. The melanoma and the carcinoma were treated with interferon-gamma to induce high levels of the antigen. The T-cell lymphoma, HUT 78, was selected specifically because it was previously reported to lack cell surface Ii, while expressing the molecule intracellularly. However, HUT 78 displayed Ii on the cell surface, as did the other cell lines tested, and catabolism of the antibody was very fast on all of the cell lines. The capacity of four of the cell lines for cumulative antibody uptake was evaluated, using 'residualizing' radiolabels, which are trapped within the cell after catabolism of the antibody to which they were conjugated. A high level of uptake was observed in all cases, although there was significant variation between the cell lines. With melanoma SK-MEL-37, the total LL1 uptake in 24 hr was nearly 10(7) molecules per cell and the average turnover time for Ii on the cell surface was 4 min; with carcinoma HT-29, the total LL1 uptake in 24 hr was approximately 10(6) molecules per cell, and the average turnover time for Ii on the cell surface was 27 min. Based on the cell content of mature class II antigens (alphabeta), these data suggest that a large fraction, or all, of immature class II molecules (alphabetaIi) reach the cell surface before entering the peptide-loading compartment, independent of the particular cell type.

Antigen-Antibody Reactions↗
PubMed2004

Antiproliferative activity of a humanized anti-CD74 monoclonal antibody, hLL1, on B-cell malignancies.

The humanized anti-CD74 monoclonal antibody (mAb) hLL1 is under evaluation as a therapeutic agent. The effects of hLL1-at times in comparison with the CD20 mAb rituximab-were assessed on non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) cell lines and in tumor-bearing SCID mice. In vitro, hLL1 caused growth inhibition and induction of apoptosis in B-cell lines when cross-linked with an antihuman immunoglobulin G (IgG) second antibody. The sensitivity profile of the cell lines was different for hLL1 and rituximab, and antiproliferative activity was augmented when the 2 mAbs were combined. Unlike rituximab, hLL1 did not induce antibody-dependent cellular cytotoxicity or complement-mediated cytotoxicity. In xenograft models of NHL and MM, treatment with hLL1 yielded significant survival benefits without cross-linking agents. Efficacy was greater in the MM model, in which median survival time was increased more than 4.5-fold. Thus, hLL1 has therapeutic potential as a naked mAb for B-cell malignancies because of high antigen expression on malignant cells, specifically MM, with limited expression on normal tissue, and because of its antiproliferative activity. Further, hLL1 may be a therapeutic candidate for rituximab-resistant disease because the 2 antibodies apparently act through distinct mechanisms and exhibit different expression and sensitivity profiles, and activity can be augmented when the mAbs are combined.

Animals↗
PubMed2005

Polarized expression of CD74 by gastric epithelial cells.

CD74 is known as the major histocompatibility complex (MHC) class II-associated invariant chain (Ii) that regulates the cell biology and functions of MHC class II molecules. Class II MHC and Ii expression was believed to be restricted to classical antigen-presenting cells (APC); however, during inflammation, other cell types, including mucosal epithelial cells, have also been reported to express class II MHC molecules. Given the importance of Ii in the biology of class II MHC, we sought to examine the expression of Ii by gastric epithelial cells (GEC) to determine whether class II MHC molecules in these nonconventional APC cells were under the control of Ii and to further support the role that these cells may play in local immune and inflammatory responses during Helicobacter pylori infection. Thus we examined the expression of Ii on GEC from human biopsy samples and then confirmed this observation using independent methods on several GEC lines. The mRNA for Ii was detected by RT-PCR, and the various protein isoforms were also detected. Interestingly, these cells have a high level expression of surface Ii, which is polarized to the apical surface. These studies are the first to demonstrate the constitutive expression of Ii by human GEC.

Antigen-Presenting Cells↗
PubMed2007

Genetic manipulation of CD74 in mouse strains of different backgrounds can result in opposite responses to central nervous system injury.

The ability to recover from CNS injuries is strain dependent. Transgenic mice that weakly express the p41 CD74 isoform (an integral membrane protein functioning as a MHC class II chaperone) on an I-A(b) genetic background have normal CD4(+) T cell populations and normal surface expression of MHC class II, but their B cell development is arrested while the cells are still immature. After a CNS injury, these mice recover better than their matched wild-type controls. We generated p41-transgenic mice on an I-A(d) background (p41-I-A(d) mice), and found that their recovery from CNS injuries was worse than that of controls. A correlative inverse effect was seen with respect to the kinetics of T cell and B cell recruitment to the injured CNS and the expression of insulin-like growth factor at the lesion site. These results, besides verifying previous findings that B cells function in the damaged CNS, demonstrate that the outcome of a particular genetic manipulation may be strain dependent.

Animals↗
PubMed2000

Radionuclides linked to a CD74 antibody as therapeutic agents for B-cell lymphoma: comparison of Auger electron emitters with beta-particle emitters.

UNLABELLED: We demonstrated previously that human B-cell lymphomas were effectively and specifically killed in vitro by an antibody to CD74 (LL1) linked to (111)In or other Auger electron emitters. This study was intended to more accurately compare the potency and specificity of 3Auger electron emitters, (111)In, 67Ga, and 125I, and to evaluate beta-particle emitters, 131I and 90Y. The unique property of LL1 is its high level of intracellular uptake. METHODS: Raji B-lymphoma cells were incubated with serial dilutions of the radiolabeled Abs for 2 d and then monitored for cell growth by 2 assays: a cell counting assay and a clonogenic assay. The uptake of radioactivity per cell was monitored at various time points, and the radiation dose was calculated using published S values for radioactivity located in the cytoplasm. Both specific and nonspecific toxicity were evaluated. RESULTS: The beta-particle emitters had considerably higher levels of nonspecific toxicity than the Auger electron emitters, but both 131I and 90Y, and particularly 131I, still had high levels of specificity. Both of these results were consistent with dosimetry calculations. Relative to the delivered disintegrations per cell, 131I and 67Ga were the most potent of the radionuclides tested, with 125I and (111)In being significantly weaker and 90Y being intermediate. The high potency of 67Ga, together with its low nonspecific toxicity, caused this radionuclide to have the highest specificity index. CONCLUSION: When delivered by Ab LL1, both Auger electron and beta-particle emitters can produce specific and effective toxicity. The choice of the optimal radionuclide for therapy may depend on the ease and efficiency of labeling, the specific activity obtained, the nature of the tumor being targeted, and other factors, but the high specificity indices of the Auger electron emitters may be an advantage.

Antibodies↗
PubMed1995

Surface expression of the invariant chain (CD74) is independent of concomitant expression of major histocompatibility complex class II antigens.

Whether or not intracellular transport and surface expression of the invariant chain (Ii; CD74) occurs independent of the presence of major histocompatibility complex (MHC) class II molecules was examined by comparing the class II-negative mutant lymphoblastoid cell line 174 x CEM.T2 (T2) and its class II-positive parental cell line 174 x CEM.T1 (T1). We found a similar proportion of Ii being transported to the Golgi complex in T1 and T2, as monitored by the degree of sialic acid addition to glycan side chains of Ii. In agreement with this result, T1 and T2 expressed comparable amounts of Ii at the cell surface, as measured by flow cytometry. This indicates that, although not associated with class II molecules, a proportion of Ii is transported to the plasma membrane. Both in T1 and T2, surface Ii (sIi) was rapidly internalized with a half-life of 3-4 min, suggesting that some Ii enters the endocytic route via the cell surface after being internalized. Our data demonstrate transport of Ii on a route alternative to the endocytic pathway. This alternative route could also account for delivery of newly synthesized class II-Ii complexes to processing compartments in antigen-presenting cells.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1997

LN-2 (CD74). A marker to distinguish atypical fibroxanthoma from malignant fibrous histiocytoma.

BACKGROUND: In this study, the authors examined the expression of LN-2, an antigen expressed by B cells, macrophages, and Reed-Sternberg cells, in a variety of spindle cell lesions of the skin to determine whether LN-2 immunoreactivity can be used to differentiate among these tumors. For comparison, they examined CD34 antigen expression in these lesions, which has been shown to be a useful marker in differentiating dermatofibrosarcoma protuberans from dermatofibroma. METHODS: Immunocytochemistry with anti-LN-2 and anti-CD34 monoclonal antibodies on formalin fixed, paraffin embedded material was performed on 102 spindle cell lesions, including dermatofibroma, dermatofibrosarcoma protuberans, atypical fibroxanthoma, malignant fibrous histiocytoma, leiomyoma, and neurofibroma. RESULTS: LN-2 immunoreactivity did not distinguish between dermatofibroma and dermatofibrosarcoma protuberans, both of which showed weak immunoreactivity. In marked contrast, 90% of cases of malignant fibrous histiocytoma showed strong staining for LN-2, whereas the vast majority (90%) of cases of atypical fibroxanthoma were negative or stained only weakly with anti-LN-2 antibodies. Of the two cases of atypical fibroxanthoma that stained strongly for LN-2, both lesions were > 2 cm in size and extended deep into the subcutaneous fat. CONCLUSIONS: Differential expression of the LN-2 antigen by atypical fibroxanthoma and malignant fibrous histiocytoma distinguishes these two lesions and suggests that acquisition of LN-2 positivity may be a marker of tumor progression.

Antibodies, Monoclonal↗
PubMedDate not supplied

CD74.

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Amino Acid Sequence↗