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At least 19 recordsLinked to original sources
PubMed1998

Cross-linking of the CAMPATH-1 antigen (CD52) mediates growth inhibition in human B- and T-lymphoma cell lines, and subsequent emergence of CD52-deficient cells.

The CAMPATH-1H (CD52) antigen is a 21 000-28 000 MW glycopeptide antigen that is highly expressed on T and B lymphocytes and is coupled to the membrane by a glycosylphosphatidylinositol (GPI) anchoring structure. The humanized CAMPATH-1H anti-CD52 antibody is extremely effective at mediating depletion of both normal and tumorigenic lymphocytes in vivo and has been used in clinical trials for lymphoid malignancy and rheumatoid arthritis. Cross-linking GPI-anchored molecules, including CD52, on the surface of T lymphocytes in the presence of phorbol 12-myristate 13-acetate or anti-CD3, results in cellular activation. In the present study we have investigated the functional effects of cross-linking CD52 on T and B tumour cell lines. Cross-linking CD52 on either a B-cell line, Wien 133, which expresses high levels of endogenous CD52 or Jurkat T cells transfected and selected to express high levels of CD52 resulted in growth inhibition. This effect showed slower kinetics and occurred in a lower percentage of cells than growth inhibition stimulated via T- or B-cell receptors. Growth inhibition of the Wien 133 line was followed by the induction of apoptosis, which appeared independent of the Fas/Fas L pathway. Wien 133 cells surviving anti-CD52 treatment were selected and cloned and found to have down-regulated CD52 expression, with a characteristic biphasic pattern of 10% CD52-positive, 90% negative by fluorescence-activated cell sorter analysis. Interestingly, surface expression of other GPI-linked molecules, such as CD59 and CD55, was also down-regulated, but other transmembrane molecules such as surface IgM, CD19, CD20, HLA-DR were unaffected. The present study and previous work show that this is due to a defect in the synthesis of mature GPI precursors. Separation of CD52-positive and negative populations in vitro resulted in a rapid redistribution to the mixed population. Injection of CD52-negative cells into nude mice to form a subcutaneous tumour resulted in a substantial increase in expression of CD52. These results suggest that the defect in the Wien 133 cells is reversible, although the molecular mechanism is not clear. These observations have relevance to the clinical situation as a similar GPI-negative phenotype has been reported to occur in lymphocytes following CAMPATH-1H treatment in vivo.

Animals↗
PubMed1995

Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes.

The CAMPATH-1 (CD52) antigen is a 21-28 kDa glycopeptide which is highly expressed on lymphocytes and macrophages and is coupled to the membrane by a glycosylphosphatidylinositol (GPI) anchoring structure. The function of this molecule is unknown. However, it is an extremely good target for complement-mediated attack and antibody-mediated cellular cytotoxicity. The humanized CAMPATH-1H antibody, which is directed against CD52, is very efficient at mediating lymphocyte depletion in vivo, and is currently being used in clinical trials for lymphoid malignancy and rheumatoid arthritis. It is therefore important to examine the functional effects of this antibody on different lymphocyte sub-populations. Because several other GPI-linked molecules expressed on the surface of T lymphocytes are capable of signal transduction resulting in cell proliferation, we have investigated whether the CAMPATH-1 antigen can also mediate these effects. In the presence of phorbol esters and cross-linking anti-Ig antibodies, mAbs specific for CD52 induced proliferation and lymphokine production in highly purified resting CD4+ and CD8+ T lymphocytes. The rat IgG2c YTH 361.10 anti-CD52 antibody, however, was able to activate resting CD4+ and CD8+ T cells directly without cross-linking or phorbol myristate acetate in the absence of Fc-bearing cells. Anti-CD52 antibodies also augmented the anti-CD3 mediated proliferative response of CD4+ and CD8+ T cells when the two antibodies were co-immobilized onto the same surface or cross-linked in solution by the same second antibody. Both CD4+ CD45RA and CD4+ CD45RO T cells were stimulated to proliferate by anti-CD52 antibodies in the presence of appropriate co-stimulatory factors. Anti-CD52 mAbs did not, however, synergize with anti-CD2 or CD28 mAb to induce CD4+ T cell proliferation. The activation of CD4+ T cells by anti-CD52 antibodies was inhibited by cyclosporin A, suggesting a role for the calcineurin-dependent signal transduction pathways. Although CD52 could transduce a signal in T cells, anti-CD52 antibodies did not inhibit antigen-specific or polyclonal T cell responses, suggesting this molecule does not play an essential co-stimulatory role in normal T cell activation.

Antibodies, Monoclonal↗
PubMed1999

A sialoglycoprotein, gp20, of the human capacitated sperm surface is a homologue of the leukocyte CD52 antigen: analysis of the effect of anti-CD52 monoclonal antibody (CAMPATH-1) on capacitated spermatozoa.

In this study we performed N-terminal sequence analysis of gp20, a 20 kDa sialoglycoprotein on the human sperm surface previously identified by radiolabelling of the sialic acid residues of sperm surface. We found 100% identity with the N-terminus of CD52, an antigen expressed on almost all human leukocytes. We also show that, like CD52, gp20 behaves as a glycosylphosphatidylinositol (GPI)-anchored protein and that anti-gp20 antiserum reacts with an antigen on leukocytes of the same molecular weight as CD52. Using CAMPATH-1, the monoclonal antibody against CD52, in fluorescent staining of capacitated spermatozoa, Western blot analysis and the zona-free hamster egg penetration test, we found that the effect of this antibody was different from that of our anti-gp20. Western blot analysis revealed a well-defined 20 kDa band with anti-gp20, whereas a 14-20 kDa band was detected with CAMPATH-1. Anti-gp20 stained the equatorial region of the sperm head, whereas CAMPATH-1 stained the tail in immunofluorescence analysis of capacitated spermatozoa. A dose-dependent inhibitory effect was seen with CAMPATH-1, similar to that previously detected with anti-gp20, in a zona-free hamster egg penetration test. However, with CAMPATH-1 agglutination of motile spermatozoa was detected, and this was not present with anti-gp20. This suggests that the epitopes recognized by the two antibodies are different.

Adult↗
PubMed2006

CD52 antigen expressed by malignant plasma cells can be targeted by alemtuzumab in vivo in NOD/SCID mice.

OBJECTIVE: To explore new treatments specifically targeting malignant plasma cells (PCs), we examined CD52 antigen expression on primary PCs as well as multiple myeloma (MM) cell lines, and investigated in vivo the antimyeloma activity of alemtuzumab. MATERIALS AND METHODS: PCs were enriched from the marrow of MM patients (n = 39) according to CD138 expression and then analyzed by 3-color flow cytometry and quantitative PCR. The in vivo activity of alemtuzumab was evaluated in a xenotransplant model of MM in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. RESULTS: CD52 expression revealed a substantial heterogeneity in terms of both percentage of positive cells and fluorescence intensity, with 25/39 (64%) MM patients showing >or=30% CD138(+) PCs expressing the CD52 antigen (mean = 79%; range, 33-100%). Similarly to primary cells, cell lines showed heterogeneous CD52 expression. Expression of CD52 mRNA by quantitative PCR analysis strongly correlated with CD52 antigen detection by flow cytometry. In vivo, alemtuzumab treatment significantly increased the median survival of animals with an early- (64 vs 77 days, p <or= 0.0005) or advanced-stage (66 vs 75 days, p <or= 0.02) disease. CONCLUSION: We conclude that: 1) CD52 is expressed on PCs of a significant proportion of MM patients; 2) alemtuzumab used as a single agent exerts a good antitumor activity in NOD/SCID mice bearing an early-stage disease; and 3) alemtuzumab might have therapeutic potential in a subset of MM patients.

Adult↗
PubMedDate not supplied

CD52 antigen--a review.

Human CD52 is a glycosylphosphatidylinositol (GPI)--anchored antigen expressed on the all lymphocytes as well as within the male genital tract, where it can be produced by epithelial cells of the distal epididymis and duct deferens. CD52 can be shed into seminal plasma and then acquired by sperm cells during their passage through the genital tract, thus it is detectable on the surface of epididymal sperm and in the ejaculate but not on either spermatogenetic cells or testicular spermatozoa. Protein core of the sperm and lymphocyte CD52 is identical and it is a product of a single copy gene located on chromosome 1. However, N-linked carbohydrate side chains (attached to Asn-3) and GPI-anchor structure are different. Physiological role of CD52 on lymphocytes is unclear, although antibody directed to CD52, CAMPATH-1, is capable of complement activation and it can be clinically useful to treat lympho-proliferative disorders and to deplete lymphocytes in bone marrow transplants. Monoclonal antibodies directed against sperm CD52 may cause sperm immobilisation and agglutination and affect hamster oocyte penetration suggesting an association of this molecule with fertilisation.

Antigens, CD↗
PubMed1995

Synthetic peptide mimotope of the CAMPATH-1 (CD52) antigen, a small glycosylphosphatidylinositol-anchored glycoprotein.

BACKGROUND: CAMPATH-1 (CD52) antibodies are among the most powerful and specific lympholytic agents in humans and have numerous potential applications for human therapy. The CD52 antigen is a GPI-anchored glycoprotein with an exceptionally short peptide sequence of only 12 amino acids and a single, complex, N-linked oligosaccharide. Antibodies bind to the deglycosylated antigen and to a proteolytic fragment, but not to the synthetic peptide alone. OBJECTIVES: To characterise the antigenic epitope more precisely and to construct a synthetic analogue. Such an analogue would be useful for assay and purification of the therapeutic CAMPATH-1 antibodies as well as for studies of the antibody-antigen binding site. STUDY DESIGN: Collections of synthetic peptides based on the natural sequence were screened with a panel of CD52 antibodies. RESULTS AND CONCLUSION: A synthetic peptide composed of the natural C-terminal amino acids plus two additional residues was found to mimic the antigen with sufficient affinity to be useful for a variety of assays and for construction of an affinity matrix for antibody purification. Systematic mutation of this peptide enabled the definition of the critical residues for antibody binding, which will be of great help in building a model of the antibody-antigen interaction. Peptide mimotopes synthesised using a natural sequence as a starting point, rather than a completely random library, may be useful in many other similar circumstances.

Amino Acid Sequence↗
PubMed1996

Surface and mRNA expression of the CD52 antigen by human eosinophils but not by neutrophils.

Eosinophilic and neutrophilic granulocytes represent major effector cells in the inflammatory response. Whereas neutrophils are predominantly involved in bacterial infections, eosinophils are of essential importance in the allergic inflammation. Surface markers have been used to distinguish neutrophils (CD16+) from eosinophils (CD16-) and might indicate different functional properties of these cells. In this study, expression and functional activity of CD52 on human eosinophils and neutrophils was investigated in nonatopic healthy donors and from patients with hypereosinophilia. Flow cytometric analysis using different anti-CD52 monoclonal antibodies (MoAbs) (mouse IgG3, humanized IgG1, and rat IgM) showed significant and homogeneous expression of CD52 on human eosinophils, but not on neutrophils. In addition, reverse transcription-polymerase chain reaction and Northern blot analysis showed that CD52 mRNA was constitutively expressed in eosinophils but not in neutrophils. Furthermore, expression of CD52 could be diminished in a dose-dependent manner by preincubation of eosinophils with phosphatidylinositol-specific phospholipase C, suggesting that CD52 on eosinophils is anchored to the membrane through a glycosylphosphatidylinositol (GPI) molecule. Whereas the phorbolester phorbol myristate acetate was able to downregulate the expression of CD52 on eosinophils in a dose-dependent manner, different eosinophil activating cytokines and chemotaxins had no effect. Cross-linking of CD52 by mouse anti-CD52 MoAb (IgG3) and humanized anti-CD52 MoAb (IgG1) with goat antimouse antibody and mouse antihuman antibody, respectively, dose-dependently resulted in an inhibition of reactive oxygen species production of eosinophils after stimulation with C5a, platelet-activating factor, and granulocyte-macrophage colony-stimulating factor. In summary, this study shows that the GPI-anchored antigen CD52 is not only a useful marker to distinguish eosinophils from neutrophils. The data point out a novel role of the CD52 antigen on human eosinophils that might be of clinical relevance, because cross-linking of this molecule will stop the destructive power of human eosinophils in the inflammatory tissue.

Antibodies, Monoclonal↗
PubMed1998

Activation of complement by human IgG1 and human IgG3 antibodies against the human leucocyte antigen CD52.

Activation of the complement cascade by immunoglobulin G (IgG) plays a major role in the host defense against pathogens. Using recombinant human antibodies specific for the leucocyte antigen CD52, different allotypes of human IgG1 subclass were compared for their ability to activate human complement. In addition the roles of the different length hinge regions of IgG1 and IgG3 were investigated. It was found that the naturally occurring allotypes G1m(a,z) and G1m(f), and one artificially created isoallotype, G1m(null), did not significantly differ in their overall ability to cause cell lysis. However, some differences in binding of individual components of the classical activation pathway were detected. More of the complement component C1s seemed to be associated with the allotype G1m(f), although this did not result in an overall improvement in lytic potency. In this system the wild-type IgG3 was found to be less effective in complement lysis than IgG1. By shortening the hinge region of IgG3 to resemble that of an IgG1 antibody, increased complement binding was observed compared with that of wild-type IgG3 and the IgG1 allotypes. The overall lytic potency of the antibody was also improved compared with wild type IgG3 and it was also slightly more effective than the IgG1 allotypes.

Antigens, CD↗
PubMed2005

Different glycoforms of the human GPI-anchored antigen CD52 associate differently with lipid microdomains in leukocytes and sperm membranes.

CD52 is a human GPI-anchored antigen, expressed exclusively in the immune system and part of the reproductive system (epididymal cells). Sperm cells acquire the antigen from the epididymal secretions when transiting in the epididymal corpus and cauda. The peptide backbone of CD52, consisting of only 12 aminoacids, is generally considered no more than a scaffold for post-translational modifications, such as GPI-anchor and especially N-glycosylation which occur at the third asparagine. The latter modification is highly heterogeneous, especially in the reproductive system, giving rise to many different glycoforms, some of which are tissue specific. A peculiar O-glycan-containing glycoform is also found in reproductive and immune systems. We determined to locate CD52 in microdomains of leukocytes and sperm membranes using two antibodies: (1) CAMPATH-1G, the epitope of which includes the last three aminoacids and part of the GPI-anchor of glycoforms present in leukocytes and sperm cells; (2) anti-gp20, the epitope of which belongs to the unique O-glycan-bearing glycoform also present in both cell types. Using a Brij 98 solubilization protocol and sucrose gradient partition we demonstrated that the CD52 glycoforms recognized by both antibodies are markers of typical raft microdomains in leukocytes, whereas in capacitated sperm the O-glycoform is included in GM3-rich microdomains different from the cholesterol and GM1-rich lipid rafts with which CAMPATH antigen is stably associated. The importance of the association between GM3 and O-glycans for formation of specialized microdomains was confirmed by heterologous CD52 insertion experiments. When prostasomes from human seminal fluid were incubated with rat sperm from different epididymal regions, the CD52 glycoform recognized by anti-gp20 decorated rat epididymal corpus and cauda sperm, associated with the same low-cholesterol GM3-rich sperm membrane fractions as in human sperm. The glycoforms recognized by CAMPATH-1G were not found in rat sperm. The relationship between this differential insertion and differences in glycosylation of rat and human CD52 is discussed.

Antigens, CD↗
PubMed1996

Body temperature (37 C) specifically down-regulates the messenger ribonucleic acid for the major sperm surface antigen CD52 in epididymal cell culture.

To study the role of scrotal vs. body temperature in epididymal function we established a simplified cell culture system from the dog epididymis in which the cells showed a pattern of gene expression similar to that in the human epididymis and retained many characteristics of epididymal epithelial cells. The cultured cells had an epithelial-type cytoskeleton, nuclear androgen receptor protein, and a striking temperature responsiveness. Exposure of the cells to a culture temperature of 37 C, compared to 33 C, had a fast and irreversibly suppressive effect on the levels of an abundant epididymal messenger RNA (mRNA), CE5, which represents the canine counterpart of the human CD52/HE5 mRNA, encoding a major glycosylphoshatidylinnositol (GPI)-anchored sperm membrane glycopeptide. The temperature effect on the mRNA was a direct and specific one, not mediated by temperature influences on the testis and not affecting other epididymal mRNAs. Exposure of the cells to 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (25 micrograms/ml culture medium) and cycloheximide (2 micrograms/ml) suggested that the steady state levels of CD52/CE5 mRNA may be controlled posttranscriptionally by changing the half-life of this specific mRNA in response to an extracellular temperature stimulus.

Animals↗
PubMed2005

Epitope analysis of immunoglobulins against gp20, a GPI-anchored protein of the human sperm surface homologous to leukocyte antigen CD52.

Gp20 is a sialylglycoprotein of the human sperm surface related to maturation and capacitation and is homologous to CD52, a glycosyl- phosphatidyl-inositol (GPI)-anchored protein highly expressed in lymphocytes, monocytes, eosinophils, and epididymal cells, described by the monoclonal antibody family CAMPATH. The CAMPATH antigen is characterized by a very short peptide (12 amino acids) and an N-linked oligosaccharide chain bound to the asparagine located in the third position and a GPI anchor bound to the C-terminal serine. The CAMPATH epitope includes three amino acids at the C-terminus and part of the GPI anchor. It has been suggested that anti-gp20 interacts with the same peptide recognized by CAMPATH antibodies but with a different epitope, since it describes the corresponding antigen in a different way. For example, it localizes the corresponding antigen in the equatorial region of the sperm head when sperm are capacitated, whereas CAMPATH antibodies bind all over the sperm surface. Our results indicate that the anti-gp20 epitope does not include the peptide backbone, the GPI anchor, or the N-glycans but consists of O-linked oligosaccharide chains bound to a unique CD52 glycoform present both in sperm and leukocytes. This is suggested by results obtained using many different approaches, such as immunoblot analysis of gp20 after removal of N- and O-glycans and after jacalin (Artocarpus integrifolia agglutinin)-affinity chromatography.

Alemtuzumab↗
PubMed2004

Monoclonal antibodies in the treatment of chronic lymphoid leukemias.

In recent years preclinical and clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) either alone or coniugated to toxins in patients with several lymphoid malignancies, including chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) and hairy cell leukemia (HCL). Two MoAbs, directed against CD20 antigen (Rituximab, RIT) and CD52 antigen (Campath-1H, alemtuzumab, ALT) demonstrate significant activity in CLL. The most notable success to data has been achieved with ALT, both in previously treated and untreated patients with CLL. ALT is a humanized rat IgG1 antibody that binds to the cell membrane of virtually all normal as well as malignant lymphocytes. In the vast majority of CLL patients ALT causes constant reduction of abnormal blood lymphocytes, usually in less than 4 weeks, and disappearance of CD5/CD19 co-expression cells from blood. The regression of lymphoid infiltration from other sites is less clear. ALT is also highly active in patients with CLL in progression, even refractory to fludarabine (FA). Hematological toxicity, especially long-lasting lymphocytopenia, was noted in the majority of patients. The most important clinical side effects of ALT treatment were infections, mainly herpes simplex virus and cytomegalovirus reactivation. RIT is also active in CLL in conventional doses. However some studies suggest that higher doses are more effective than standard doses, used routinely in other lymphoid malignancies. The activity of ALT and RIT in CLL patients resistant to FA and their synergistic interactions with cytotoxic drugs suggests that a combination of these agents may lead to further progress in the treatment of this disease. The T-cell variant of PLL has demonstrated impressive responses to ALT in several trials even if the patients were refractory to deoxycoformycin (DCF) and other agents. However, this MoAb is not curative, because all patients eventually relapsed. Consequently, treatment with ALT may need to be associated with stem cell transplantation to consolidate and maintain long-term remissions. Recently anti-CD22 and anti-CD25 immunotoxins have been investigated in purine analogues refractory or relapsed HCL. The presented results indicate that these agents are highly active and well tolerated even if the patients were resistant to 2-CdA or DCF.

Adult↗
PubMed2003

CD52 expression in hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder characterized by splenomegaly, pancytopenia, and circulating atypical lymphocytes with circumferential cytoplasmic projections. Although uncommon, HCL cases refractory to standard therapy occur, and effective alternatives are limited. There is evolving literature supporting monoclonal antibody therapy in the treatment of B-cell lymphoid malignancies, including anti-CD52 (Campath-1H, alemtuzumab). We have examined nine cases of HCL and one case of HCL variant by flow cytometry for CD52 expression. All cases expressed CD52 antigen in 92-100% of the malignant cells. The demonstration of CD52 antigen expression on HCL cells provides the rationale for the use of alemtuzumab in refractory HCL.

Adult↗
PubMed2002

CD52 expression in mantle cell lymphoma.

Mantle cell lymphoma is one of the most difficult to treat of all the non-Hodgkin's lymphomas. CAMPATH-1H, a humanized monoclonal antibody against the CD52 antigen, has been used with some success in other lymphoproliferative diseases, especially chronic lymphocytic leukemia. This report demonstrates that tumor samples from patients with mantle cell lymphoma express the CD52 antigen and suggests that CAMPATH-1H should be studied in patients with mantle cell lymphoma.

Aged↗
PubMed2006

Alemtuzumab in T-cell lymphoproliferative disorders.

The humanized monoclonal antibody alemtuzumab binds to the CD52 antigen, a glycoprotein which is widely expressed on normal and malignant B and T lymphocytes. Recently it has been demonstrated in a number of clinical trials that alemtuzumab has clinical activity in mature T-cell diseases such as T-prolymphocytic leukaemia and cutaneous T-cell lymphoma, inducing responses in up to two thirds of heavily pre-treated relapsed/refractory patients. Response was associated with improved survival. The toxicity profile for the antibody is manageable. The major complications are infusional reactions associated with initial injections, and prolonged lymphopenia associated with reactivation of viruses. Future studies will be directed towards alternative (subcutaneous) routes and schedules of administration, use as first-line therapy, combination strategies, and role of alemtuzumab to purge minimal residual bone-marrow disease prior to stem-cell transplantation.

Alemtuzumab↗
PubMed2002

Convergent synthesis of an inner core GPI of sperm CD52.

An inner core of the GPI anchor of sperm CD52 antigens was synthesized by a highly convergent process using specially modified inositol, glucosamine and phospholipid as key building blocks. This paper also presents a new and efficient procedure to prepare 1,2,6-differentiated derivatives of inositol for GPI syntheses.

Antigens, CD↗
PubMed2003

First total synthesis of a GPI-anchored peptide.

A GPI-anchored dipeptide of sperm CD52 antigen was prepared through a convergent synthesis. First, the dipeptide with its C-terminus free and the GPI with its nonreducing end phosphoethanolamine bearing a free amino group were synthesized separately. Then, the two building blocks were coupled with use of EDC/HOBt as the condensation reagent. Finally, the GPI-anchored peptide was deprotected to give the target molecule 1.

Antigens, CD↗