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Current Hematologic Malignancy Reports Oct 2008The treatment of non-Hodgkin lymphoma (NHL) has changed dramatically since the introduction of rituximab, a monoclonal antibody that binds to the B-cell transmembrane... (Review)
Review
The treatment of non-Hodgkin lymphoma (NHL) has changed dramatically since the introduction of rituximab, a monoclonal antibody that binds to the B-cell transmembrane protein CD20 and causes lysis of the lymphoma cells. Since then, a number of additional antibodies have been tested against other B-cell targets, resulting in variable efficacies. The goal of these newer agents is to achieve similar or better response rates as seen with rituximab and perhaps demonstrate activity in rituximab-refractory disease. Several of the antibodies have been investigated in combination with each other as well as with conventional chemotherapeutic regimens. Approval of such antibodies by regulatory committees and their eventual integration into clinical practice will likely depend on positive results from randomized trials.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Agents; Clinical Trials as Topic; Humans; Lymphoma, B-Cell; Rituximab
PubMed: 20425465
DOI: 10.1007/s11899-008-0027-5 -
Blood Feb 2008Combination immunotherapy with anti-CD20 and anti-CD22 mAbs shows promising activity in non-Hodgkin lymphoma. Therefore, bispecific mAbs (bsAbs) were recombinantly...
Combination immunotherapy with anti-CD20 and anti-CD22 mAbs shows promising activity in non-Hodgkin lymphoma. Therefore, bispecific mAbs (bsAbs) were recombinantly constructed from veltuzumab (humanized anti-CD20) and epratuzumab (humanized anti-CD22) and evaluated in vitro and in vivo. While none of the parental mAbs alone or mixed had notable antiproliferative activity against Burkitt lymphoma cells when not cross-linked, the bsAbs [eg, anti-CD20 IgG-anti-CD22 (scFv)(2)] were inhibitory without cross-linking and synergistic with B-cell antigen (BCR)-mediated inhibition. The bsAbs demonstrated higher antibody-dependent cellulary cytoxicity (ADCC) activity than the parental mAbs, but not complement-dependent cytoxicity (CDC) of the parental CD20 mAb. Cross-linking both CD20 and CD22 with the bsAbs resulted in the prominent redistribution of not only CD20 but also CD22 and BCR into lipid rafts. Surprisingly, appreciable translocation of CD22 into lipid rafts was also observed after treatment with epratuzumab. Finally, the bsAbs inhibited Daudi lymphoma transplant growth, but showed a significant advantage over the parental anti-CD20 mAb only at the highest dose tested. These results suggest that recombinantly fused, complementary, bispecific, anti-CD20/22 antibodies exhibit functional features distinct from their parental antibodies, perhaps representing new candidate therapeutic molecules.
Topics: Antibodies, Bispecific; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Burkitt Lymphoma; Cell Division; Cell Line; Humans; Immunotherapy; Lymphoma, B-Cell; Rituximab; Sialic Acid Binding Ig-like Lectin 2
PubMed: 18025153
DOI: 10.1182/blood-2007-08-110072 -
Cancer Oct 2005Intestinal metaplasia (IM) is often a component of Barrett esophagus (BE) and is characterized by a distinctive type of epithelium. Because IM has the potential to...
BACKGROUND
Intestinal metaplasia (IM) is often a component of Barrett esophagus (BE) and is characterized by a distinctive type of epithelium. Because IM has the potential to progress to dysplasia or adenocarcinoma, an accurate identification of its presence is important clinically. A cytopathologic diagnosis of IM on esophageal brushings by morphology alone can be difficult. The authors investigated the role of hepatocyte paraffin 1 (Heppar-1) immunostaining as a possible marker of IM in cytologic samples of BE.
METHODS
Eleven samples each of BE with and without IM diagnosed on esophageal brushings were retrieved from the cytopathology files of The Johns Hopkins Hospital over an 8-year period (1993-2001). All 22 specimens were confirmed histologically on subsequent tissue biopsies. Slides initially were prepared by cytospin and stained with Papanicolaou stain. After destaining, the slides were immunostained with hepatocyte paraffin 1 (Heppar-1) antibody at 1:100 dilution employing conventional methodology.
RESULTS
Among the samples of BE with IM, 9 of 11 samples (82%) were immunoreactive for Heppar-1, compared with 0 of 11 specimens of BE with only cardiac-type metaplasia. The immunoexpression was cytoplasmic and granular and was seen only focally in the glandular fragments.
CONCLUSIONS
Heppar-1 was a moderately sensitive (82%) and highly specific (100%) immunomarker for IM in BE. It was easy to use in limited cytologic samples that originally were stained with Papanicolaou stain and is recommended for inclusion in morphologically difficult samples of BE with questionable IM. The immunostaining pattern predominantly was focal, necessitating a careful evaluation of positive reactions on cytologic samples.
Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens; Barrett Esophagus; Biomarkers; Cytological Techniques; Esophageal Neoplasms; Hepatocytes; Humans; Immunoassay; Metaplasia; Middle Aged; Retrospective Studies; Sensitivity and Specificity
PubMed: 15918175
DOI: 10.1002/cncr.21099 -
Leukemia Jun 2005A comparison of the therapeutic efficacy of a new bispecific monoclonal antibody (bsMAb)-pretargeting system vs the conventional direct targeting modality was...
A comparison of the therapeutic efficacy of a new bispecific monoclonal antibody (bsMAb)-pretargeting system vs the conventional direct targeting modality was undertaken. A bsMAb was made by coupling the Fab' of a humanized anti-CD20 antibody to the Fab' of a murine antibody directed against the peptide histamine-succinyl-glycine (HSG). The tumor targeting of the bsMAb was separated from the subsequent delivery of the radionuclide-bearing HSG peptide conjugated with (111)In or (90)Y. Nude mice bearing s.c. Ramos human B-cell lymphomas were injected with the bsMAb and then, 48 h later, (111)In/(90)Y-HSG peptide was given. At 3 h postinjection, tumor/blood ratios for pretargeted (111)In-HSG-peptide were similar to that observed with the directly conjugated (111)In-anti-CD20 IgG at its highest level on day 7, but by day 1, tumor/blood ratios were about 10-fold higher than the IgG. Tumors progressed rapidly in animals given 800 microCi of (90)Y-HSG peptide alone, whereas 5/10 animals in the group pretargeted by the anti-CD20 bsMAb were tumor-free 18 weeks later. The antitumor response in animals administered the pretargeted (90)Y-HSG peptide was also significantly superior to treatment with the directly radiolabeled (90)Y-anti-CD20 IgG, whether given as a single injection (P<0.007) or as a divided dose (P=0.016). This bsMAb-pretargeting procedure significantly improves the therapeutic response of targeted radionuclides in non-Hodgkin's lymphoma, warranting further development of this method of radioimmunotherapy.
Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Disease Models, Animal; Female; Humans; Immunoglobulin G; Indium Radioisotopes; Lymphoma, Non-Hodgkin; Mice; Mice, Inbred BALB C; Mice, Nude; Radioimmunotherapy; Xenograft Model Antitumor Assays
PubMed: 15815716
DOI: 10.1038/sj.leu.2403751 -
Clinical Cancer Research : An Official... Apr 2004A new humanized anti-CD20 monoclonal antibody (MAb), IMMU-106, was evaluated to elucidate its action as an antilymphoma therapeutic, as a single agent, and in...
Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and Its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma.
PURPOSE
A new humanized anti-CD20 monoclonal antibody (MAb), IMMU-106, was evaluated to elucidate its action as an antilymphoma therapeutic, as a single agent, and in combination with the anti-CD22 MAb, epratuzumab.
EXPERIMENTAL DESIGN
Antiproliferative effects, apoptotic effects, and the ability of IMMU-106 to mediate complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity on a panel of non-Hodgkin's lymphoma (NHL) cell lines were compared with the chimeric anti-CD20 MAb, rituximab, and evaluated in light of the various levels of antigen expression by the cell lines. In vivo therapy studies were performed in SCID mice bearing disseminated Raji lymphoma.
RESULTS
The mechanisms of cytotoxicity of IMMU-106 were found to be similar to rituximab, and include direct apoptosis, antibody-dependent cellular cytotoxicity, and complement-mediated cytotoxicity. IMMU-106 was also found to be very similar to rituximab in terms of antigen-binding specificity, binding avidity, and dissociation constant. Treatment of Raji-bearing SCID mice with IMMU-106 yielded median survival increases of up to 4.2-fold compared with control mice. Survival in mice treated with IMMU-106 plus epratuzumab was compared with IMMU-106 treatment alone. Although the combined treatment did not improve median survival, an increased proportion of long-term survivors was observed. An enhanced antiproliferative effect was also observed in vitro in SU-DHL-6 cells when IMMU-106 was combined with epratuzumab. These findings are consistent with the up-regulation of CD22 expression observed after pretreatment of NHL cells in vitro with CD20 MAb (IMMU-106).
CONCLUSIONS
It is expected that in humans IMMU-106 should be at least as effective as rituximab and, due to its human framework construction, it may exhibit different pharmacokinetic, toxicity, and therapy profiles. In addition, it may be possible to enhance efficacy by combination therapy comprised of anti-CD20 and other B-cell lineage targeting MAbs, such as epratuzumab. The current results emphasize that in vitro as well as in vivo studies with many of the NHL cell lines were generally predictive of the known activity of anti-CD20 MAbs in NHL patients, as well as the enhanced efficacy of epratuzumab combined with rituximab observed in early clinical trials.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens; Antigens, CD; Antigens, CD20; Antigens, Differentiation, B-Lymphocyte; Apoptosis; Cell Adhesion Molecules; Cell Division; Cell Line, Tumor; Cell Membrane; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Immunophenotyping; Immunotherapy; Lectins; Lymphocytes; Lymphoma; Lymphoma, Non-Hodgkin; Mice; Mice, SCID; Sialic Acid Binding Ig-like Lectin 2; Time Factors; Up-Regulation
PubMed: 15102696
DOI: 10.1158/1078-0432.ccr-03-0493