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Haematologica Apr 2011Subcutaneous injections of anti-CD20 antibodies may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies. (Clinical Trial)
Clinical Trial
BACKGROUND
Subcutaneous injections of anti-CD20 antibodies may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies.
DESIGN AND METHODS
A pilot study was undertaken to evaluate the potential for subcutaneous dosing with 2(nd) generation anti-CD20 antibody veltuzumab in patients with CD20(+) indolent non-Hodgkin's lymphoma. Patients with previously untreated or relapsed disease received 4 doses of 80, 160, or 320 mg veltuzumab injected subcutaneously every two weeks. Responses were assessed by computed tomography scans, with other evaluations including adverse events, safety laboratories, B-cell blood levels, serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers.
RESULTS
Seventeen patients (14 follicular lymphoma; 13 stage III or IV disease; 5 treatment-naive) completed treatment with only occasional, mild-moderate, transient injection reactions and no other safety issues. Subcutaneous veltuzumab demonstrated a slow release pattern over several days, achieving a mean Cmax of 19, 25 and 63 μg/mL at 80, 160, and 320 mg doses for a total of 4 administrations, respectively. Depletion of circulating B cells occurred after the first injection. The objective response rate (partial responses plus complete responses plus complete responses unconfirmed) was 47% (8/17) with a complete response/complete response unconfirmed rate of 24% (4/17); 4 of 8 objective responses continued for 60 weeks or more. All serum samples evaluated for human anti-veltuzumab antibody were negative.
CONCLUSIONS
Subcutaneous injections of low-dose veltuzumab are convenient, well tolerated, and capable of achieving sustained serum levels, B-cell depletion, and durable objective responses in indolent non-Hodgkin's lymphoma. (Clinicaltrials.gov identifier: NCT00546793).
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antineoplastic Agents; Female; Hematologic Tests; Humans; Injections, Subcutaneous; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Staging; Treatment Outcome
PubMed: 21173095
DOI: 10.3324/haematol.2010.037390 -
World Journal of Gastroenterology Nov 2010In recent years, therapies for follicular lymphoma (FL) have steadily improved. A series of phase III trials comparing the effect of rituximab with chemotherapy vs... (Review)
Review
In recent years, therapies for follicular lymphoma (FL) have steadily improved. A series of phase III trials comparing the effect of rituximab with chemotherapy vs chemotherapy alone in treating FL have indicated significant improvements in progression-free survival (PFS) and overall survival. Recent studies have found that prolonged response durations and PFS were obtained with maintenance therapy using rituximab or interferon after completion of first line therapy. For patients with relapsed or refractory FL, phase II studies have assessed the effectiveness of combination therapies using a Toll-like receptor-9 agonist (1018ISS), oblimersen sodium (a Bcl-2 antisense oligonucleotide), bendamustine, and rituximab, as well as veltuzumab, a new humanized anti-CD20 antibody, and epratuzumab. In addition, the effectiveness of yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab as radioimmunotherapies has been reported. Furthermore, three phase III studies on an idiotype vaccine are near completion. Unfortunately, these vaccines, which appeared highly effective in phase I and II trials, do not appear to result in prolonged PFS. This report will summarize the current knowledge on therapies for treatment of FL, and will conclude with a brief discussion of feasible future options for effective treatments. Lastly, we added descriptions of the management of gastrointestinal FL, which is considered to be controversial because it is rare.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Disease-Free Survival; Gastrointestinal Neoplasms; Humans; Immunotherapy; Lymphoma, Follicular; Neoplasm Staging; Radioimmunotherapy; Time Factors; Treatment Outcome
PubMed: 21105187
DOI: 10.3748/wjg.v16.i44.5543 -
BioDrugs : Clinical Immunotherapeutics,... Feb 2011Over the last few years, new generations of anti-CD20 monoclonal antibodies (mAbs) have been developed for potential benefits over the classical, first-generation mAb... (Review)
Review
Over the last few years, new generations of anti-CD20 monoclonal antibodies (mAbs) have been developed for potential benefits over the classical, first-generation mAb rituximab. Compared with rituximab, new mAbs have enhanced antitumor activity resulting from increased complement-dependent cytotoxicity (CDC) and/or antibody-dependent cellular cytotoxicity (ADCC) and increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor (CD16) on immune effector cells. The second-generation mAbs, which include ofatumumab, veltuzumab, and ocrelizumab, are humanized or fully human to reduce immunogenicity, but with an unmodified Fc region. Ofatumumab is a fully human anti-CD20 IgG1 mAb in clinical development for hematological malignancies and autoimmune diseases. Ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of CD20 molecule, and is more effective than rituximab at CDC induction and killing target cells. Veltuzumab (IMMU-106, hA20) is a humanized anti-CD20 mAb with complementarity-determining regions similar to rituximab. This antibody has enhanced binding avidities and a stronger effect on CDC compared with rituximab. Ocrelizumab is a humanized mAb with the potential for enhanced efficacy in lymphoid malignancies compared with rituximab due to increased binding affinity for the low-affinity variants of the FcγRIIIa receptor. The third-generation mAbs are also humanized mAbs, but in addition they have an engineered Fc to increase their binding affinity for the FcγRIIIa receptor. The third-generation mAbs include AME-133v, PRO131921 and GA-101. AME-133v (LY2469298) is a type I, humanized IgG1 mAb with enhanced affinity for FcγRIIIa receptor and an enhanced ADCC activity compared with rituximab. PRO131921 is a humanized anti-CD20 mAb engineered to have improved binding to FcγRIIIa and better ADCC compared with rituximab. GA-101 (RO5072759) is a fully humanized, type II, IgG1 mAb derived from humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering using GlycoMab® technology. GA-101 was designed for enhanced ADCC and superior direct cell-killing properties, in comparison with currently available type I antibodies. TRU-015 is a small modular immunopharmaceutical (SMIP) derived from key domains of an anti-CD20 antibody. TRU-015 represents a novel biological compound that retains Fc-mediated effector functions and is smaller than mAbs. In this article we review data on new anti-CD20 mAbs that are potentially useful in the treatment of lymphoid malignancies.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; B-Lymphocytes; Clinical Trials as Topic; Humans; Leukemia, B-Cell; Treatment Outcome
PubMed: 21090841
DOI: 10.2165/11539590-000000000-00000 -
Cancer Research Oct 2010The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting monoclonal antibody (MAb-IFNα)...
The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting monoclonal antibody (MAb-IFNα) can enhance potency due to increased tumor localization and improved pharmacokinetics. We report the generation and characterization of the first bispecific MAb-IFNα, designated 20-C2-2b, which comprises two copies of IFNα2b and a stabilized F(ab)(2) of hL243 (humanized anti-HLA-DR; IMMU-114) site-specifically linked to veltuzumab (humanized anti-CD20). In vitro, 20-C2-2b inhibited each of four lymphoma and eight myeloma cell lines, and was more effective than monospecific CD20-targeted MAb-IFNα or a mixture comprising the parental antibodies and IFNα in all but one (HLA-DR(-)/CD20(-)) myeloma line, suggesting that 20-C2-2b should be useful in the treatment of various hematopoietic malignancies. 20-C2-2b displayed greater cytotoxicity against KMS12-BM (CD20(+)/HLA-DR(+) myeloma) compared with monospecific MAb-IFNα, which targets only HLA-DR or CD20, indicating that all three components in 20-C2-2b could contribute to toxicity. Our findings indicate that a given cell's responsiveness to MAb-IFNα depends on its sensitivity to IFNα and the specific antibodies, as well as the expression and density of the targeted antigens.
Topics: Antibodies, Bispecific; Antibody-Dependent Cell Cytotoxicity; Antigens, CD20; HLA-DR Antigens; Humans; Immunoglobulin G; Interferon alpha-2; Interferon-alpha; Lymphoma, Non-Hodgkin; Multiple Myeloma; Neoplastic Stem Cells; Recombinant Proteins
PubMed: 20876805
DOI: 10.1158/0008-5472.CAN-10-2126 -
Blood Oct 2010We have generated hexavalent antibodies (HexAbs) comprising 6 Fabs tethered to one Fc of human IgG1. Three such constructs, 20-20, a monospecific HexAb comprising 6 Fabs...
Multiple signaling pathways induced by hexavalent, monospecific, anti-CD20 and hexavalent, bispecific, anti-CD20/CD22 humanized antibodies correlate with enhanced toxicity to B-cell lymphomas and leukemias.
We have generated hexavalent antibodies (HexAbs) comprising 6 Fabs tethered to one Fc of human IgG1. Three such constructs, 20-20, a monospecific HexAb comprising 6 Fabs of veltuzumab (humanized anti-CD20 immunoglobulin G1κ [IgG1κ]), 20-22, a bispecific HexAb comprising veltuzumab and 4 Fabs of epratuzumab (humanized anti-CD22 IgG1κ), and 22-20, a bispecific HexAb comprising epratuzumab and 4 Fabs of veltuzumab, were previously shown to inhibit pro-liferation of several lymphoma cell lines at nanomolar concentrations in the absence of a crosslinking antibody. We now report an in-depth analysis of the apoptotic and survival signals induced by the 3 HexAbs in Burkitt lymphomas and provide in vitro cytotoxicity data for additional lymphoma cell lines and also chronic lymphocytic leukemia patient specimens. Among the key findings are the significant increase in the levels of phosphorylated p38 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by all 3 HexAbs and the notable differences in the signaling events triggered by the HexAbs from those incurred by crosslinking veltuzumab or rituximab with a secondary antibody. Thus, the greatly enhanced direct toxicity of these HexAbs correlates with their ability to alter the basal expression of various intracellular proteins involved in regulating cell growth, survival, and apoptosis, with the net outcome leading to cell death.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Leukemia; Lymphoma, B-Cell; MAP Kinase Signaling System; Mitochondrial Membranes; NF-kappa B; PTEN Phosphohydrolase; Proto-Oncogene Proteins c-bcl-2; Rituximab; Sialic Acid Binding Ig-like Lectin 2; Signal Transduction
PubMed: 20628151
DOI: 10.1182/blood-2010-03-276857 -
Lupus Sep 2010
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; B-Lymphocytes; Female; Humans; Lupus Erythematosus, Systemic; Rituximab; Young Adult
PubMed: 20534646
DOI: 10.1177/0961203310373107 -
Leukemia & Lymphoma Jun 2010Limitations of therapeutic options for chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) have necessitated the development of novel... (Review)
Review
Limitations of therapeutic options for chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) have necessitated the development of novel treatments/strategies. Rituximab (chimeric anti-CD20 monoclonal antibody [mAb]) considerably improved therapeutic outcomes for patients with B-cell malignancies, particularly when combined with chemotherapy; outcomes, however, are limited by rituximab resistance or reduced response upon re-treatment. Novel anti-CD20 mAbs are in development that may enhance mAb therapy. Ofatumumab (human anti-CD20 mAb) induces highly potent cell lysis, including in cells with low CD20 expression, and is the most clinically advanced new anti-CD20 mAb. Positive phase III interim data for ofatumumab in fludarabine-refractory CLL that is also refractory to alemtuzumab or less suitable for alemtuzumab due to bulky (>5 cm) lymphadenopathy has led to FDA approval of this agent in this population. Preclinical and early clinical assessment of other novel anti-CD20 mAbs include: ocrelizumab, veltuzumab, GA101, AME-133v, and PRO131921; data suggest potential for improved efficacy over rituximab that will require substantiation in large-scale clinical trials. New treatment strategies and novel anti-CD20 mAbs have the potential to enhance long-term outcomes for CLL and NHL.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antigens, CD20; B-Lymphocytes; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Rituximab
PubMed: 20367564
DOI: 10.3109/10428191003717746 -
Seminars in Hematology Apr 2010Targeting the CD20 antigen on B lymphocytes with the monoclonal antibody (MoAb) rituximab has greatly improved the outcome of patients with B-cell malignancies. Despite... (Review)
Review
Targeting the CD20 antigen on B lymphocytes with the monoclonal antibody (MoAb) rituximab has greatly improved the outcome of patients with B-cell malignancies. Despite the success of rituximab, resistance occurs in about half of the patients, resulting in non-response to treatment or early relapse with the original disease. A better understanding of the mechanism of rituximab resistance has led to the development of novel, improved anti-CD20 antibodies. This review describes the development of CD20-targeted therapy from its historical background towards the next generation of anti-CD20 MoAbs and explains new strategies to overcome resistance.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibody Specificity; Antibody-Dependent Cell Cytotoxicity; Antigens, CD20; Apoptosis; B-Lymphocytes; Complement Activation; Drug Delivery Systems; Drug Resistance; Humans; Recombinant Fusion Proteins; Rituximab
PubMed: 20350667
DOI: 10.1053/j.seminhematol.2010.01.007 -
Leukemia & Lymphoma May 2010Veltuzumab is a humanized, anti-CD20 monoclonal IgG(1) antibody (MAb), constructed recombinantly on the framework regions of epratuzumab, with... (Review)
Review
Veltuzumab is a humanized, anti-CD20 monoclonal IgG(1) antibody (MAb), constructed recombinantly on the framework regions of epratuzumab, with complementarity-determining regions (CDRs) identical to rituximab, except for a single amino acid in CDR3 of the variable heavy chain. Veltuzumab showed anti-proliferative, apoptotic, and antibody-dependent cellular cytotoxicity effects in vitro similar to rituximab, but with significantly slower off-rates and increased complement-dependent cytotoxicity in several human lymphoma cell lines. In addition, very low doses of veltuzumab, given either intravenously or subcutaneously, depleted B cells in normal cynomolgus monkeys, and controlled tumor growth in mice bearing human lymphomas. Clinically, veltuzumab has been studied in > 150 patients with lymphomas and autoimmune diseases. In non-Hodgkin lymphoma (NHL), infusions of 80-750 mg/m(2) were well tolerated when given once-weekly for four doses, with the only toxicity being transient mild-moderate infusion reactions. Objective tumor responses, including durable complete responses, occurred at all dose levels. Subcutaneous injections of low doses (80-320 mg) have also proved to be safe and pharmacologically active, producing objective responses, including durable complete responses, at rates comparable to those reported with rituximab, in patients with NHL and immune thrombocytopenia.
Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Humans; Lymphoma; Molecular Sequence Data; Sequence Homology, Amino Acid
PubMed: 20214444
DOI: 10.3109/10428191003672123 -
Cancer Feb 2010Radioimmunotherapy of non-Hodgkin lymphoma comprises a (90)Y- or (131)I-labeled murine anti-CD20 IgG, but both agents also include a substantial dose of unlabeled...
Radioimmunotherapy of non-Hodgkin lymphoma comprises a (90)Y- or (131)I-labeled murine anti-CD20 IgG, but both agents also include a substantial dose of unlabeled anti-CD20 IgG given immediately before the radioconjugate to reduce its uptake in the spleen (primary normal B-cell antigen sink); this extends its plasma half-life and improves tumor visualization. Thus, these treatments combine an effective anti-CD20 radioconjugate with an unconjugated anti-CD20 antibody that is also therapeutically active, but the large anti-CD20 IgG predose ( approximately 900 mg) may diminish the tumor localization of the radioimmunoconjugate (eg, 10-35 mg). We have examined alternative approaches that enhance radionuclide targeting and improve antitumor responses. One uses a (90)Y-labeled anti-CD22 IgG (epratuzumab) combined with an antibody therapy regimen of a humanized anti-CD20 IgG (veltuzumab). Pretargeted radionuclide therapy using a trivalent, humanized, recombinant bispecific anti-CD20 antibody with a (90)Y-hapten-peptide is another highly effective method that is also less toxic than directly radiolabeled IgG. Finally, all approaches benefit from the addition of a consolidation-dosing regimen of the anti-CD20 IgG antibody. This article reviews these various options and discusses how some fundamental changes could potentially enhance the response and duration from radionuclide-targeted therapy.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Humans; Immunoconjugates; Indium Radioisotopes; Lymphoma, Non-Hodgkin; Mice; Mice, Nude; Radioimmunotherapy
PubMed: 20127947
DOI: 10.1002/cncr.24802