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British Journal of Haematology Apr 2014
Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Humans; Lymphoma, Follicular; MAP Kinase Signaling System; Mice; NF-kappa B
PubMed: 24386925
DOI: 10.1111/bjh.12711 -
British Journal of Haematology Sep 2013Low doses of the humanized anti-CD20 monoclonal antibody, veltuzumab, were evaluated in 41 patients with immune thrombocytopenia (ITP), including 9 with ITP ≤1 year...
Low doses of the humanized anti-CD20 monoclonal antibody, veltuzumab, were evaluated in 41 patients with immune thrombocytopenia (ITP), including 9 with ITP ≤1 year duration previously treated with steroids and/or immunoglobulins, and 32 with ITP >1 year and additional prior therapies. They received two doses of 80-320 mg veltuzumab 2 weeks apart, initially by intravenous (IV) infusion (N = 7), or later by subcutaneous (SC) injections (N = 34), with only one Grade 3 infusion reaction and no other safety issues. Thirty-eight response-assessable patients had 21 (55%) objective responses (platelet count ≥30 × 10(9) /l and ≥2 × baseline), including 11 (29%) complete responses (CRs) (platelet count ≥100 × 10(9) /l). Responses (including CRs) occurred with both IV and SC administration, at all veltuzumab dose levels, and regardless of ITP duration. Responders with ITP ≤1 year had a longer median time to relapse (14·4 months) than those with ITP >1 year (5·8 months). Three patients have maintained a response for up to 4·3 years. SC injections resulted in delayed and lower peak serum levels of veltuzumab, but B-cell depletion occurred after first administration even at the lowest doses. Eight patients, including 6 responders, developed anti-veltuzumab antibodies following treatment (human anti-veltuzumab antibody, 19·5%). Low-dose SC veltuzumab appears convenient, well-tolerated, and with promising clinical activity in relapsed ITP.(Clinicaltrials.gov identifier: NCT00547066.).
Topics: Antibodies, Monoclonal, Humanized; Antigens, CD20; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Purpura, Thrombocytopenic, Idiopathic; Recurrence; Treatment Outcome
PubMed: 23829485
DOI: 10.1111/bjh.12448 -
PloS One 2013The type III interferons (IFNs), comprising IFN-λ1, IFN-λ2, and IFN-λ3, behave similarly to IFN-α in eliciting antiviral, antitumor, and immune-modulating...
The type III interferons (IFNs), comprising IFN-λ1, IFN-λ2, and IFN-λ3, behave similarly to IFN-α in eliciting antiviral, antitumor, and immune-modulating activities. Due to their more restricted cellular targets, IFN-λs are attractive as potential alternatives to existing therapeutic regimens based on IFN-αs. We have applied the DOCK-AND-LOCK™ method to improve the anti-proliferative potency of IFN-λ1 up to 1,000-fold in targeted cancer cell lines by tethering stabilized Fab dimers, derived from hRS7 (humanized anti-Trop-2), hMN-15 (humanized anti-CEACAM6), hL243 (humanized anti-HLA-DR), and c225 (chimeric anti-EGFR), to IFN-λ1 site-specifically, resulting in novel immunocytokines designated (E1)-λ1, (15)-λ1, (C2)-λ1, and (c225)-λ1, respectively. Targeted delivery of IFN-λ1 via (15)-λ1 or (c225)-λ1 to respective antigen-expressing cells also significantly increased antiviral activity when compared with non-targeting (C2)-λ1, as demonstrated in human lung adenocarcinoma cell line A549 by (15)-λ1 against encephalomyocarditis virus (EC50 = 22.2 pM versus 223 pM), and in human hepatocarcinoma cell line Huh-7 by (c225)-λ1 against hepatitis C virus (EC50 = 0.56 pM versus 91.2 pM). These promising results, which are attributed to better localization and stronger binding of IFN-λ1 to antibody-targeted cells, together with the favorable pharmacokinetic profile of (E1)-λ1 in mice (T(1/2) = 8.6 h), support further investigation of selective prototypes as potential antiviral and antitumor therapeutic agents.
Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cell Line, Tumor; Cell Proliferation; Electrophoresis, Polyacrylamide Gel; Encephalomyocarditis virus; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Hepacivirus; Humans; Immunoglobulin Fab Fragments; Interferons; Mice; Mice, Nude
PubMed: 23696859
DOI: 10.1371/journal.pone.0063940 -
Journal of Hematology & Oncology May 2013Chronic lymphocytic leukemia (CLL) is a heterogeneous group of B-cell neoplasm. CLL is typically sensitive to a variety of cytotoxic agents, but relapse frequently... (Review)
Review
Chronic lymphocytic leukemia (CLL) is a heterogeneous group of B-cell neoplasm. CLL is typically sensitive to a variety of cytotoxic agents, but relapse frequently occurs with conventional approaches. The treatment of CLL is evolving rapidly with the introduction of novel drugs, such as bendamustine, ofatumumab, lenalidomide, ibrutinib, idelalisib, veltuzumab, XmAb5574, navitoclax, dasatinib, alvespimycin, and TRU-016. This review summarizes the most current clinical experiences with these agents in the treatment of CLL.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Humans; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Nitrogen Mustard Compounds; Thalidomide
PubMed: 23680477
DOI: 10.1186/1756-8722-6-36 -
Seminars in Hematology Jan 2013B cells play an important role in the immune response and can lead to the development of autoimmune diseases and particularly immune thrombocytopenia (ITP). A rational... (Review)
Review
B cells play an important role in the immune response and can lead to the development of autoimmune diseases and particularly immune thrombocytopenia (ITP). A rational approach to ITP treatment could involve B-cell depletion such as with rituximab. Rituximab is a chimeric monoclonal antibody directed against CD20 molecule. It has direct effects on antibody production and indirect effects on cellular immunity. Rituximab demonstrated an overall response rate of 62.5% that lasted from 2-48 months. The ability of rituximab as an effective splenectomy-avoiding option was recently confirmed in a meta-analysis of randomized clinical trials and observational studies including 368 patients with an overall response rate of 57%. However, the estimated 5- year response is only 21% in adults. Rituximab appears to be well tolerated, but we lack studies of long-term tolerance. The optimal time to administer rituximab for ITP remains unclear. There is consensus to administer corticosteroids or intravenous immunoglobulin (IVIg) as first-line therapy in ITP. A panel of experts was unable to formulate a clear strategy for the respective place of splenectomy, thrombopoietin-receptor agonists, and rituximab as second-line treatment. Among new-generation CD20-targeted therapy, only veltuzumab has been tested for ITP. Preliminary study suggests that it could have similar efficacy to rituximab. Options other than anti-CD20 treatment may modulate and/or inhibit the B-cell compartment. Several monoclonal antibodies (MoAbs) directed against different B-lymphocyte receptors or structures implicated in the cooperation between B and T lymphocytes have been successfully tested in various autoimmune diseases. Testing these options in ITP will be an exciting challenge.
Topics: Antigens, CD20; B-Lymphocytes; Humans; Thrombocytopenia
PubMed: 23664523
DOI: 10.1053/j.seminhematol.2013.03.014 -
Journal of Hematology & Oncology Oct 2012Rituximab (RTX), a monoclonal antibody (mAb) against CD20, has been widely used for lymphoma therapy. RTX in combination with cyclophosphamide /doxorubicin /vincristine... (Review)
Review
Rituximab (RTX), a monoclonal antibody (mAb) against CD20, has been widely used for lymphoma therapy. RTX in combination with cyclophosphamide /doxorubicin /vincristine /prednisone (R-CHOP) remains the standard frontline regimen for diffuse large B-cell lymphoma. However, suboptimal response and /or resistance to rituximab have remained a challenge in the therapy of B-cell non-Hodgkin's lymphoma (NHL). Novel agents are under active clinical trials. This review will summarize the latest development in new mAbs against CD20, which include second-generation mAbs, ofatumumab, veltuzumab (IMMU-106), ocrelizumab (PRO70769), and third-generation mAbs, AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutumumab).
Topics: Antibodies, Monoclonal; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoma, Non-Hodgkin
PubMed: 23057966
DOI: 10.1186/1756-8722-5-64 -
Blood Apr 2012We describe the use of novel bispecific hexavalent Abs (HexAbs) to enhance anticancer immunotherapy. Two bispecific HexAbs [IgG-(Fab)(4) constructed from veltuzumab...
We describe the use of novel bispecific hexavalent Abs (HexAbs) to enhance anticancer immunotherapy. Two bispecific HexAbs [IgG-(Fab)(4) constructed from veltuzumab (anti-CD20 IgG) and milatuzumab (anti-CD74 IgG)] show enhanced cytotoxicity in mantle cell lymphoma (MCL) and other lymphoma/leukemia cell lines, as well as patient tumor samples, without a crosslinking Ab, compared with their parental mAb counterparts, alone or in combination. The bispecific HexAbs have different properties from and are more potent than their parental mAbs in vitro. The juxtaposition of CD20 and CD74 on MCL cells by the HexAbs resulted in homotypic adhesion and triggered intracellular changes that include loss of mitochondrial transmembrane potential, production of reactive oxygen species, rapid and sustained phosphorylation of ERKs and JNK, down-regulation of pAkt and Bcl-xL, actin reorganization, and lysosomal membrane permeabilization, culminating in cell death. They also displayed different potencies in depleting lymphoma cells and normal B cells from whole blood ex vivo and significantly extended the survival of nude mice bearing MCL xenografts in a dose-dependent manner, thus indicating stability and antitumor activity in vivo. Such bispecific HexAbs may constitute a new class of therapeutic agents for improved cancer immunotherapy, as shown here for MCL and other CD20(+)/CD74(+) malignancies.
Topics: Actin Cytoskeleton; Animals; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antigens, Differentiation, B-Lymphocyte; Apoptosis; B-Lymphocytes; Cell Line, Tumor; Cytotoxins; Drug Design; Female; Histocompatibility Antigens Class II; Humans; Immunoglobulin G; Immunotherapy; Lymphoma, Mantle-Cell; Lysosomes; MAP Kinase Signaling System; Mice; Mice, SCID; Xenograft Model Antitumor Assays
PubMed: 22271448
DOI: 10.1182/blood-2011-09-381988 -
Best Practice & Research. Clinical... Jun 2011Rituximab has become a ubiquitous component of treatment regimens for follicular non-Hodgkin lymphoma. Despite widespread clinical use, the mechanisms by which tumor... (Review)
Review
Rituximab has become a ubiquitous component of treatment regimens for follicular non-Hodgkin lymphoma. Despite widespread clinical use, the mechanisms by which tumor cells resist rituximab-mediated destruction remain unclear. Rituximab relies in part on immune effector mechanisms for its antitumor effect, and thus resistance may be mediated not only by intrinsic tumor-cell alterations but also by the host immunological environment. In this article, we explore the mechanisms of action of rituximab, the incidence of rituximab resistance, and potential mechanisms of resistance. Finally, we discuss novel approaches to modulate the antibody, the tumor cell, and the host immunologic environment to overcome rituximab resistance. Further research into the mechanisms of rituximab resistance will be essential to improving the efficacy of anti-CD20 therapy in NHL, and may also pay dividends in the optimization of monoclonal antibody therapy across a wide range of diseases.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Apoptosis; Complement System Proteins; Drug Administration Schedule; Drug Dosage Calculations; Drug Resistance, Neoplasm; Humans; Immunotherapy; Lymphoma, Follicular; Mice; Polymorphism, Single Nucleotide; Receptors, Fc; Rituximab; Tumor Microenvironment
PubMed: 21658619
DOI: 10.1016/j.beha.2011.02.009 -
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