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At least 199 records · Page 11Linked to original sources
PubMed1995

Phase I clinical trial of serotherapy in patients with acute myeloid leukemia with an immunoglobulin M monoclonal antibody to CD15.

Sixteen patients with acute myeloid leukemia (AML) were treated with a continuous i.v. infusion of mAb PM-81, an IgM mAb directed against the cellular differentiation antigen CD15, which is expressed on leukemia cells of >95% of patients with AML. MAb PM-81, also referred to as MDX-11, is capable of activating human and rabbit complement and lysing CD15-positive AML cells. In this Phase I study, patients were treated with 0.5, 1.0, or 1.5 mg/kg MDX-11 delivered over a 24-h period followed by conventional chemotherapy. Transient decreases in circulating blast cells postinfusion (prior to chemotherapy) were observed at all doses. We were able to show MDX-11 binding to bone marrow blasts in those patients who achieved stable serum levels of MDX-11. Serum MDX-11 was detectable at the 1. 0- and 1.5-mg/kg doses. Doses of 0.5 and 1.0 mg/kg were generally well tolerated, with no toxicities greater than grade II (Eastern Cooperative Oncology Group) reported. However, two of five patients receiving the 1.5-mg/kg dose experienced grade IV toxicities that resolved with treatment (one of these patients completed the infusion). Common toxicities reported included fever, chills, and hypotension. Only one patient developed human antimouse antibodies at 4 weeks posttreatment. This study determined that 1.0 mg/kg is a biologically effective dose that can be administered safely with little toxicity. Based on these results, we are pursuing a Phase I/II study of MDX-11 infusion following chemotherapy for patients with relapsed AML.

Acute Disease↗
PubMed1999

Treatment of plasma cell dyscrasias by antibody-mediated immunotherapy.

The use of serotherapy to treat patients with plasma cell dyscrasias (PCDs) has been sought by us and others. Candidate antigens that have been targeted or proposed for targeting in PCDs include the immunoglobulin idiotype, CD19, CD38, CD54, CD126, HM1.24, and Muc-1 core protein. Unfortunately, many of these antigens are not ideal for use in serotherapy since they are not selectively expressed, are either shed or secreted, or have not been fully characterized. Serotherapy with an anti-CD19 monoclonal antibody (B4) conjugated to a blocked ricin toxin had no significant activity in patients with multiple myeloma (MM). Circulating CD20+ clonotypic B cells have been detected in the circulation of most MM and Waldenstrom's macroglobulinemia (WM) patients. Plasma cells from most WM patients express CD20, but most MM patient plasma cells either lack CD20 or express it weakly. In view of recent successes with anti-CD20-directed serotherapy in other B-cell malignancies, we initiated a phase II trial to study the anti-CD20 monoclonal antibody rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA) in patients with MM. We describe two PCD patients (one with WM and one with MM) who responded to therapy. By flow cytometric analysis, CD20+ plasma cells and B cells present in the bone marrow and peripheral blood of a patient with MM disappeared with response to rituximab therapy. However, residual CD20- tumor cells remained in the bone marrow following rituximab therapy, and after 6 months this patient progressed with CD20- myeloma cells. As a potential strategy to overcome this limitation, we demonstrated that interferon-gamma at pharmacologically achievable levels induced CD20 expression on these CD20- plasma cells, consistent with our recent findings that interferon-gamma is a potent inducer of CD20 expression on MM patient plasma cells and B cells. We also characterize a response to rituximab with a decrease in paraprotein and resolution of anemia in a patient with WM whose response to rituximab is ongoing after 19+ months. This preliminary experience supports the potential use of serotherapy targeting CD20 in PCDs. Our studies further suggest that interferon-gamma may enhance CD20 expression on MM plasma cells, thereby increasing their susceptibility to anti-CD20 monoclonal antibody therapies.

Aged↗
PubMed2000

Treatment of multiple myeloma by antibody mediated immunotherapy and induction of myeloma selective antigens.

BACKGROUND: In view of the successful use of serotherapy in many B-cell malignancies, we and others have sought to identify tumor selective antigens for the serotherapy of plasma cell dyscrasias (PCD) including multiple myeloma (MM), and Waldenstrom's macroglobulinemia (WM). We recently identified Muc-1 core protein as a MM selective antigen. Though Muc-1 core protein is abundantly expressed on most MM plasma cells, expression of this antigen can be absent, or weak on some plasma cells which could potentially result in the selection of Muc-1 core protein negative clones following serotherapy of PCD. In addition to Muc-1 core protein, we have also been examining the use of CD20 directed serotherapy for PCD. DESIGN: As part of these efforts, we recently initiated a phase II clinical trial examining the use of Rituximab (Rituxan, MabThera) as a single agent in MM patients; as well several WM patients have been treated with Rituximab at our Institutions. RESULTS: In previous studies, we have shown that CD20 is abundantly expressed on the plasma cells of most WM patients; in contrast, CD20 is expressed on plasma cells from a minority of MM patients, and in these patients expression of CD20 can be weak or heterogeneous with both CD20+ and CD20- plasma cells present. As such, we have sought out clinically useful inducers of Muc-1 core protein, and of CD20 on malignant plasma cells. CONCLUSIONS: These efforts resulted in the identification of dexamethasone (Dex) as a potent inducer of Muc-1 core protein on MM plasma cells, and interferon-gamma (IFN-gamma) as a potent inducer of CD20 on MM plasma cells and B-cells. Importantly, these agents induced their respective antigens at pharmacologically achievable doses.

Animals↗
PubMed2000

Immunotherapeutic strategies for the treatment of plasma cell malignancies.

The use of immunotherapy to treat patients with plasma cell dyscrasias (PCD) such as multiple myeloma (MM) and Waldenström's macroglobulinemia (WM) has gained enormous interest in recent years, with considerable efforts being mounted by many investigators. These efforts have included the use of serotherapy (antibody-mediated immunotherapy), vaccination strategies aimed at inducing allogeneic as well as autologous anti-MM immunity, and the use of donor lymphocyte infusions (DLIs). A number of cell surface antigens on malignant plasma cells and/or B cells in MM and/or WM patients have been proposed for use in tumor cell-targeted serotherapy, including immunoglobulin idiotype, CD19, CD20, CD38, CD54, CD138, HM1.24, and MUC1 core protein. Ongoing clinical trials are examining serotherapy targeting CD20 (in MM and WM) and CD38 (in MM), with early reports of responses to the anti-CD20 monoclonal antibody (mAb) Rituximab (Genentech, South San Francisco, CA) in patients with WM and certain patients with MM. The use of agents to induce MM- and WM-selective antigens for targeting in serotherapy has been proposed based on studies demonstrating the upregulation of CD20 by interferon-gamma (IFN-gamma), and of MUC1 core protein by dexamethasone (DEX) on malignant plasma cells. Strategies to induce allogeneic anti-MM immunity have included immunization of the marrow donor to idiotypic protein, as well as DLI. In addition, proposed immunization strategies aimed at inducing autologous immunity include vaccination with dendritic cells pulsed with MM antigens, MM cell-dendritic cell fusions, carrier-linked idiotype protein, catalytic subunit of telomerase, or DNA encoding for single-chain variable fragments (scFv) linked to a carrier protein gene. Whole tumor vaccination strategies are also being examined and include the use of MM cells transfected and/or stimulated with cytokines, costimulatory molecules, or CD40 ligand. Finally, potential obstacles to the use of immunotherapy, including the presence of resistance antigens on MM and WM tumor cells, are discussed.

Cancer Vaccines↗
PubMed1995

Treatment of arthritis in Lewis rats by a monoclonal antibody against alpha beta T cell receptor: differential sensitivity of Yersinia-induced arthritis versus adjuvant arthritis.

Lewis rats experimentally infected with Yersinia enterocolitica develop sterile arthritis similar to Yersinia-associated reactive arthritis in humans. To investigate the putative role of alpha beta T cells in the pathogenesis of Yersinia-induced arthritis (YIA) rats were treated with the monoclonal antibody (mAb) R73 mAb directed against the rat alpha beta T cell receptor. In spite of reduction of alpha beta T cells in peripheral blood and in liver lesions of Yersinia-infected rats this serotherapy had no suppressive effect on YIA. Moreover, R73 mAb treatment had no influence on the number of alpha beta T cells in the inflammed synovial tissue. In contrast, R73 mAb serotherapy in Mycobaterium tuberculosis-immunized rats blocked development of adjuvant arthritis (AA) and suppressed the presence of alpha beta T cells in the synovial tissue. These results suggest fundamental differences between the immunopatho-mechanism of YIA caused by bacterial infection and AA induced by bacterial immunization and known to be T cell mediated. These data might have consequences for putative serotherapy of arthritis in humans.

Animals↗
PubMed1981

Use of monoclonal antibodies as diagnostic and therapeutic reagents in acute lymphoblastic leukemia.

A monoclonal antibody specific for a common acute lymphoblastic leukemia (ALL) antigen has been generated and characterized. This antibody (J-5) is reactive with leukemic cells from most patients with non-T-cell ALL and some patients with chronic myelocytic leukemia in blast crisis. J-5 antibody is not reactive with leukemic cells from patients with either T-cell ALL, chronic lymphocytic leukemia, acute myeloblastic leukemia, or stable-phase chronic myelocytic leukemia. In addition to diagnostic applications, anti-common ALL antigen monoclonal antibody has been used to study the effect of specific serotherapy in the treatment of ALL. In the first patient with ALL treated with J-5 antibody, a 90% reduction in circulating lymphoblasts occurred within 1 hr of starting antibody infusion. Despite continued serotherapy, however, lymphoblasts persisted in peripheral blood and bone marrow. Analysis of cell surface markers during serotherapy suggested that resistance to antibody-mediated lysis in vivo may have been due to antigenic modulation of leukemic cells in response to J-5 monoclonal antibody.

Acute Disease↗
PubMed1986

Monoclonal antibodies to CALLA do not alter polymorphonuclear functions.

The common acute lymphoblastic leukemia antigen (CALLA) is present on the malignant cells of most patients with acute lymphoblastic leukemia (ALL). Monoclonal antibodies (MoAbs) to CALLA have been useful for differentiating lymphoblastic from nonlymphoblastic leukemias as well as for serotherapy in ALL. Since this MoAb also reacts with polymorphonuclear (PMN) leukocytes, it was of interest to determine whether or not MoAbs to CALLA affected PMN function. We therefore evaluated four MoAbs to CALLA for their effect on PMN function. Two of the MoAbs were IgG and two were IgM. Chemotaxis was studied using Micro-Boyden chambers. Intraleukocyte bacterial killing was studied using Staph:PMN of 2:1 and 10:1, and metabolic activation was evaluated by hexose monophosphate shunt activity. The results showed that these MoAbs to CALLA did not impair the parameters of PMN function studied. These findings have relevance to the usefulness of MoAbs to CALLA for serotherapy and also as a probe for understanding the surface molecule properties that have a bearing on PMN host defense functions.

Antibodies, Monoclonal↗
PubMed1993

Utilization of aspirin, quinine and verapamil in the prevention and treatment of scorpion venom intoxication.

Aside from serotherapy, the treatment of scorpion venom intoxication is symptomatic. The aim of this study was to compare the efficacy of drugs usually used in scorpion venom intoxications (atropine, propranolol) to that of other compounds, chosen in light of the pathophysiology of scorpion venom intoxication: dipyridamole, doxapram, quinine formate, lysine-acetyl-salicylate, valproate and verapamil. Using mice, the parameters evaluated were the preventive and therapeutic effects of drugs during experimental venom intoxication by Androctonus australis Hector and one of its toxins AaH 1, and by Buthus occitanus and Tityus serrulatus tunetanus on the other hand. It was found that although most of the drugs used could prolong the survival of the animals, the administration of verapamil and more so that of aspirin or quinine formate led to a 50 to 100% loss of venom and toxin toxicity, depending on the drug and the origin of the venom. In the case of propranolol, doxapram, atropine, dipyridamole and valproate, no or little protection were observed. If these results are confirmed in humans, the systematic use of these drugs could be a simple means for treating scorpion venom intoxication. The problem of scorpion venom intoxication poses a health problem both in the North African Maghreb and in the Americas. As a result of considerable information campaigns, the number of scorpion venom intoxications in Tunisia has dropped from 3000 in 1967 to 1000 per year in the 1980s. Serotherapy has reduced mortality to 0.35%, most deaths occurring in underweight children. In light of the large number of countries in which there is a risk of scorpion venom intoxication in the summertime, however, its prevention and treatment remain a major problem.

Animals↗
PubMed2004

Quantitative variability in the biodistribution and in toxinokinetic studies of the three main alpha toxins from the Androctonus australis hector scorpion venom.

Scorpion stings represent a medical problem in numerous countries. The scorpion Androctonus australis hector produces three alpha toxins (Aah I to III), which are responsible for most of the lethality in mammals. These toxins act on sodium channel and do not cross-react immunologically. We used RIA and ELISA to measure the concentrations of these three toxins in plasma, urine and different organs after i.v. and s.c. injections of water extracts of venoms in rabbits or mice. In both animals, the toxins rapidly appeared in plasma after s.c. injection as it was previously described for the whole venom. However, the toxins disappeared from the blood more quickly than did other main components of the venom. Thus, serotherapy must be initiated immediately to prevent the toxin from reaching its target. We also detected the toxins in urine, kidneys, heart and lungs, but not in the brain. However, the concentration of Aah II was always lower than that of Aah I. Analysis of five samples of venom collected in different areas of southern Tunisia showed that a large polymorphism exists for the three toxins. This is yet another difficulty for serotherapy as there is no cross-antigenicity between them.

Animals↗
PubMed1998

Pharmacokinetics of 125I-labelled Walterinnesia aegyptia venom and its distribution of the venom and its toxin versus slow absorption and distribution of IGG, F(AB')2 and F(AB) of the antivenin.

A three-compartment open pharmacokinetic model best fitted the data obtained following the i.v. injection of the venom, toxin and the immunoglobulin fractions into either rabbits or mice. The venom and toxin, however, possessed pharmacokinetic characteristics that were significantly different from the immunoglobulin fractions. The venom and toxin had very highly significantly greater disposition rate constants to the shallow and deep tissue compartments and overall elimination rate constant from the central compartment than any of the immunoglobulin fractions. This was reflected in other pharmacokinetic parameters, including highly significantly smaller areas under the curve (AUC) and highly significantly greater volumes of the central compartment (Vc), shallow tissue compartment (Vt shallow), deep tissue compartment (Vt deep) and total body clearance (TBC). In rabbits, F(ab')2 possessed the fastest disposition rate constants and the shortest distribution half-lives, while Fab showed the slowest disposition rate constants and the longest distribution half-lives. The same picture occurred in mice except that the values for Fab were between those of F(ab')2 and IgG. The time needed by the venom and toxin to reach maximum tissue concentration (tmax) ranged between 7 and 15 min and 60 and 180 min for the shallow and deep tissue compartments, respectively. The immunoglobulin fractions required 8-26-fold these times to attain tmax; F(ab')2 was the fastest to achieve its maximal concentration. Following i.m. injection, very fast absorption of venom and toxin took place, with the toxin reaching tmax within 5-20 min and 90% of the injected dose absorbed within 60 min. The bioavailability factor (F) was 0.82 and 0.88 for the venom and toxin, respectively. Fab had an F-value of 0.36 and required 4.3 and 47.4-fold the time taken by the venom and toxin to achieve tmax. The calculated values of F for F(ab')2 and IgG were 0.25 and 0.26, respectively. In the physiologically based pharmacokinetics (PBPK), the venom and toxin reached tmax in the different organs studied very rapidly while the immunoglobulin fractions required several-fold this time to attain tmax. F(ab')2 possessed the highest CPmax, the smallest AUC and the shortest t1/2 beta in the different tissues; Fab had values between F(ab)2 and IgG. It is concluded that F(ab')2 possesses pharmacokinetic characteristics that render it most suitable for use in serotherapy of snake and scorpion envenoming. It should be injected i.v. in doses higher than calculated neutralizing doses to compensate for the slow rate of distribution. Because of slow and incomplete absorption, the i.m. injection of the immunoglobulin fractions would be of little value in serotherapy.

Absorption↗
PubMed1998

South American rattlesnake bite (Crotalus durissus SP) without envenoming: insights on diagnosis and treatment.

A South American rattlesnake bite without clinical manifestations of envenoming (termed 'dry-bite') has not been recognized to occur by the Brazilian Ministry of Health, which recommends the administration of antivenom to all bitten patients. During 36 months of an observational study on South American rattlesnake bites in Minas Gerais, Brazil, 12% of 41 patients with fang marks at the bite-site did not present clinical or laboratory features of envenoming and had no plasma venom detected before specific serotherapy, fulfilling the criteria for the diagnosis of true 'dry-bite'. Data from these preliminary observations suggest that these patients should be correctly diagnosed since they should not be treated with unnecessary and sometimes hazardous and expensive serotherapy.

Adolescent↗
PubMed1984

Monoclonal antibodies in the treatment of cancer.

Potential uses of monoclonal antibodies in anti-cancer treatment include passive serotherapy, radioisotope conjugates, toxin-linked conjugates, and chemotherapy-monoclonal antibody conjugates. The bases for these applications have been founded in research with heterologous antisera, and in some cases with monoclonal antibodies in animal tumor models. Human trials with passive serotherapy have already begun in both hematopoietic and solid tumor malignancies. Promising results have been reported in cutaneous T cell lymphoma with anti-T cell monoclonal antibody, and in nodular lymphoma with anti-idiotype monoclonal antibody. Radioisotope conjugate work appears promising for imaging in both animals and humans, and this work will lay the foundation for possible therapeutic application of radio-immunotherapy. Toxin-linked conjugates are promising in vitro and may have application in autologous bone marrow transplantation. Research with chemotherapy conjugates is also underway. Preliminary results suggest that murine monoclonal antibodies will be well tolerated clinically except in the setting of circulating cells which bear the target antigen, where rapid infusions may be associated with intolerable side effects. In certain diseases, production of endogenous anti-mouse antibodies may also limit application. Advances in the technology for human-human hybridoma production may help solve some of these problems.

Animals↗