Rapid Clearance of Cytomegalovirus-Specific IgG After Repeated Intravenous Infusions of Human Immunoglobulin into Allogeneic Bone Marrow Transplant Recipients

Hagenbeek, Anton; Brummelhuis, H. G. J.; Donkers, Bas; Dumas, An M.; Haaft, Annemarie ten; Schaap, Bert J. P.; Sizoo, W.; Löwenberg, Bob

doi:10.1093/infdis/155.5.897

Cited by 43 publications

(27 citation statements)

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“…After administration of the hyperimmunoglobulin, half-life is reduced to about 1-2 days. This corresponds to the findings of Hagenbeek et al [6], who investigated two different anti-CMV hyperim munoglobulin preparations. Principally, the type of hyper immunoglobulin used seems to be the major criterion, this being valid not only for the relative content of IgG sub classes but also for the qualitative differences as related to the content of antibodies and VN titre, respectively [5], Summarizing the findings of our study and the results reported in the literature yields a non-uniform pattern of the kinetics of anti-CMV hyperimmunoglobulins.…”

Section: Resultssupporting

confidence: 91%

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Pharmacokinetics of an Anti-Cytomegalovirus Hyperimmunoglobulin after Single Intravenous Administration to Healthy Volunteers

Millendorfer¹,

Scriba²,

Bachmayer³

et al. 1991

Vox Sanguinis

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By selecting blood donors with high cytomegalovirus (CMV) antibody titres, a plasma pool was obtained which was used to produce an IgG hyperimmunoglobulin by means of pepsin fractionation. After administration of approximately 100 mg/kg body weight to healthy subjects, the time course both of anti-CMV IgG antibody titres by ELISA and of virus neutralisation (VN) titres was followed for 15 days. Seronegative subjects showed an increase in CMV-IgG antibodies as well as a significant enhancement of VN. The time course of both titres was non-uniform. The decline of both titres was biphasic: CMV-IgG antibodies fell slowly during the first week and remained unchanged thereafter, whereas VN titres decreased markedly faster in the first than in the second week. In seropositive subjects, on the other hand, VN remained unchanged. CMV-IgG antibodies increased by approximately 3 times, followed by a similar biphasic decline as seen in seronegative subjects. Due to the differences between seronegative and seropositive subjects and to the non- uniform time course, no calculations of the elimination rate were feasible.

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Section: Resultssupporting

confidence: 91%

“…While the problem was originally tackled in a strictly empirical way, a few authors have recently investigated the qualitative differences between the anti-CMV immunoglo bulins presently available or have conducted pharmacoki netic studies of hyperimmunoglobulins following intrave nous administration [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of an Anti-Cytomegalovirus Hyperimmunoglobulin after Single Intravenous Administration to Healthy Volunteers

Millendorfer¹,

Scriba²,

Bachmayer³

et al. 1991

Vox Sanguinis

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“…In investigations using mouse-human chimeric antibodies, half-lives werecomparable to thoseofthe twoantibodies used day of study in our study [11]. Although human IgG has been reported as beingeliminated muchmore slowly thanSDZ89-104 and 89-109witha {j half-life of20 days, thehalf-lives ofCMV-specific IgG measured after treatment of BMT recipients with anti-CMV hyperimmunoglobulin were similar to those observed with SDZ 89-109 and 89-104 [12,13]. Two mechanisms mightcontributeto the acceleratedclearance of both the CMV-specific monoclonal antibodies and CMV-specific IgG in BMT patients: First, such patients are in a highly catabolic state during the posttransplant period and accelerated elimination mighttherefore merelyreflect enhanced protein turnover [14].…”

Section: Discussionsupporting

confidence: 74%

Human Monoclonal Antibodies Neutralizing Cytomegalovirus (CMV) for Prophylaxis of CMV Disease: Report of a Phase I Trial in Bone Marrow Transplant Recipients

Aulitzky

Schulz

Tilg

et al. 1991

Journal of Infectious Diseases

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The safetyand pharmacokinetics of the twoneutralizing human IgGl monoclonal antibodies to cytomegalovirus (CMV) SDZ89-104 and 89-109 in bonemarrowtransplant (BM1)recipients was assessed in an open phase I trial. Thirteen patients, 8 seropositive and 5 seronegative for CMV, were treated with allogeneic or autologous bonemarrowtransplantation. SDZ89-104 was given to 5 and SDZ 89-109 to 8 patients. Patients were dividedinto high-and low-dose groups. A fixed prestudy doseof 0.1 mglkgwasgiven4 daysbefore BMT. On days3, 17, 31, 45, 59, and 73, patients were treated with either 0.5or 2 mglkgof the respective antibody. Results indicate that doses of2 mglkgofSDZ89-104 or SDZ89-109 in alternating weekscan besafely administered to BMT patients. Serum trough levels measured by antiidiotypeELISA were "'10 JLg/mi after administrationof 0.5mglkgand "'50 JLg/mi after treatment with2 mglkgofSDZ89-104 or SDZ 89-109. High serum levels defined by antiidiotypeELISA techniques closely paralleledincreased neutralizing activity. Serum half-lives calculated from these data were "'6 days.Human cytomegalovirus (CMV) causes most interstitial pneumonias in bone marrow transplant (BMT) recipients, the most frequent and serious infectious complication after allogeneic BMT. Despite all therapeutic efforts, mortality consistently reaches 50% [1]. Thus, clinical interest has focused on the prevention of CMV infection. Trials using human hyperimmune globulin for prophylaxis of CMV disease have had contradictory results [2]. Although the reasons for these discrepancies are unclear, varying content of neutralizing antibodies in different immunoglobulin preparations may be responsible [3].Monoclonal antibodies, in contrast, are highly standardizable reagents with defined functional and pharmacokinetic properties. The clinical application of murine monoclonalantibodies, however, is limited by several obstacles. Frequent administrationis required because of their short half-lives and the rapid development of human anti-mouse antibodies can Moreover, most murine monoclonalantibodieslack important immune effectorfunctions [6]. Human monoclonalantibodies maybeless immunogenic, should havelonger circulationhalflives, and thus may be superior for prolonged treatment of patients. We report here the results of the first clinical phase I trial with human monoclonal antibodies in BMT patients. Patients, Materials, and MethodsHumanmonoclonal antibodies neutralizing CMV designated SDZ 89-109 (formerly EV2-7) andSDZ89-104 (formerly EV 1-15) were established at theSandoz Research Institute. Both antibodies are of IgGl isotype butcarrydifferent idiotypes. They were shown to neutralize 50-100 times the IDso of laboratory CMV strains Towne, Davis, andAD169 andfourclinical isolates in theabsence of complement in concentrations as littleas 1 pg/ml (Scriba M, personal communication). SDZ89-109 neutralizes by binding to an 82-kDa protein, whereas SDZ89-104 binds to a disulfide-bonded complex consisting of 58-, 107-, and 163-kDa proteins [7]. The target antigenofSDZ89-104...

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“…Unfortunately, each of these modifications reduced important antibody activities (Pollack 1983;Kim et al 1986;Bender and Hetherington 1987;Steele and Steele 1989) and shortened the half-lives of some antibodies (Janeway et al 1968;Winston et al 1982;Hagenbeek et al 1987Hagenbeek et al -1928. Today most commercial IVIGs are produced by first using Cohn cold ethanol fractionation followed by (Turner, 1989).…”

Section: Intravenous Immunoglobulin (Ivig)mentioning

confidence: 99%

The history and evolution of immunoglobulin products and their clinical indications

Hooper¹

2015

LymphoSign Journal

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The history of providing antibodies to treat diseases began in the 19th century with the discovery of tetanus and diphtheria toxins and the demonstration that immunity to tetanus and diphtheria infections could be transferred by immune sera. Characterization of the mediators of this immunity resulted in the discovery that antibodies are proteins that can be isolated and used to protect against infectious diseases. Development of a method to isolate antibodies from human plasma that could be safely injected into people initiated the development of human gamma globulin preparations to provide antibodies to patients with inherited antibody deficiencies. To overcome the limitations imposed by intramuscular injection of gamma globulin, intravenous gamma globulin preparations were developed that began to be used in a wide variety of clinical conditions. Thus the original clinical indication for infection prevention was expanded to several other indications that employ large doses to suppress inflammatory and autoimmune disorders. The most recent development in immunoglobulin therapy is the production of concentrated immune globulins for subcutaneous injection. Home infusions of subcutaneous immunoglobulin are increasingly used to treat immunodeficient patients and are being studied for other clinical applications.

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Rapid Clearance of Cytomegalovirus-Specific IgG After Repeated Intravenous Infusions of Human Immunoglobulin into Allogeneic Bone Marrow Transplant Recipients

Cited by 43 publications

References 0 publications

Pharmacokinetics of an Anti-Cytomegalovirus Hyperimmunoglobulin after Single Intravenous Administration to Healthy Volunteers

Pharmacokinetics of an Anti-Cytomegalovirus Hyperimmunoglobulin after Single Intravenous Administration to Healthy Volunteers

Human Monoclonal Antibodies Neutralizing Cytomegalovirus (CMV) for Prophylaxis of CMV Disease: Report of a Phase I Trial in Bone Marrow Transplant Recipients

The history and evolution of immunoglobulin products and their clinical indications

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