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Ouabain and Digoxin Between Two Related Digitalis Glycosides

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Ouabain and Digoxin Between Two Related Digitalis Glycosides Monoclonal Antibodies That Distinguish Between Two Related Digitalis Glycosides, Ouabain and Digoxin This information is current as Behnaz Parhami-Seren, Charles Bell, Michael N. Margolies of September 28, 2021. and Garner T. Haupert, Jr. J Immunol 1999; 163:4360-4366; ; http://www.jimmunol.org/content/163/8/4360 Downloaded from References This article cites 37 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/163/8/4360.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Monoclonal Antibodies That Distinguish Between Two Related Digitalis Glycosides, Ouabain and Digoxin1 Behnaz Parhami-Seren,* Charles Bell,2† Michael N. Margolies,* and Garner T. Haupert, Jr.3† The exogenous digitalis glycosides, ouabain and digoxin, have been widely used in humans to treat congestive heart failure and cardiac arrhythmias. Several reports have also pointed to the existence of endogenous ouabain- and digoxin-like compounds, but their precise roles in mammalian physiology and various disorders of the circulation are not clear. In an attempt to produce specific Abs for the purification and identification of endogenous ouabain-like compounds, somatic cell fusion was used to produce mAbs specific for ouabain. Our attempts to produce ouabain-specific mAbs were unsuccessful when ouabain was coupled to exogenous proteins such as bovine g-globulins, BSA, and human serum albumin. However, when ouabain was coupled to an Ab of A/J mice origin and the same strain of mouse was used for immunization with ouabain-Ab conjugate, three Abs (1-10, 5A12, and 7-1) specific for ouabain were obtained. In assays of fluorescence quenching and saturation equilibrium with tritiated ouabain, Downloaded from Ab 1-10 exhibited 200 nM affinity for ouabain. These three mAbs are distinguished from existing Abs to ouabain and digoxin by their specificity for ouabain and lack of cross-reactivity with digoxin. Specificity studies showed that the loss of cross-reactivity was correlated with the presence of a hydroxyl group at either position 12b (digoxin) or 16b (gitoxin) of the steroid ring. These Abs can be used to develop assays for detection and characterization of ouabain-like molecules in vivo. The Journal of Immunology, 1999, 163: 4360–4366. http://www.jimmunol.org/ igitalis glycosides have been used widely in the clinical Whether this endogenous Oua is truly endogenous, vs accumu- treatment of congestive heart failure and certain cardiac lated from the environment, or exists in the circulation as a regu- D arrhythmias for hundreds of years. The therapeutic index latory hormone is currently debated. In an effort to answer these of these drugs is narrow, and clinical toxicity is frequent (1). The crucial questions, several groups have developed polyclonal anti- advent of somatic cell fusion techniques (2) permitted the produc- Oua Abs for use in RIA and ELISA-type biological assays. Using tion of mAbs with high sensitivity and specificity to digoxin (Dig)4 different Abs, findings have continued to be contradictory. Some (3) for use in the study of Ab structure-function relationships, de- laboratories have obtained immunoassay data supporting not only velopment of clinical assays, and emergency treatment for life- the existence of OLC in mammalian plasma and tissues (9, 10), but threatening digitalis overdoses (4, 5). that OLC can be secreted by adrenal cells in culture in response to by guest on September 28, 2021 In recent years, a body of evidence has accumulated to suggest receptor stimulation (11) and feeding of steroid hormone precur- the existence in mammals, including man, of compounds with bi- sors (12). To our knowledge, only one group has provided phys- ological properties similar to or identical with those of the plant- icochemical structural analysis of immunoreactive isolates. Liquid derived cardiotonic steroids. Structural analysis of tissue and chromatography mass spectrometry using selected ion recording plasma extracts has indicated that one of these compounds is iden- and positive electrospray mass spectrometry indicated a compound tical in structure to the plant-derived cardenolide, ouabain (Oua) in tissue isolates and adrenal cell culture supernatants, respec- (6, 7) (Fig. 1). This Oua-like compound (OLC) has been impli- tively, with a molecular mass identical with that of authentic plant- cated in the control of renal sodium excretion, blood pressure reg- derived Oua (12). ulation, cardiac muscle performance, and the pathogenesis of hy- Other investigators, using their own polyclonal Abs to Oua, pertension through endogenous regulation (or dysregulation) of have questioned the existence of authentic Oua in plasma and ad- 1 1 Na ,K -ATPase (sodium pump) in pertinent target tissues (8). renal cell culture supernatants and have provided data that struc- tural identity of OLC from these sources with plant Oua is un- likely. The primary basis for these conclusions rests on the *Department of Surgery, Massachusetts General Hospital and Harvard Medical demonstration that HPLC retention times for immunoreactive School, and †Renal Unit, Medical Services, Massachusetts General Hospital, Harvard OLC and authentic plant Oua spiked into the chromatographic Medical School, Charlestown, MA 02129 samples are different (13–15) Received for publication May 14, 1999. Accepted for publication July 28, 1999. One obvious explanation for these discrepant results is that the The costs of publication of this article were defrayed in part by the payment of page assays employed do not recognize the same compounds; that is, charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. that the polyclonal Abs are not specific for plant Oua or a putative Oua isomer of mammalian origin. One approach to enhance the 1 This work was supported by National Institutes of Health Grant RO1HL52282 (to G.T.H) and in part by National Institutes of Health Grants R29AI33175 (to B.P.S.) specificity of and/or provide a standardization for immunoassay and RO1 CA24432 and HL47415 (to M.N.M.). detection of OLC would be the development of anti-Oua mAbs 2 Current address: Franklin Pierce Law Center, Two White Street, Concord, NH with high specificity for Oua. To our knowledge, there is only one 03301. report in the literature of an mAb to Oua, but this Ab showed a 3 Address correspondence and reprint requests to Dr. Garner T. Haupert, Jr., Renal high degree of cross-reactivity with Dig, the cardiac glycoside in Unit, CNY-8, Massachusetts General Hospital, Building 149, 13th Street, Charles- town, MA 02129. E-mail address: [email protected] prevalent clinical use (16) (Fig. 1). 4 Abbreviations in this paper: Oua, ouabain; Dig, digoxin; BGG, bovine g-globulin; We set out to raise such Abs by techniques previously used in OLC, ouabain-like compound(s); HSA, human serum albumin. our laboratory for the production of anti-Dig mAbs (3). Initial Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 The Journal of Immunology 4361 Downloaded from FIGURE 1. Schematic representation of Oua and Dig structures, showing the numbering system of the cardenolide steroid rings. http://www.jimmunol.org/ attempts were unsuccessful; all the mAbs recognized the Oua-pro- subsequent fusion experiments, a similar immunization protocol was used, tein conjugate, but not the hapten Oua itself. By using a novel Ag but a different strain of mice (A/J, The Jackson Laboratory) and different presentation technique, we were able to overcome this problem of immunizing Ags (Oua-BGG, Oua-HSA, or Oua coupled to 26-10 Ab) were used. Mice that were immunized with Oua-26-10 Ab conjugate received specificity for the Oua-protein complex. We report here the iden- six additional booster injections of 10 mg of Ag in soluble form every 15 tification of mAbs with high specificity for Oua that do not rec- days (hyperimmunized). Before fusion, mouse sera were tested for Ab ognize the clinically used cardiac glycoside, Dig. We propose that titers. Fifty percent binding to Oua-protein conjugates was achieved at further development of these Abs could make possible standard- 30,000- to 45,000-fold serum dilutions. Fusions were conducted using Sp2/0-Ag14(Sp2/0) cell lines (23). After ization in bioassays and allow clarification of ambiguities in the fusion, cells were distributed into 96-well microtiter plates. literature regarding the presence, source, pathogenetic role, and by guest on September 28, 2021 mammalian biosynthetic possibilities of OLC. Immunoassays for selection of Oua-specific mAbs Clones producing Oua-specific mAbs were selected by testing the ability of Materials and Methods culture supernatants from wells showing cell growth to bind to immobi- Cell lines lized Oua-protein conjugates in ELISA assays. Fifty microliters of a solu- tion of Oua-protein conjugates (5 mg/ml in PBSA (0.15 M NaCl, 0.1 M The generation, selection, and characterization of cell lines producing the sodium phosphate, and 0.02% sodium azide, pH 7.2)) were immobilized in 26-10 (IgG2a, k) and 36-71 (IgG1, k) mAbs were previously reported (3, the wells of microtiter plates.
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