/ nternationa
`
`Official Journal of the European Society
`for Organ Transplantation
`
`Univ. of Minn.
`Bio-Medical
`Library
`92
`
`1,' u
`
`Springer International
`
`147 Transplant Int
`
`ISSN 0934-0874 TRINES 5 (4) 189-248 September 1992
`
`Printed on acid-free paper
`
`NOVARTIS EXHIBIT 2020
`Par v Novartis, IPR 2016-00084
`Page 1 of 17
`
`

`
`Original articles
`
`G. Gannedahl, S. Ohlman, U. Persson, S. Gudmundsson, E. Larsson,
`G. Tyden, T. H. TOtterman, B. Wikstrom, L. Weiss, C.-G. Groth,
`G. Tufveson Rejection associated with early appearance of
`donor-reactive antibodies after kidney transplantation treated with
`plasmapheresis and administration of 15-deoxyspergualin. A report of
`two cases
`
`A. Tokuka, A. Tanaka, T. Fujita, M. Hayashi, T. Kitai, Y. Yamaoka, K. Ozawa,
`S. T. Ohnishi Protective effect of a prostaglandin oligomer on liver
`mitochondria in situ: time-shared measurements of fluorescence and
`reflectance in the cold-preserved rat liver
`
`T. G. Wreghitt, J. J. Gray, P. Pavel, A. Balfour, A. Fabbri, L. D. Sharples,
`J. Wallwork Efficacy of pyrimethamine for the prevention of
`donor-acquired Toxop/asma gondii infection in heart and heart-lung
`transplant patients
`
`A. Secchi, V. Di Carlo, S. Martinenghi, E. La Rocca, R. Caldara,
`C. Staudacher, G. Ferrari, R. Castoldi, G. Torri, G. Pozza Octreotide
`administration in the treatment of pancreatic fistulae after pancreas
`transplantation
`
`I. Yokoyama, A.G. Tzakis, O. lmventarza, S. Todo, A. Casavilla, A. Leggio,
`T. E. Starzl Pediatric liver transplantation from neonatal donors
`
`I. M. M. Dooper, M.J.J. T. Bogman, A.J. Hoitsma, C. N. Maass,
`K.J. M.Assmann, A.A. P. Koene Detection of interstitial increase in
`macrophages, characteristic of acute interstitial rejection, in routinely
`processed renal allograft biopsies using the monoclonal antibody KP1
`
`G. Kotzke, C. Kauert, S. Lucke, H.J. Hahn Transplantation of allogeneic
`fetal pancreases combined from MHC-different donor strains does not
`change rejection of the graft
`
`A. Johansson Borg, S. Ohlman 15-Deoxyspergualin treatment of graft
`rejection in man: effect on mononuclear cells
`
`X.Xiao, Y. Li, J.Ao, Y. Chen Analysis of prognostic factors affecting renal
`allograft survival
`
`M. Salas Sironvalle, A. Gelet, X. Martin, S. Gabriele, J.M. Clavel,
`J.M. Dubernard Endoscopic treatment of vesicoureteral reflux prior to
`renal transplantation
`
`Review article
`
`K. J. Parlevliet, P. T. A. Schellekens Monoclonal antibodies in renal
`transplantation: a review
`
`Announcements
`
`Contents of Volume 5/Subject index
`
`Indexed in Current Contents (CC/CM, ASCA and B!OMED)
`
`Included in the MEDLARS system
`
`189
`
`193
`
`197
`
`201
`
`205
`
`209
`
`214
`
`219
`
`226
`
`231
`
`234
`
`247
`
`248
`
`Editor-in-Chief
`
`G. Kootstra
`Department of Surgery,
`University Hospital,
`P. Debyelaan 25,
`P.O. Box 5800,
`6202 AZ Maastricht,
`The Netherlands
`
`Editorial Board
`
`H. Brynger, Goteborg
`J. Fabre, London
`P. Hayry, Helsinki
`R.A. P. Koene, Nijmegen
`R. Margreiter, Innsbruck
`M.J. Mihatsch, Basel
`E. Moller, Stockholm
`G. Opelz, Heidelberg
`B. Ringe, Hannover
`R. van Schilfgaarde, Groningen
`G. Sirchia, Milan
`J.P. Soulillou, Nantes
`J.P. Squifflet, Brussels
`J. Wallwork, Cambridge
`
`International Advisory Board
`
`R. Y. Caine, Cambridge
`L. Fernandez-Cruz, Barcelona
`A. Flatmark, Oslo
`F. Frey, Bern
`D. Fries, Paris
`C. G. Groth, Stockholm
`J. Lloveras, Barcelona
`C. Mawas, Marseille
`P. Michielsen, Leuven
`P. Morris, Oxford
`J. A. Myburgh, Johannesburg
`G. Offermann, Berlin
`W. L. Olszewski, Warsaw
`K. Ota, Tokyo
`R.H. Rubin, Boston, Mass.
`A.G.R.Sheil, Sydney
`R. Sibley, Stanford
`S. Slavin, Jerusalem
`M.J. H. Slooff, Groningen
`H. W. Sollinger, Madison, Wis.
`J. H. Southard, Madison, Wis.
`T. E. Starzl, Pittsburgh, Pa.
`S. Stewart, Cambridge
`F. Valderrabano, Madrid
`D. White, Cambridge
`
`Assistants to the Editor
`
`Pamela Falger
`Sylvia van Roosmalen
`
`Springer International
`
`NOVARTIS EXHIBIT 2020
`Par v Novartis, IPR 2016-00084
`Page 2 of 17
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`

`
`TRANSPLANT
`International
`
`Official Journal of the European Society for Organ Transplantation
`
`SPRINGER
`
`FOR SCIENCE
`
`Transplant International is the official journal of the European So(cid:173)
`ciety for Organ Transplantation ( ESOT). The aim of the journal is to
`serve as a forum for the exchange of scientific information in the
`form of original and high quality papers in the field of transplanta(cid:173)
`tion. Clinical and experimental studies, as well as editorials, letters
`to the editor, and, occasionally, reviews on the biology, physiology,
`and immunology of transplantation of tissues and organs, will be
`published. Both full-length articles and short papers will be includ(cid:173)
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`six months, provided major revisions are not needed. The journal
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`NOVARTIS EXHIBIT 2020
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`

`
`Review article
`
`Transplantlnt(1992)5:234--246
`
`TRANSPLANT
`International
`©Springer-Verlag 1992
`
`Monoclonal antibodies in renal transplantation: a review
`
`K. J. Parle vii et and P. T. A. Schellekens
`
`Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9,
`NL-1105 AZ Amsterdam, The Netherlands
`
`Received May 22, 1991/Received after revision October 29, 1991/Accepted January 13, 1992
`
`Abstract. OKT3 is the first anti-CD3 monoclonal anti(cid:173)
`body available for treatment in humans. Over the last few
`years it has proven to be a very powerful immunosup(cid:173)
`pressive agent in renal transplantation. Clinical studies
`have shown that OKT3 is superior to high-dose steroids as
`first-line treatment for acute renal allograft rejection. Fur(cid:173)
`thermore, it is comparable to antithymocyte globulin
`(ATG) in treating steroid-resistant rejection and is also ef(cid:173)
`fective as rescue treatment in ATG- and antilymphocyte
`globulin- (ALG-) resistant rejection. Despite its excellent
`rejection-reversal rate, OKT3 treatment is fo!lowed by a
`substantital percentage ofre-rejections, most of which re(cid:173)
`spond well to steroids. In the early post-transplantation
`period, a prophylactic course of OKT3 is very effective in
`preventing acute rejections, and in this respect it is prob(cid:173)
`ably equivalent to ATG. Indirect evidence exists that a
`prophylactic course of OKT3 may be beneficial in immu(cid:173)
`nologically high-risk patients and in patients with delayed
`graft function. However, more clinical studies are re(cid:173)
`quired to answer the question whether OKT3 should be
`given as induction treatment, as first-line treatment, or as
`rescue treatment. To answer this question, the side effects
`of OKT3 should also be taken into account. First-dose-re(cid:173)
`lated side effects, although frequent and disturbing, are
`usually transient and seldom life-threatening, provided
`overhydration has been corrected and steroids have been
`given before the first administration. These side effects
`are attributed to the release of cytokines as a result of
`T-cell activation or lysis. After exposure of patients to
`OKT3 an increased incidence of infections and malignan(cid:173)
`ies has been reported. However, it is not yet clear whether
`this is due to OKT3 as such, or whether it merely reflects
`the total burden of immunosuppression. Xenosensitiza(cid:173)
`tion represents an important limitation to OKT3 treat(cid:173)
`ment, although a second or third course can still be effec(cid:173)
`tive in patients with low antibody titers. The precise
`immunosuppressive mechanism of anti-CD3 monoclonal
`antibodies is yet unknown. Monitoring of patients treated
`
`Correspondence to: K. J. Parlevliet
`
`with OKT3 revealed CD3 and/or T-cell antigen receptor
`depletion and immunological incompetence of remaining
`T cells. More clinical data are required to establish the
`correct dose and duration of OKT3 treatment. In conclu(cid:173)
`sion, OKT3 is a powerful immunosuppressive agent but
`its real value in renal transplantation remains to be deter(cid:173)
`mined. A practical approach may be to reserve it for the
`treatment of steroid-resistant
`rejections. Research
`strategies for the development of new monoclonal anti(cid:173)
`bodies for future use in renal transplant patients should be
`aimed at evading the major hazards of OKT3 treatment,
`namely side effects and xenoimmunization. Many promi(cid:173)
`sing monoclonal antibodies are currently under study:
`theoretically, anti-CD3/TCR monoclonal antibodies that
`are not mitogenic (such as CLB-T3/4.A, BMA 031,
`T10.B9.1A-31A, and OKT3 F[ab']2 fragments) may be
`expected to cause less immediate toxicity than OKT3.
`However, their immunosuppressive properties still have
`to be established. Monoclonal antibodies that are reactive
`with more restricted T-cell markers such as the inter(cid:173)
`leukin-2 receptor (33B3.1 and anti-Tac), CD4 (BL4), and
`CDS (Leu 2a) are generally better tolerated than OKT3.
`On theoretical grounds they may also be expected to
`cause fewer long-term complications. However, their im(cid:173)
`munosuppressive properties also remain to be estab(cid:173)
`lished. In patients with high titers of anti-idiotypic anti(cid:173)
`bodies to OKT3, WT 32 and perhaps RIV 9 and
`T10B9.1A-31A may be good alternatives.
`
`Key words: Monoclonal antibodies, in kidney transplanta(cid:173)
`tion - Kidney transplantation, monoclonal antibodies -
`Antibodies, monoclonal, in kidney transplantation
`
`Since the introduction of the hybridoma technique for the
`production of monoclonal antibodies (mAbs) by Kohler
`and Milstein in 1975 [113], mAbs have been increasingly
`used not only in the laboratory but also in hospitals, in par(cid:173)
`ticular for the treatment of renal allograft rejection. Brief(cid:173)
`ly, hybridoma cells result from the fusion of a murine
`myeloma cell line with spleen cells of a mouse that has
`
`NOVARTIS EXHIBIT 2020
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`

`
`been immunized with an antigen. Each hybridoma cell has
`the potential to produce one type of antibody. By means of
`a limiting dilution technique it is possible to produce
`clones of hybridomas, each of which can provide a nearly
`limitless amount of one specific mAb, directed against one
`epitope on the immunizing antigen.
`Before the introduction of mAbs, polyclonal anti(cid:173)
`bodies such as antithymocyte globulin (ATG) or antilym(cid:173)
`phocyte globulin (ALG ), produced by immunizing rab(cid:173)
`bits or horses with thymocytes or lymphocytes, were
`considered most effective in treating renal allograft rejec(cid:173)
`tion [44, 73, 93, 120, 135, 162, 176, 178]. However, their
`clinical use is hampered by a few important drawbacks.
`Since these polyclonal antibodies are derived from indi(cid:173)
`vidual animals, there is considerable batch-to-batch vari(cid:173)
`ability with respect to specificity and affinity, which affects
`their immunosuppressive properties and toxicity in an un(cid:173)
`predictable way [176]. MAbs lack this batch-to-batch vari(cid:173)
`ability as they are characterized by absolute identity and
`monospecificity. Furthermore, a course of ATG or ALG
`often has to be terminated within 2 or 3 weeks because of
`clinical intolerance due to acute serum sickness. As we
`shall see, mAbs do not cause acute serum sickness. Lastly,
`but not least, the administration of polyclonal antibodies
`in peripheral veins is complicated by a high rate of throm(cid:173)
`botic complications and therefore requires the presence
`of a central venous catheter.
`At Ortho Pharmaceutical Corporation Kung et al. de(cid:173)
`veloped a panel of mAbs to human T-cell surface antigens
`- the OKT series, the third of which was Orthoclone
`OKT3 [116]. Over the last 5 years it has proved to be a
`powerful immunosuppressive agent and at this moment
`OKT3 is still the only mAb that is commercially available
`for administration in transplant patients.
`After a short introduction to the immunobiological
`backgrounds of OKT3 and other anti-CD3 mAbs, we shall
`focus on the clinical experience with OKT3; finally we
`shall briefly discuss possible future developments and
`mention some other mAbs currently under study for treat(cid:173)
`ment of renal transplant patients.
`
`Immunobiological backgrounds of OKT3
`and other anti-CD3 monoclonal antibodies
`
`OKT3 is a murine mAb of the IgG2a class directed against
`the CD3 molecule, which is present on the surface of thy(cid:173)
`mocytes and mature human T cells [116]. The CD3 mole(cid:173)
`cule is closely associated with the T-cell antigen receptor
`(TCR) in the so-called CD3/TCR complex. This complex
`plays a vital role in T-cell function: antigen recognition by
`the TCR results in signal transduction via the CD3 mole(cid:173)
`cule and subsequent T-cell proliferation and activation of
`cytotoxic cells [41, 77, 97, 98]. In vitro at high concentra(cid:173)
`tions, OKT3 blocks antigen-stimulated T-cell prolifera(cid:173)
`tion and the activation of cytotoxic T cells [5, 29, 30, 122,
`155, 160, 161 ]. In doing so, it blocks both the T-cell induc(cid:173)
`tion phase and the effector functions involved in allograft
`rejection. In vivo, administration of OKT3 initially results
`in coating of all circulating T cells. Within minutes, these
`OKT3-coated cells then disappear almost completely
`from the circulation, as evidenced by depletion of CD2-,
`
`235
`
`CD3-, CD4-, and CDS-expressing cells [32-34, 47, 48, 69,
`86, 168, 17 5, 207]. Whether this is due to cell lysis or se(cid:173)
`questration of opsonized cells by the mononuclear phago(cid:173)
`cytic system (MPS) remains unclear. Because murine im(cid:173)
`munoglobulins only poorly activate human complement,
`it appears that direct, complement-mediated cell lysis is
`not involved. During anti-CD3 treatment T-cell depletion
`in lymph nodes and spleen was found to be incomplete;
`also anti-CD3 treatment did not prevent the recurrence of
`CD3 + cells in thymectomized mice [89], suggesting that at
`least some CD3 +cells escape lysis. After a few (2-5) days'
`treatment with OKT3 - T cells reappear in the circulation.
`However, these T cells are functionally inactive [11, 29, 32,
`122, 155, 161, 215]. It is generally assumed that the disap(cid:173)
`pearance of the CD3 molecule from the surface of the
`T lymphocyte - a process called "antigenic modulation" -
`contributes to the immunosuppressive effect of anti-CD3
`mAbs [5, 11, 34]. This is substantiated by the observation
`that in cases where OKT3 + cells reappear in peripheral
`blood during OKT3 treatment, OKT3 is ineffective [175].
`Remarkable and as yet unexplained is the finding that
`the above-mentioned OKT3 - T cells react weakly with
`anti-Leu 4, a mAb that recognizes a CD3 epitope distinct
`from OKT3 [71, 72, 218, 224]. However, these weakly anti(cid:173)
`Leu 4 + cells do not express the TCR, they are functionally
`inactive, and their presence does not correlate with ineffec(cid:173)
`tiveness of OKT3 treatment. The cause of this discordant
`CD3 expression is not understood. The detection of large
`numbers of OKT3-coated cells in the circulation during
`OKT3 treatment suggests that masking of the CD3 mole(cid:173)
`cule may also play a role [26]. However, which of the above(cid:173)
`mentioned mechanisms - blocking and/or modulation of
`the CD3/TCR complex or disappearance of T cells from
`the circulation - is responsible for the immunosuppressive
`effect of OKT3 in vivo remains undefined. During OKT3
`treatment CD3 modulation has also been observed in the
`transplanted kidney, although data on this subject are con(cid:173)
`flicting [17, 18, 42, 107, 108]. Upon discontinuation of
`OKT3 treatment the number of CD3 + cells in peripheral
`blood rapidly returns to normal values, but in a murine
`model it was found that normal immunocompetence was
`not recovered until 2 months after treatment [89].
`In vitro, apart from its immunosuppressive action at
`high concentrations, OKT3 at low concentrations is
`known to be a potent T-cell mitogen [30, 214]. Monocytes
`are probably required for this T-cell activation in two
`ways: first, by binding of the antibodies of their Fe recep(cid:173)
`tors (FcR), which causes cross-linking of the CD3/TCR
`complex, and, second, by producing interleukin-1 (IL-1)
`[31, 150, 164, 213]. However, FcR polymorphism on
`human monocytes for murine immunoglobulins results in
`a donor-dependent variation of anti-CD3 mAbs of differ(cid:173)
`ent (sub )classes to induce T-cell proliferation: whereas all
`human monocytes carry the appropriate FcR for murine
`IgG2a and IgG3, only 70% of the donors express FcR for
`murine IgGl, only 10% express FcR for IgG2b, and all
`donors completely lack the proper FcR for murine IgA
`[27, 28, 172, 192-194, 213]. Hence, murine anti-CD3 mAbs
`of the IgG2a and IgG3 isotypes can cause T-cell activation
`in 100 % of human donors, whereas an IgA anti-CD3
`mAb and anti-CD3 F(ab')2 fragments never can. Further-
`
`NOVARTIS EXHIBIT 2020
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`
`236
`
`more, F(ab')2 fragments are immunosuppressive in mice
`without causing T-cell activation [91, 92], suggesting that
`mitogenicity of anti-CD3 mAbs is not a prerequisite for
`immunosuppressive capacity. The possible implications
`for toxicity of the different mitogenic properties of anti(cid:173)
`CD3 mAbs of different isotypes will be discussed below.
`The question whether OKT3-mediated T-cell activation
`may even enhance the process of acute allograft rejection
`remains to be resolved.
`
`Present state of knowledge regarding OKT3
`
`Efficacy in treatment of acute renal allograft rejection
`
`In the early 1980s the first clinical studies on OKT3 for
`treatment of acute allograft rejection were published [15,
`47, 48, 139, 196]. They were uncontrolled studies, describ(cid:173)
`ing the experiences with a course of OKT3 in renal trans(cid:173)
`plant patients with acute allograft rejection. The most
`important observation was the reversal of rejection in al(cid:173)
`most all patients within 2-7 days after the start of OKT3
`treatment. A course of OKT3 usually consisted of one in(cid:173)
`travenous bolus injection of 5 mg daily for 10 or 14 days.
`As far as we know this dosage was not based on a phase-I
`trial. Based on in vitro studies, trough levels in the range of
`1 µg/ml were considered to be effective and were usually
`reached within a few days [78, 81]. These trials were fol(cid:173)
`lowed by a controlled study from the Ortho Multicenter
`Transplant Study Group in which 123 patients with acute
`rejection of a cadaveric renal transplant were treated with
`either OKT3 or with high-dose steroids [148]. The rejec(cid:173)
`tion-reversal rate after OKT3 (94 % ) was significantly
`better than after high-dose steroids (75 % ). The thera(cid:173)
`peutic superiority of OKT3 was also reflected in an im(cid:173)
`proved 1-year graft survival of 62 % in the OKT3 group, as
`compared with 45 % in the steroid-treated group. These
`excellent results with OKT3 have been confirmed by
`manyreports[6,7,9,13,45,49,50,55,69,77,79,80,82,88,
`94,95,104,114,125,126,132, 138,140,141,144,146,149,
`156,168,186-188,197,198,200,204,219,220,223].
`The general conclusion is that OKT3 is very effective as a
`first-line treatment ofacute renalallograftrejection. In this
`respect it is superior to high-dose steroids. Moreover,
`OKT3 was as effective as ATG in treating steroid-resistant
`acute rejection episodes [9], and it proved to be effective as
`rescue treatmentinATG-andALG-resistantrejection [ 49,
`144, 146, 156, 219]. OKT3 appeared to be most effective in
`treating acute cellular rejection [223]: only a few patients
`were reported with predominantly vascular acute renal al(cid:173)
`lograft rejection that responded well to OKT3 [55, 171].
`Furthermore, it was equally effective in patients with aza(cid:173)
`thioprine and cyclosporine maintenance immunosup(cid:173)
`pression. There has been a reluctance to continue cyclo(cid:173)
`sporine during OKT3 treatment, based on fear of
`overimmunosuppression and nephrotoxicity [75, 179]. In(cid:173)
`deed, some authors report a diminished rejection-reversal
`rate when cyclosporine is continued during OKT3 treat(cid:173)
`ment [88], but this was not confirmed by others [94-96].
`Despite the excellent rejection-reversal rate, the number of
`recurrent rejections after OKT3 was substantial, amount(cid:173)
`ing to 67 % within the 1st month after cesssation of OKT3
`
`[50, 77, 140, 141, 146, 148, 223]. Fortunately, the majority of
`these re-rejections responded well to high-dose steroids.
`In an attempt to answer the question whether OKT3 is
`more effective when used as first-line treatment or whether
`it should only be given in steroid-resistant acute rejections,
`Kovarik et al. and Deierhoi et al. reported comparative re(cid:173)
`sults of OKT3 and steroids for primary treatment of acute
`rejections and rescue treatment. Kovariaketal. [114] found
`that the rejection-reversal rate was significantly better
`when OKT3wasgivenasfirst-line, whileDeierhoietal. [54]
`found no difference in rejection-reversal rate whether
`OKT3 was given as first-line or as rescue treatment. How(cid:173)
`ever, irrespective of the fact that patients were not ran(cid:173)
`domized, the interpretation of these results is hampered by
`the short interval between first-line and rescue treatment,
`which makes it impossible to differentiate between a late
`response to first-line treatment and an early response to
`rescue treatment. Furthermore, the question whether
`OKT3 is superior to steroids cannot be answered without
`considering the side effects (see below).
`
`Efficacy for prophylaxis of acute renal allograft rejection
`
`The hypothesis that blocking of T-cell function at the very
`moment of transplantation could induce immunologic
`tolerance to the graft led to the prophylactic use of OKT3.
`The first experiences with prophylactic treatment began
`to be published from 1986 onwards [23, 24, 42, 53, 77, 105,
`115, 128, 142, 168, 169, 201, 202, 207, 217]. The average
`duration of a full prophylactic course of OKT3 was
`15 days (varying from 6 to 30 days) and the average daily
`OKT3 dose amounted to 5 mg. However, recent reports
`indicate that lower doses may perhaps be equally effective
`[145]. Basic immunosuppression during OKT3 prophy(cid:173)
`laxis usually consisted of prednisone and azathioprine and
`was extended with cyclosporine towards the end of the
`course, provided graft function was satisfactory. The ma(cid:173)
`jority of these reports were of controlled studies. Basic im(cid:173)
`munosuppression in the control group consisted of pred(cid:173)
`nisone and azathioprine with or without cyclosporine. It
`was noted that rejections hardly ever occurred during
`OKT3 prophylaxis and that OKT3 significantly delayed
`the mean onset of rejection. Between these reports there
`is a large variation in rejection rate in both the OKT3 and
`the control group that can be explained by variations in
`the period of follow-up and the amount of basic immuno(cid:173)
`suppression. Overall there were a significantly lower num(cid:173)
`ber of acute rejections in the OKT3 prophylaxis group
`(varying from 6 % to 29 % ) than in the control group
`(varying from 50 % to 94 % ), a difference that was still
`present after 1 year [51, 53, 76, 77, 105, 106, 142, 202].
`Therefore, OKT3 prophylaxis was considered very effec(cid:173)
`tive in preventing acute rejections compared to conven(cid:173)
`tional basic immunosuppression, although the mere
`occurrence of acute rejection after OKT3 induction did
`not favor the notion of immunologic tolerance.
`In a nonrandomized prospective study of 110 renal
`transplant patients with triple therapy (prednisone, aza(cid:173)
`thioprine, and cyclosporine) as basic immunosuppression,
`OKT3 prophylaxis was superior to ALG in preventing
`acute rejections [128]. However, in three randomized
`
`NOVARTIS EXHIBIT 2020
`Par v Novartis, IPR 2016-00084
`Page 6 of 17
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`
`prospective studies induction therapy with OKT3 and
`ATG gave more or less similar survival of patients and
`grafts [67, 85, 124]. In immunologically high-risk patients
`OKT3 prophylaxis resulted in improved graft survival
`compared to a historical control group [23, 169]. Since cy(cid:173)
`closporine can prolong the duration of acute tubular ne(cid:173)
`crosis (ATN) after transplantation, and a severe rejection
`can remain unnoticed during a period of initial graft dys(cid:173)
`function, while on the other hand withholding cyclospo(cid:173)
`rine may increase the risk of rejection, special attention
`was given to prophylactic use of OKT3 in patients with de(cid:173)
`layed graft function. This led to somewhat conflicting
`data. Thislethwaite et al. [201] found an excellent graft
`survival rate (97 % ) in patients with delayed graft function
`who were prophylactically treated with OKT3. However,
`as there was no control group and the follow-up was only
`2-8 months, this observation does not permit any definite
`conclusions. Similar results were reported by Cohen et al.
`[42] and Benvenisty et al. [4], who compared graft survival
`in patients with delayed graft function receiving OKT3
`prophylaxis with a historical control group: they found a
`much better 1-year graft survival rate in the OKT3 pro(cid:173)
`phylaxis group (83 % and 80 % respectively vs. 55 % ). In a
`prospective study Kahana et al. [106] found a decrease in
`the duration of ATN in the OKT3 induction group com(cid:173)
`pared to a control group treated with triple therapy, while
`Toussaint et al. [51, 202] reported an increased incidence
`of delayed graft function following OKT3 prophylaxis
`compared to cyclosporine, and suggested that OKT3
`might be nephrotoxic. This issue certainly needs further
`investigation.
`In an attempt to answer the strategical question of
`whether OKT3 is preferable as induction treatment or
`whether it should be reserved for the treatment of acute
`rejection episodes, Kreis et al. [115] prospectively com(cid:173)
`pared the results of OKT3 prophylaxis to the results of
`OKT3 treatment for acute rejection in patients with the
`same basal immunosuppression (prednisone and azathio(cid:173)
`prine ). They found a difference in graft survival - al(cid:173)
`though not statistically significant - between the two
`groups: 18-month graft survival was 89.3 % in the OKT3
`prophylaxis group and 66 % in the OKT3 antirejection(cid:173)
`treated group. Obviously, these results cannot be extrapo(cid:173)
`lated to cyclosporine-treated patients. Also, this question
`can only be answered when the side effects of OKT3 are
`taken into account (see below).
`
`Side effects
`
`The first administration of OKT3 is almost invariably fol(cid:173)
`lowed by a spectrum of symptoms, including pyrexia,
`dyspnea, headache, nausea, vomiting, and diarrhea [45,
`148, 199]. These symptoms usually start within 1 h after
`administration of the first dose of OKT3, reverse sponta(cid:173)
`neously after several hours, and tend to diminish after the
`subsequent OKT3 administrations. In patients who were
`overhydrated at the start of OKT3 treatment, acute
`life-threatening pulmonary edema has been described
`[148, 199]. For this reason the beginning of OKT3 treat(cid:173)
`ment, either therapeutic or prophylactic, is nowadays