The New England
`
`Journal of Medicine
`AUGUST 8, 1985
`
`.. 1Copyright, 1985. by the Massachusetts Medical Society
`
`Number 6
`
`Volume 313
`
`A RANDOMIZED CLINICAL TRIAL OF OKT3 MONOCLONAL ANTIBODY FOR ACUTE
`REJECTION OF CADA VERIC RENAL TRANSPLANTS
`
`0RTHO MuLTrCENTER TRANSPLANT STuov GROUP*
`
`Abstract Since the murine monoclonal antibody OKT3
`reacts with human T cells and blocks their function, we
`explored its effectiveness in treating T-cell-mediated re­
`jection of renal allografts. In a prospective randomized
`multicenter trial, 123 patients undergoing acute rejection
`of cadaveric renal transplants were treated either with
`OKT3 daily for a mean of 14 days, with concomitant lower­
`ing of the dosage of other immunosuppressive drugs (63
`patients), or with conventional high-dose steroids (60 pa­
`tients). OKT3 reversed 94 per cent of the rejections - a
`figure that was significantly better (P = 0.009) than the 75
`
`per cent reversal rate obtained with conventional steroid
`treatment. This superior reversal rate with OKT3 was
`reflected in an improved one-year graft survival of 62
`per cent for the OKT3-treated group, as compared with 45
`per cent for the steroid-treated group (P = 0.029), in
`patients who were all selected by virtue of having had
`acute rejection. We conclude that treatment with OKT3
`(with concomitant lowering of the dosage of other im­
`munosuppressive drugs) is an effective approach for
`acute renal-allograft rejection. (N Engl J Med 1985; 313:
`337-42.)
`
`human T cells and the generation
`DESPITE improvements
`tions9"11; furthermore,
`of newer immunosuppressive
`
`in tissue matching and
`
`of other T-cell func­
`
`T-cell function is lost if0KT3
`the introduction
`interacts with and causes the removal of the antigen
`
`agents, acute rejection of the allograft remains a major
`
`
`T3 on the T-cell surface.12·13
`
`impediment to the success of clinical renal transplan­
`
`We have previously reported an open pilot study
`
`
`tation. Conventional therapies include the use ofhigh­
`showing that OKT3 reversed acute renal-allograft re­
`
`
`globulins.1·4 dose steroid pulses and of antithymocyte
`
`jection in all of 10 patients.14-16 We now present the
`The use of high-dose steroids results in a high inci­
`
`
`
`dence of infection and other side effects. Antithymo­
`
`results of a randomized prospective protocol compar­
`
`ing the safety and efficacy of OKT3 (with reduction in
`
`
`cyte globulins are more effective than steroids in re­
`
`the dosage of concomitant immunosuppressive medi­
`
`
`versing acute renal rejection, but difficulties in lot
`
`
`standardization, giving variations in efficacy and in
`
`cation) with those of conventional steroid treatment in
`
`
`reversing acute renal-allograft rejection.
`
`the incidence of adverse reactions among lots, contin­
`ue to be a major problem. OKT3 is a murine mono­
`clonal antibody that is reactive with a 20,000-dalton
`molecule found only on the surface of thymocytes or
`Production of OKT3
`
`
`
`mature human T cells.5 The structure recognized by
`
`OKT3 is linked to the T-cell antigen receptor6.7 and
`OKT3 was produced from seed lots of the parent hybridoma. The
`
`immunoglobulin was purified from ascites and form ulated, and am­
`of human T cells.8
`pules were filled under sterile
`batch was tested for
`conditions. E�ch
`Thus, OKT3 in vitro blocks both killing by cytotoxic
`purity and safety and conformed to the standards of the Food and
`Drug Administration.
`
`appears vital for the functioning
`
`METHODS
`
`"'The Onho
`Multicemer Transplant Study Group comprised Gideon Goldstein,
`M.D., Ph.D .• John Schindler, Ph.D., and Huci Tsai, Ph.D. (Onho Pharmaceuti­
`cal Corp., Raritan, N.J.); A. Benedict Cosimi. M.D., and Paul S. Russell. M.D.
`(Mass. General Hospital, Boston); Douglas Norman, M.D., and John Barry,
`M.D. (University of Oregon Health Sciences Center, Ponland); Charles F.
`Shield, M.D. (St. Francis Hospital, Wichita, Kans.); Sang I. Cho. M.D .. and
`Andrew S. Levey. M.D. (New England Medical Cente.r Hmpital. Boston);
`James F. Burdick, M.D., and G. Melvin Williams. M.D. (Johns Hopkins Hospi·
`!.al, Baltimore); Frank P. Stuart, M.D. (The University of Chicago, Chicago);
`J. Wesley Alexander, M.D., and Roy First, M.D. (University of Cincinnati.
`Cincinnati, Ohio); ·Peter Gailiunas, M.D .• and J. Harold Helderman. M.D.
`(Southwest Medical School, Dallas); Ronald L. Wathen, M.D., and Robcf1 E.
`Lonlon, M.D. (The Jewish Hospital, University of Lou isville, Louisville. Ky.);
`Derrick Sampson. M.D. (deceased), and Barry S. Levin, M.D. (Presbyterian
`Hospital of Pacific Medical Center. San Francisco); and Anthony Monaco. M.D.
`(New England Deaconess Hospital. Boston).
`Address reprint requests to Dr. Goldstein at !he lmmunobiology Division,
`Onho Pharmaceutical
`Corporation, Raritan, NJ 08869.
`
`Organization
`
`This clinical trial was organized by the lmm unobiology Division
`
`
`of the Ortho Pharmaceutical Corporation after a preliminary inves­
`meeting at which a consensus was reached on protocol
`tigators'
`design. At each participating center an in stitutional review board
`approved the protocol and the informed-consent form and followed
`the progress of the study. All the patients were fully informed of the
`nature of the study and signed consent forms.
`
`Ellglblllty Criteria
`
`Patients had to be diagnosed as having their first rejection episode
`
`after cadaveric renal transplantation. Rejection
`
`criteria were docu­
`mented and were those used by Shield et al.1 To avoid cases of renal
`failure attributable to causes other than acute cellular rejection,
`
`The New England Journal of Medicine
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`
`1 of 6
`
`BI Exhibit 1026
`
`

`

`338
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 8, 1985
`
`entry was restricted to patients with rejections occurring from 6 to
`
`
`of I mg of mcthylprednisolonc
`
`
`
`occurred. A bolus injection
`
`per kilo­
`93 days after transplantation.
`
`gram and concomitant acetaminophen and antihistamines
`were
`Patients
`
`
`received a standard regimen ofimmunosuppression after
`
`permitted with the first dose ofOKT3 to reduce the fever and chills
`
`
`This comprised prednisone, starting at 2 mg per
`transplantation.
`that were known to accompany this first dose.
`to 0.5 mg per kilo­
`kilogram of body weight per day and tapering
`
`gram per day by Week 9, and the maximal tolerated dose of azathio­
`100 to 150 mg per day.
`prine - approximately
`
`Conventlonal..sterolds
`
`Group
`
`Azathioprinc and prednisone were continued at prerejcction
`
`(500 mg per day) was givcn17,18 for
`levels. Methylprednisolone
`could be given
`a maximum of three days, after which prednisonc
`at a dosage of3 mg per kilogram per day, if necessary, and tapered
`at Patients meeting the eligibility criteria were randomly assigned
`
`
`
`over the next seven days so that a dose of I mg per kilogram per
`
`entry to receive either OKT3 or steroid treatment, the randomiza­
`
`day was achieved on the seventh day. The prednisone dosage was
`
`tion schedule being generated by computer for each center.
`
`then tapered to what it would have been if rejection had not oc­
`curred (Fig. I).
`
`Rllndomlatlon
`
`OKT3 Group
`
`"Rescue" Treatment
`After a negative skin test (0. I ml of a 1-µ.g-per-milliliter solution
`
`
`push at a by intravenous intradermally), OKT3 was administered
`
`Any patient whose scrum crcatinine level did not decrease on the
`
`
`days (Fig. I). Investigators
`dose of 5 mg per day for 14 consecutive
`sixth day or later and whose transplant
`
`rejection was judged not to
`
`
`
`and 14 patients had the option of continuing therapy, were treated
`have been reversed could be treated with additional conventional
`periods of I to 14days. During OKT3 administration
`for additional
`
`globulin treatment (for the OKT3 group) or equine antithymocyte
`
`
`the dosages of concomitant immunosuppressive agents were re­
`(for the steroid group).
`to 0.5 mg duced - azathioprinc to 25 mg per day and prednisone
`
`
`
`per kilogram per day. These were raised to the continuing dosages
`Reverul
`on the day after OKT3 therapy was stopped, as if rejection had not
`
`
`of Rejection
`
`OKT3 TREATMENT
`Rejection
`Tranaplant I
`t
`�
`
`Q.Q§E
`
`rejection as of renal-allograft The therapeutic goal was reversal
`
`
`
`
`fall in scrum crcatinine
`levels.
`judged by a three-day progressive
`
`The investigators judged that reversal had occurred in an additional
`
`
`in the steroid three patients in the OKT3 group and eight patients
`
`group, on the basis of clinical criteria alone, such as reduetion
`in
`
`
`
`
`kidney swelling and tenderness, decreased fever, and resumption of
`diuresis.
`
`Procedures
`
`mg;kg ::: t � g METHYLPREDNISOLONE. 1.V.
`[�PRE'Q .. jS9)iE.
`150t 25
`
`mg/day
`'- ��
`15[
`mg/day
`0
`I
`
`AZA THIOPRINE
`
`-- ·-.. �·"-"'•'"�'' '�·"�' �·'-""�'"•'"•'"•""-' ·�·
`
`111111111111o�t31111111111111
`I I I I I I I I I I I I I ! I
`, ..
`O DAYS
`
`Before treatment for rejection, demographic data and a medical
`
`
`
`history were recorded for each patient. In addition, the patient
`physical exam ination,
`underwent a complete pretreatment
`with full
`
`
`
`clinical laboratory evaluation (blood-chemistry and hematologic
`
`
`During treatment studies and urinalysis) and chest radiography.
`
`for rejection, there were daily recordings of the scrum creatinine
`
`
`
`and white-cell level, body temperature, blood pressure, count with
`
`
`differential cell count, and periodic measurement of other clinical
`
`laboratory indexes. On the termination of rejection
`therapy, all
`
`
`clinical laboratory measurements were repeated. Routine
`follow-up
`at 3, 6, 12, and 24 months after trans­
`
`examinations were performed
`CONVENTIONAL STEROID TREATMENT
`
`
`plantation and included a determination of graft status and the
`Rejection
`
`same physical and laboratory
`
`performed before rejec­
`examinations
`•
`
`
`and in­tion therapy. Throughout the trial, all adverse experiences
`500 mg METHYLPREDNISOLONE, 1.V.
`
`fections were rccordtcl.
`
`+H
`
`3.0
`
`QQli
`I
`2.0
`mg/kg
`1.0
`
`SUtlstlcal Methods
`
`19 Wilcoxon's rank-sum test,20 or the extended
`exact test,
`Fisher's
`
`
`com­Mantcl-Hacnszcl chi-square tcst21 was used for pretreatment
`
`
`parisons based on demographic and disease-history variables.
`
`was analyzed with stratification by investiga­
`Reversal of rejection
`
`
`tcst.22 When reversal tors using the Mantel-Hacnszcl chi-square
`
`
`one OKT3-treated and graft-survival rates were being calculated,
`
`
`patient "rescued" with steroids was counted as constituting a treat­
`
`
`
`ment failure, as were 10 steroid-treated patients rescued with anti­
`
`
`
`thymocytc globulin. Steroid-treated patients rescued with addition­
`
`
`
`exact test successes. Fisher's al steroids were considered treatment
`was also used to compare the incidence rates in the two treatment
`groups for the following
`
`repeated rejection, adverse experi­
`indexes:
`were performed with
`
`
`ences, and infections. Life-table comparisons
`
`use of Brcslow's tcst.23
`
`,,,,,,,,,,,,,,,
`O DAYS
`
`, ..
`
`Drug Regimens for
`Figure 1. Plan of Daily lmmunosuppressive
`to OKT3 or Steroid Treatment for
`Patients Randomly Assigned
`Acute Renal-Allograft Rejection.
`
`During OKT3 treatment, dosages of steroids and azathiOprlne
`Patient Entry
`were reduced, with resumption of the prerejection tapered dos­
`age of steroids and the azathioprl
`ne dosage when OKT3 was
`In all, 123 patients - 63 in the OKT3 group and
`steroid treatment
`a high ste-­
`
`discontinued. By contrast,
`involved
`60 in the steroids group - were treated with study
`rold dosage, with malntenanoe of the azathioprine dosage.
`l.V.
`denotes Intravenous.
`
`medications. Summary data on demographic factors
`
`R£suLTS
`
`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on April 24, 2015. For personal use only. No other uses without permission.
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`2 of 6
`
`BI Exhibit 1026
`
`

`

`Vol. 313 No. 6
`
`TRIAL OF OKT3 - ORTHO MULTICENTER TRANSPLANT STUDY GROUP
`
`339
`
`CHA.RACTEUSTIC
`
`Table 1. Clinical
`and pertinent medical history for
`
`Characteristics of Patients Randomly Assigned to OKT3 or Steroid
`
`
`
`
`Treatment for Acute Renal-Allograft Rejection.
`
`the study population are shown
`in Table l. There were no sta­
`
`
`tistically significant differences be­
`tween the groups in any of these
`Sex (M/F)
`
`
`base-line characteristics, and the
`Median age (yr)t
`patients overall appeared repre­
`Median weight (kg)t
`
`
`sentative of the population expe­
`Race (white/nonwhite)
`
`riencing a first episode of acute re­
`No. with diabetes mellitus
`
`nal-allograft rejection. However,
`No. with prior transplants (0/ 112)
`l of the 63 patients treated with
`No. with intransplant transfusions
`
`OKT3 was diagnosed in retrospect
`(0/1-41>4)
`as having undergone a deteriora­
`Acute tubular necrosis and dialysis at entry
`tion in renal function due to cyto­
`Renal disease (glomeruloncphritis)
`
`
`megalovirus infection rather than
`Crossmatch (-I+)
`
`
`acute renal rejection, and he was
`Preformed antibodies
`(0-24%126-100% positive)
`
`
`therefore excluded from the efficacy
`Median time from transplant to rejection (days)t
`analysis.
`
`TUA1MENT Ga.our•
`
`OKT3
`
`STEJOlDS
`
`43120
`
`39121
`
`38 (17-65)
`
`67 (42-103)
`
`50/13
`
`20
`
`551711
`
`1112144
`
`12
`
`23
`
`63/0
`
`44/10
`
`36 (l<>-64)
`66 (30-111)
`49/11
`
`14
`
`521612
`
`3110/40
`
`9
`
`18
`
`5911
`
`39118
`
`10 (6-74)
`
`11 (6-91)
`
`Medication
`
`die two groups in any of <hose indexes. *lbc:re were no Slalistically significant differences between
`
`tNumbefs in parentheses represent <he range of values.
`
`OKT3 was administered intrave­
`
`nously at a dosage of 5 mg per day
`for a mean period of 14 days (range, l to 28}. In­
`maintenance and repeated episodes of rejection. Be­
`
`
`
`
`creased amounts of steroids were also administered as
`
`cause of the efficacy ofOKT3 in reversing acute rejec­
`therapy in the control group for a mean
`rejection
`
`tion there were more patients (58) in whom rejection
`of 14 days (range, 3 to 36). On the day before rejec­
`had been reversed by OKT3 than by conventional
`
`and azathio­tion, the mean daily doses of prednisone
`
`
`
`steroid treatment (45). A second rejection was com­
`prine among patients entered into the OKT3 group
`
`
`
`mon in both groups, occurring in 38 of 58 patients (66
`were 1.07 mg per kilogram and 142 mg, respectively.
`
`per cent) initially treated with OKT3 and 33 of 45
`
`During the period ofOKT3 administration, the mean
`
`
`patients (73 per cent} initially treated with conven­
`
`
`daily doses of prednisone and azathioprine were
`
`
`tional steroids (P = 0.52). The incidence of kidney
`reduced to 0.56 mg per kilogram and 30 mg, respec­
`
`loss due to repeated rejection was also similar in
`
`
`tively. Table 2 shows the cumulative doses of the con­
`both groups: 19 of 58 patients (33 per cent) initially
`
`
`ventional immunosuppressives for each group for the
`treated with OKT3 and 17 of 45 (38 per cent) initial­
`
`
`28 days beginning with the day of rejection and indi­
`
`ly treated with conventional steroids lost a kidney
`
`cates the marked steroid-sparing effect of the OKT3
`(P = 0.68).
`regimen.
`
`Patient and Kidney Survival
`
`MEDICATION
`
`OKT3
`
`STEAOIDS
`
`Reversal of Rejection
`Two patients in the steroid-treated group were lost
`
`
`OKT3 reversed acute renal-allograft rejection in
`
`to follow-up. At one year, 53 of 62 patients (85 per
`
`cent} treated with OKT3 and 52 of 58 (90 per cent}
`
`
`58 of 62 patients (94 per cent} - a significantly high­
`
`er reversal rate (P = 0.009) than that for convention­
`
`of those treated with steroids were alive (P = 0.47)
`
`
`al steroid treatment, which reversed rejection in 45
`
`(Table 3). All 53 living patients treated with OKT3
`
`
`of60 patients (75 per cent} (Table 3). If reversal was
`
`
`and the 52 living patients treated with steroids were
`
`
`
`
`judged strictly according to the objective criterion of
`
`followed for one year. According to life-table anal-
`
`
`the occurrence of a progressive decrease in the serum
`
`
`creatinine level, the reversal rates became 55 of 62
`Table 2. Mean Cumulative Dosage
`of lmmunosuppressive Med·
`
`(89 per cent} for the OKT3 group and 37 of 60 (62
`over the First 28 Days of Treatment for Patients
`ications
`Ran·
`
`
`per cent} for the steroids group (P<0.001). The distri­
`domly Assigned to OKT3 or Steroids
`for Acute Renal-Allograft
`
`bution of reversal results was generally consistent
`Rejection.
`
`among investigators, and there was no statistically
`
`significant difference among the centers (P = 0.36).
`
`
`Among patients in whom rejection was reversed,
`
`the mean time to reversal was shorter in the OKT3-
`treated group (3.3 days) than in the steroid-treated
`group (4.9 days).
`Prednisone
`
`NO. OF CVMULA nvE
`
`MEAN
`
`PA neHTS
`
`DOSAG.e
`mg
`
`ME.AH'
`NO. OF CUitoWLATIVE
`PATIE.NTS OOSAOE
`
`63
`
`1218
`
`60
`
`mg
`
`2042
`
`Kidney Fate after AeverNI of lnltl•I Rejection
`59•
`63
`
`
`After the reversal of acute rejection by OKT3 or
`Azathioprine
`
`
`conventional steroid treatment, both groups were
`•One OKT3-group patien1 did noc receive metliylprednisolone. and one sleroid·group patient
`received cyclopbosplwnidc:
`l'llhet lhan uathioprinc.
`
`
`
`· treated similarly with conventional therapy for both
`
`Methylprednisolone
`sodium suecinate
`
`62*
`
`965
`
`60
`
`2019
`
`1765
`
`2711
`
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`BI Exhibit 1026
`
`

`

`340
`
`THE KEW E�GLAi\D JOURNAL Of MEDICINE
`
`i\ug. 8, 1985
`
`
`ysis, kidney survival rates for the OKT3 group and the
`
`tablished.
`
`steroid group were 62 and 45 per cent, respectively
`(P = 0.029) (Fig. 2).
`
`
`
`ness; in all four cases reversal had already been es­
`
`Infections
`
`
`
`Discontinuance of Initial Reversal Treatment
`
`Adverse Experiences
`
`D1scuss10N
`
`O KT3
`
`STEROIO..'i
`
`P VALUE
`
`Infections
`occurred at comparable rates in both
`
`
`OKT3 was discontinued prematurely in 13 patiencs
`
`
`
`groups. During the first 45 days after the start of treat­
`
`
`
`
`because of failure of reversal (two patients), a second
`
`
`ment, infection developed in 43 of 63 patients
`( 68 per
`
`
`
`
`rejection during treatment (one), adverse experiences
`
`cent) and 39 of60 patients (65 per cent) in the OKT3
`
`
`(six, four of whom had already had reversal), or ad­
`
`
`
`and steroid groups, respectively. During this period,
`
`
`
`ministrative error (four, all of whom had already had
`
`11 patients in each group (18 per cent) had severe
`reversal).
`
`
`infections. In the follow-up period of one year, the
`
`
`
`Steroid treatment was discontinued prematurely
`
`
`
`incidence of infection continued to remain comparable
`for the two groups (54 and 50 per cent, respectively).
`
`
`
`in 15 patients because of its failure to reverse re­
`
`jection; rescue with equine antithymocyte globulin
`Skin Tests and Development of Antibodies
`
`was attempted in I 0 of these cases, with reversal
`
`achieved in 7.
`No patient had a positive skin test in response to
`
`
`
`
`
`OKT3. Antibodies to OKT3 developed in 80 per cent
`
`
`of the patients either during or after the second week of
`
`
`
`The first and, to a lesser extent, second injections of
`treatment
`
`with the drug. These antibodies were pri­
`
`OKT3 were associated with a symptom complex that
`
`
`marily of the IgG class, with titers from 1: 100 to
`I: 1000 in the enzyme-linked
`
`
`
`did not occur with subsequent injections. This typical­
`
`immunosorbent assay
`
`
`ly commenced 45 to 60 minutes after the first injec­
`
`
`system used for their detection. They did not affect the
`
`
`tion ofOKT3 and lasted for several hours. It involved
`
`
`
`success of treatment, and there was no evident devel­
`
`
`
`
`pyrexia (73 per cent), chills (57 per cent), tremor (10
`
`
`opment of allergy, anaphylaxis, or serum sickness, al­
`
`
`
`per cent), dyspnea (21 per cent), chest pain and tight­
`
`
`
`that though one patient acquired a rash and pruritus
`
`
`
`ness (14 per cent), wheezing (11 per cent), nausea (11
`
`were subsequently attributed to other medications.
`
`
`
`per cent), and vomiting (13 per cent). This symptom
`
`complex was considered to be due to a physiolog­
`
`
`
`ic response to mediators released from T cells after
`The efficacy of reversal of rejection by OKT3 (94
`
`
`
`
`
`
`the initial OKT3 treatment, with resulting effects on
`
`per cent) was significantly better (P = 0.009) than
`
`
`
`
`temperature control, bronchial smooth-muscle tone,
`
`
`
`that with conventional steroid treatment (75 per cent),
`
`
`
`and the gastrointestinal tract. In one patient who was
`
`and the high reversal rate with OKT3 was obtained
`
`
`in a state of fluid overload before treatment, chills,
`
`
`
`with a significant reduction in the concomitant dos­
`
`
`
`bronchospasm, wheezing, shortness of breath, anxi­
`
`
`ages of steroids and azathioprine. Once the reversal
`
`
`
`ety, increased blood pressure, and pulmonary ede­
`
`
`
`patients in both groups of rejection was achieved,
`
`ma developed after the first dose of OKT3. The pa­
`
`
`and azathio­were treated similarly with prednisone
`
`
`
`tient was treated promptly and successfully with
`
`
`prine maintenance immunosuppression, and they were
`
`
`fluid reduction and steroids. The trial in one patient
`
`
`
`
`treated with high-dose steroids or antithymocyte glob­
`
`in the OKT3 group was discontinued because of
`
`
`
`ulin for repeated episodes of rejection. Both groups
`
`
`renal-artery thrombosis. OKT3 was discontinued
`
`
`
`had similar subsequent rates of repeated r�jection
`
`
`in four other patients because of high fever, rash
`
`and consequent kidney loss, so that the number of
`
`
`
`and pruritus, thrombocytopenia, or profound weak-
`
`
`saved as a result of a superior reversal rate
`kidneys
`
`with OKT3 was reflected in the
`
`higher numbers of functioning kid­
`
`Table 3. Efficacy of Treatment with OKT3 or Steroids for Acute Renal-Allograft
`neys in this group at one year.
`Rejection.
`
`
`Thus, in patients selected by virtue
`
`of having had acute rejection, one­
`
`year kidney survival according
`to
`
`
`life-table analysis was 62 per cent
`
`for the OKT3-treated group and
`45 per cent for the steroid-treated
`group (P = 0.029).
`Since 15 to 20
`
`per cent of the recipients of cadaver
`
`
`kidneys never have rejection, the
`
`
`overall kidney survival rates would
`
`be proportionately higher.
`
`
`Patient survival and the inci­
`
`
`dence of infections were similar in
`
`
`both treatment groups. The main
`
`of rejection (according 10
`Reversal
`
`different criteria)
`58162 {94)
`Serum creatinine level plus clinical
`indexes
`55/62 {89)
`
`Serum crca!inine level alone
`One-year follow-up
`Patient survival
`Actual
`Life table
`Kidney survival
`Actual
`Life table
`-Two patient$ were lost ro follow.up.
`tNS denotes not significant.
`
`36153 (68)
`-(62)
`
`53/62 (85)
`-(85)
`
`45160 (75)
`0.009
`<0.()()1
`37/60 (62)
`
`52158* (90)
`(90)
`047 (NS)t
`
`25152 (48)
`(45)
`
`0.029
`
`The New England Journal of Medicine
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`
`4 of 6
`
`BI Exhibit 1026
`
`

`

`Vol. 313 No. 6
`
`TRIAL OF OKT3 -ORTHO MULTICENTER TRANSPLANT STUDY GROUP
`
`341
`
`100
`
`MEAN END OF
`/ TREATMENT PERIOD
`
`OKT3 TREATED GROUP
`/
`
`�····�··:./ ............ ! .... .. .. ,
`
`"":. ........... .
`STEROID TREATED GROUP
`
`to fluid overload; patients should be brought to appro­
`priate fluid balance before treatment with OKT3 is
`initiated.
`Other monoclonal antibodies have been used thera­
`peutically for acute renal-allograft rejection. 25-27 Al­
`though these antibodies have resulted in the removal
`of circulating T cells, they have not produced the strik­
`ing reversal rate obtained with OKT3; it may well be
`that the pharmacologic effect of OKT3 in blocking
`T-cell function is essential for its therapeutic efficacy.
`Host antibodies to the murine immunoglobulin
`OKT3 frequently developed shortly after treatment
`with OKT3 was stopped.28•29 These antibodies did
`not result in hypersensitivity, anaphylaxis, or serum
`sickness. OKT3 administered in the presence of these
`antibodies may be consumed and rendered unavail­
`able for binding to T3 antigen on T cells.30 Thus, if
`OKT3 is to be used for the treatment of subsequent
`episodes of rejection after successful reversal of initial
`rejection, it will be necessary to develop protocols for
`Figure 2. Life-Table
`of Kidney Survival
`in Patients Ran­
`Analysis
`
`preventing antibody formation or to give sufficient
`for Acute Renal-
`domly Assigned to OKT3 or Steroid Treatment
`amounts of OKT3 to consume the host antibody and
`
`Allograft Rejection.
`establish adequate levels of free OKT3 in the circu­
`
`
`All 53 living OKT3-treated patients were followed for one year. In
`
`lation.
`the steroid-treated group, two patients were lost to follow-up,
`and
`all 52 remaining
`Our results were achieved in patients receiving con­
`
`
`living patients were followed for one year. The
`end of the treatment
`bar.
`period is shown by the vertical
`ventional azathioprine and prednisone therapy. Pre­
`liminary studies in patients treated with cyclosporine
`and prednisone show similar high reversal rates and
`give promise that even better overall rates of kidney
`survival may be attainable.
`
`.. -
`
`..
`�
`
`� 80
`
`c G> 0
`�
`e;
`_, 60
`<
`>
`
`"'
`
`> a: ::> 40
`> w z
`Q 20
`::.:
`
`0
`
`0
`
`100
`
`200
`
`300
`
`400
`
`TIME (Days)
`
`adverse reaction attributable to OKT3 was a symp­
`tom complex involving fever and pulmonary and
`gastrointestinal symptoms and occurring 45 to 60
`minutes after the initial dose. We attribute these
`symptoms to mediators released from T cells opso­
`nized by OKT3 and localized in the reticuloendothe­
`lial system.24 These first-dose symptoms were not due
`to hypersensitivity, since they occurred in almost all
`the patients (with no previous exposure to mouse im­
`munoglobulin), the skin tests before OKT3 adminis­
`tration were uniformly negative, and symptoms were
`absent with later injections of OKT3.
`One case of pulmonary edema occurred in this
`study after a first injection of OKT3 in a patient in a
`state of fluid overload. Four additional cases of pulmo­
`nary edema have occurred after the initial injection of
`OKT3 for acute renal-allograft rejection in other stud­
`ies, and two of those patients died of anoxic sequelae
`(Ortho Pharmaceutical: unpublished data). It is note­
`worthy that in all cases there was evidence of fluid
`overload, as judged by weight gain and chest-film
`changes before OKT3 injection. No cases of pulmo­
`nary edema have occurred in 136 patients treated for
`conditions other than acute renal rejection, and no
`cases have occurred in 197 patients treated for acute
`renal-allograft rejection who did not have fluid over­
`load; as judged by chest filmS"and a weight gain of less
`than 3 per cent in the week preceding treatment. We
`conclude that the pharmacologic effects of the media­
`tors released after the first dose can impose a left ven­
`tricular strain and cause pulmonary edema, but only
`in patients with impending left ventricular failure due
`
`usefulness of antilymphocyte antibodies. Trans·
`
`
`
`REFERENCES
`1. Shield CF Ill. Cosimi AB, Tolkoff-Rubin
`N, Rubin RH, Herrin J, Russell
`PS. Use of antithymocyte
`
`
`
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`
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`
`plant Proc 1983; 15:583·9.
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`
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`
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`
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`The New England Journal of Medicine
`Downloaded from nejm.org at REPRINTS DESK INC on April 24, 2015. For personal use only. No other uses without permission.
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`5 of 6
`
`BI Exhibit 1026
`
`

`

`342
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 8, 1985
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`13. Giorgi JV, Cosimi AB. Colvin RB. Goldstein G. Delmonico A... Russell
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`
`
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