The New England
`Journal of Medicine
`
`.. 1Copyright, 1985. by the Massachusetts Medical Society
`
`Volume 313
`
`AUGUST 8, 1985
`
`Number 6
`
`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(cid:173)
`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(cid:173)
`ing of the dosage of other immunosuppressive drugs (63
`patients), or with conventional high-dose steroids (60 pa(cid:173)
`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(cid:173)
`munosuppressive drugs) is an effective approach for
`acute renal-allograft rejection. (N Engl J Med 1985; 313:
`337-42.)
`
`D ESPITE improvements in tissue matching and
`
`the introduction of newer immunosuppressive
`agents, acute rejection of the allograft remains a major
`impediment to the success of clinical renal transplan(cid:173)
`tation. Conventional therapies include the use ofhigh(cid:173)
`dose steroid pulses and of antithymocyte globulins.1·4
`The use of high-dose steroids results in a high inci(cid:173)
`dence of infection and other side effects. Antithymo(cid:173)
`cyte globulins are more effective than steroids in re(cid:173)
`versing acute renal rejection, but difficulties in lot
`standardization, giving variations in efficacy and in
`the incidence of adverse reactions among lots, contin(cid:173)
`ue to be a major problem. OKT3 is a murine mono(cid:173)
`clonal antibody that is reactive with a 20,000-dalton
`molecule found only on the surface of thymocytes or
`mature human T cells.5 The structure recognized by
`OKT3 is linked to the T-cell antigen receptor6.7 and
`appears vital for the functioning of human T cells.8
`Thus, OKT3 in vitro blocks both killing by cytotoxic
`
`"'The Onho Multicemer Transplant Study Group comprised Gideon Goldstein,
`M.D., Ph.D .• John Schindler, Ph.D., and Huci Tsai, Ph.D. (Onho Pharmaceuti(cid:173)
`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 Louisville, 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.
`
`human T cells and the generation of other T-cell func(cid:173)
`tions9"11; furthermore, T-cell function is lost if0KT3
`interacts with and causes the removal of the antigen
`T3 on the T-cell surface. 12·13
`We have previously reported an open pilot study
`showing that OKT3 reversed acute renal-allograft re(cid:173)
`jection in all of 10 patients.14-16 We now present the
`results of a randomized prospective protocol compar(cid:173)
`ing the safety and efficacy of OKT3 (with reduction in
`the dosage of concomitant immunosuppressive medi(cid:173)
`cation) with those of conventional steroid treatment in
`reversing acute renal-allograft rejection.
`
`METHODS
`
`Production of OKT3
`
`OKT3 was produced from seed lots of the parent hybridoma. The
`immunoglobulin was purified from ascites and formulated, and am(cid:173)
`pules were filled under sterile conditions. E~ch batch was tested for
`purity and safety and conformed to the standards of the Food and
`Drug Administration.
`
`Organization
`
`This clinical trial was organized by the lmmunobiology Division
`of the Ortho Pharmaceutical Corporation after a preliminary inves(cid:173)
`tigators' m eeting at which a consensus was reached on protocol
`design. At each participating center an institutional 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(cid:173)
`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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`

`

`338
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Aug. 8, 1985
`
`entry was restricted to patients with rejections occurring from 6 to
`93 days after transplantation.
`Patients received a standard regimen ofimmunosuppression after
`transplantation. This comprised prednisone, starting at 2 mg per
`kilogram of body weight per day and tapering to 0.5 mg per kilo(cid:173)
`gram per day by Week 9, and the maximal tolerated dose of azathio(cid:173)
`prine -
`approximately 100 to 150 mg per day.
`
`Rllndomlatlon
`
`Patients meeting the eligibility criteria were randomly assigned at
`entry to receive either OKT3 or steroid treatment, the randomiza(cid:173)
`tion schedule being generated by computer for each center.
`
`OKT3 Group
`
`After a negative skin test (0. I ml of a 1-µ.g-per-milliliter solution
`intradermally), O KT3 was administered by intravenous push at a
`dose of 5 mg per day for 14 consecutive days (Fig. I). Investigators
`had the option of continuing therapy, and 14 patients were treated
`for additional periods of I to 14 days. During O KT3 administration
`the dosages of concomitant immunosuppressive agents were re(cid:173)
`duced -
`azathioprinc to 25 mg per day and prednisone to 0.5 mg
`per kilogram per day. T hese were raised to the continuing dosages
`on the day after O KT3 therapy was stopped, as if rejection had not
`
`occurred . A bolus injection of I mg of mcthylprednisolonc per kilo(cid:173)
`gram and concomitant acetaminophen and antihistamines were
`permitted with the first dose ofOKT3 to reduce the fever and chills
`that were known to accompany this first dose.
`
`Conventlonal..sterolds Group
`
`Azathioprinc and prednisone were continued at prerejcction
`levels. Methylprednisolone (500 mg per day) was givcn17,18 for
`a maximum of th ree days, after which prednisonc could be given
`at a dosage of 3 mg per kilogram per day, if necessary, and tapered
`over the next seven days so that a dose of I mg per kilogram per
`day was achieved on the seventh day. T he prednisone dosage was
`then tapered to what it would have been if rejection had not oc(cid:173)
`curred (Fig. I).
`
`"Rescue" Treatment
`
`Any patient whose scrum crcatinine level did not decrease on the
`sixth day or later and whose transplant rejection was j udged not to
`have been reversed could be treated with additional conventional
`treatment (for the O KT3 group) or equine antithymocyte globulin
`(for the steroid group) .
`
`Reverul of Rejection
`
`T he therapeutic goal was reversal of renal-allograft rejection as
`judged by a three-day progressive fall in scrum crcatinine levels.
`T he investigators j udged that reversal had occurred in an additional
`three patients in the O KT3 group and eight patients in the steroid
`group, on the basis of clinical criteria alone, such as reduetion in
`kidney swelling and tenderness, decreased fever , and resumption of
`diuresis.
`
`Procedures
`
`Before treatment for rejection, demographic data and a medical
`history were recorded for each patient. In addition, the patient
`underwent a complete pretreatment physical examination, with full
`clinical laboratory evaluation (blood-chemistry and hematologic
`studies and urinalysis) and chest radiography. During treatment
`for rejection, there were daily recordings of the scrum creatinine
`level, body temperature, blood pressure, and white-cell count with
`differential cell count, and periodic measurement of other clinical
`laboratory indexes. O n the termination of rejection therapy, all
`clinical laboratory measurements were repeated. Routine follow-up
`examinations were performed at 3, 6, 12, and 24 months after trans(cid:173)
`plantation and included a determination of graft status and the
`same physical and laboratory examinations performed before rejec(cid:173)
`tion therapy. T hroughout the trial, all adverse experiences and in(cid:173)
`fections were rccordtcl.
`
`SUtlstlcal Methods
`
`Fisher's exact test, 19 Wilcoxon's rank-sum test,20 or the extended
`Mantcl-Hacnszcl chi-square tcst21 was used for pretreatment com(cid:173)
`parisons based on demographic and disease-history variables.
`Reversal of rejection was analyzed with stratification by investiga(cid:173)
`tors using the Mantel-Hacnszcl chi-square tcst.22 When reversal
`and graft-survival rates were being calculated, one O KT3-treated
`patient "rescued" with steroids was counted as constituting a treat(cid:173)
`ment failure, as were 10 steroid-treated patients rescued with anti(cid:173)
`thymocytc globulin. Steroid-treated patients rescued with addition(cid:173)
`al steroids were considered treatment successes. Fisher's exact test
`was also used to compare the incidence rates in the two trea tment
`groups for the following indexes: repeated rejection, adverse experi(cid:173)
`ences, and infections. Life-table comparisons were performed with
`use of Brcslow's tcst.23
`
`R£suLTS
`
`Patient Entry
`In all, 123 patients -
`63 in the OKT3 group and
`60 in the steroids group - were treated with study
`medications. Summary data on demographic factors
`
`OKT3 TREATMENT
`Rejection
`I
`Tranaplant
`t
`~
`
`: :: t ~g METHYLPREDNISOLONE. 1.V.
`[~PRE'Q .. jS9)iE .
`'-~~--·-.. ~·"-"'•'"~'''~·"~' ~·'-""~'"•'"•'"•""-'·~·
`111111111111o~t31111111111111
`
`AZA THIOPRINE
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`!
`
`I
`
`O
`
`DAYS
`
`, ..
`
`Q.Q§E
`mg;kg
`
`mg/ da y
`
`mg/ day 150 t
`25
`5[
`I
`
`01
`
`C ONVENTIONAL STEROID TREATMENT
`Rejection
`
`• 500 mg METHYLPREDNISOLONE, 1.V.
`+H
`
`QQli
`I
`
`mg/kg
`
`3 .0
`
`2.0
`
`1.0
`
`,,,,,,,,, , ,,,,,
`O
`DAYS
`, ..
`
`Figure 1. Plan of Daily lmmunosuppressive Drug Regimens for
`Patients Randomly Assigned to OKT3 or Steroid Treatment for
`Acute Renal-Allograft Rejection.
`During OKT3 treatment, dosages of steroids and azathiOprlne
`were reduced, with resumption of the prerejection tapered dos(cid:173)
`age of steroids and the azathioprlne dosage when OKT3 was
`discontinued. By contrast, steroid treatment involved a high ste-(cid:173)
`rold dosage, with malntenanoe of the azathioprine dosage. l.V.
`denotes Intravenous.
`
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`

`Vol. 313 No. 6
`
`TRIAL OF OKT3 - ORTHO MULTICENTER TRANSPLANT STUDY GROUP
`
`339
`
`and pertinent medical history for
`the study population are shown
`in Table l. There were no sta(cid:173)
`tistically significant differences be(cid:173)
`tween the groups in any of these
`base-line characteristics, and the
`patients overall appeared repre(cid:173)
`sentative of the population expe(cid:173)
`riencing a first episode of acute re(cid:173)
`nal-allograft rejection. However,
`l of the 63 patients treated with
`OKT3 was diagnosed in retrospect
`as having undergone a deteriora(cid:173)
`tion in renal function due to cyto(cid:173)
`megalovirus infection rather than
`acute renal rejection, and he was
`therefore excluded from the efficacy
`analysis.
`
`Table 1. Clinical Characteristics of Patients Randomly Assigned to OKT3 or Steroid
`Treatment for Acute Renal-Allograft Rejection.
`
`CHA.RACTEUSTIC
`
`Sex (M/F)
`Median age (yr)t
`Median weight (kg)t
`Race (white/nonwhite)
`No. with diabetes mellitus
`No. with prior transplants (0/ 112)
`No. with intransplant transfusions
`(0/1-41>4)
`Acute tubular necrosis and dialysis at entry
`Renal disease (glomeruloncphritis)
`Crossmatch ( -I+)
`
`Preformed antibodies
`(0-24%126-100% positive)
`Median time from transplant to rejection (days)t
`
`TUA1MENT Ga.our•
`OKT3
`
`STEJOlDS
`
`43120
`38 (17-65)
`67 (42-103)
`
`50/13
`20
`551711
`1112144
`
`12
`23
`63/0
`44/10
`
`39121
`36 (l<>-64)
`66 (30-111)
`49/11
`14
`521612
`3110/40
`
`9
`18
`5911
`39118
`
`10 (6-74)
`
`11 (6-91)
`
`*lbc:re were no Slalistically significant differences between die two groups in any of <hose indexes.
`tNumbefs in parentheses represent <he range of values.
`
`Medication
`OKT3 was administered intrave(cid:173)
`nously at a dosage of 5 mg per day
`for a mean period of 14 days (range, l to 28}. In(cid:173)
`creased amounts of steroids were also administered as
`rejection therapy in the control group for a mean
`of 14 days (range, 3 to 36). On the day before rejec(cid:173)
`tion, the mean daily doses of prednisone and azathio(cid:173)
`prine among patients entered into the OKT3 group
`were 1.07 mg per kilogram and 142 mg, respectively.
`During the period ofOKT3 administration, the mean
`daily doses of prednisone and azathioprine were
`reduced to 0.56 mg per kilogram and 30 mg, respec(cid:173)
`tively. Table 2 shows the cumulative doses of the con(cid:173)
`ventional immunosuppressives for each group for the
`28 days beginning with the day of rejection and indi(cid:173)
`cates the marked steroid-sparing effect of the OKT3
`regimen.
`
`Reversal of Rejection
`OKT3 reversed acute renal-allograft rejection in
`58 of 62 patients (94 per cent} -
`a significantly high(cid:173)
`er reversal rate (P = 0.009) than that for convention(cid:173)
`al steroid treatment, which reversed rejection in 45
`of60 patients (75 per cent} (Table 3). If reversal was
`judged strictly according to the objective criterion of
`the occurrence of a progressive decrease in the serum
`creatinine level, the reversal rates became 55 of 62
`(89 per cent} for the OKT3 group and 37 of 60 (62
`per cent} for the steroids group (P<0.001). The distri(cid:173)
`bution of reversal results was generally consistent
`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) .
`
`Kidney Fate after AeverNI of lnltl•I Rejection
`After the reversal of acute rejection by OKT3 or
`conventional steroid treatment, both groups were
`· treated similarly with conventional therapy for both
`
`maintenance and repeated episodes of rejection. Be(cid:173)
`cause of the efficacy ofOKT3 in reversing acute rejec(cid:173)
`tion there were more patients (58) in whom rejection
`had been reversed by OKT3 than by conventional
`steroid treatment (45). A second rejection was com(cid:173)
`mon in both groups, occurring in 38 of 58 patients (66
`per cent) initially treated with OKT3 and 33 of 45
`patients (73 per cent} initially treated with conven(cid:173)
`tional steroids (P = 0.52). The incidence of kidney
`loss due to repeated rejection was also similar in
`both groups: 19 of 58 patients (33 per cent) initially
`treated with OKT3 and 17 of 45 (38 per cent) initial(cid:173)
`ly treated with conventional steroids lost a kidney
`(P = 0.68).
`Patient and Kidney Survival
`Two patients in the steroid-treated group were lost
`to follow-up. At one year, 53 of 62 patients (85 per
`cent} treated with OKT3 and 52 of 58 (90 per cent}
`of those treated with steroids were alive (P = 0.47)
`(Table 3). All 53 living patients treated with OKT3
`and the 52 living patients treated with steroids were
`followed for one year. According to life-table anal-
`
`Table 2. Mean Cumulative Dosage of lmmunosuppressive Med·
`ications over the First 28 Days of Treatment for Patients Ran·
`domly Assigned to OKT3 or Steroids for Acute Renal-Allograft
`Rejection.
`
`MEDICATION
`
`OKT3
`
`STEAOIDS
`
`NO. OF
`PA neHTS
`
`MEAN
`CVMULA nvE
`DOSAG.e
`
`NO. OF
`PATIE.NTS
`
`ME.AH'
`CUitoWLATIVE
`OOSAOE
`mg
`
`Prednisone
`
`Methylprednisolone
`sodium suecinate
`
`Azathioprine
`
`63
`
`62*
`
`63
`
`mg
`
`1218
`
`965
`
`1765
`
`60
`60
`
`2042
`
`2019
`
`59•
`
`2711
`
`•One OKT3-group patien1 did noc receive metliylprednisolone. and one sleroid·group patient
`received cyclopbosplwnidc: l'llhet lhan uathioprinc.
`
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`

`340
`
`THE KEW E~G LAi\D JOURNAL Of MEDICINE
`
`i\ug. 8, 1985
`
`ness; in all four cases reversal had a lready been es(cid:173)
`tablished.
`
`Infections
`Infections occurred at comparable rates in both
`groups. During the first 45 days after the start of treat(cid:173)
`ment, infection developed in 43 of 63 patients ( 68 per
`cen t) and 39 of60 patients (65 per cent) in the OKT3
`and steroid groups, respectively. During this period,
`11 patients in each group ( 18 per cent) had severe
`infections. In the fo llow-up period of one year, the
`incidence of infection continued to remain comparable
`for the two groups (54 and 50 per cent, respectively).
`
`Skin Tests and Development of Antibodies
`
`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
`treatment with the drug. These antibodies were pri(cid:173)
`marily of the I gG class, with titers from 1: 100 to
`I: 1000 in the enzyme-linked immunosorbent assay
`system used for their detection. They did not affect the
`success of treatment, and there was no evident devel(cid:173)
`opment of a llergy, anaphylaxis, or serum sickness, al(cid:173)
`though one patient acquired a rash and pruritus that
`were subsequently a ttributed to other medications.
`
`Table 3. Efficacy of Treatment with OKT3 or Steroids for Acute Renal-Allograft
`Rejection.
`
`ysis, kidney survival rates for the OKT3 group and the
`steroid group were 62 and 45 per cent, respectively
`( P = 0.029) (Fig. 2).
`Discontinuance of Initial Reversal Treatment
`
`OKT3 was discontinued prematurely in 13 patiencs
`because of failure of reversal (two patients), a second
`rejection during treatment (one), ad verse experiences
`(six, fou r of whom had already had reversal), or ad(cid:173)
`ministrative error (four, all of whom had already had
`reversal) .
`Steroid treatment was discontinued prematurely
`in 15 patients because of its failure to reverse re(cid:173)
`jection; rescue with equine antithymocyte globulin
`was attempted in I 0 of these cases, with reversal
`achieved in 7.
`
`Adverse Experiences
`The first and, to a lesser extent, second injections of
`OKT3 were associated with a symptom complex that
`did not occur with subsequent injections. This typical(cid:173)
`ly commenced 45 to 60 minutes after the first injec(cid:173)
`tion ofOKT3 and lasted for several hours. It involved
`pyrexia (73 per cent), chills (57 per cent), tremor (10
`per cent), dyspnea (2 1 per cent), chest pain and tight(cid:173)
`ness (14 per cent), wheezing (11 per cent), nausea (11
`per cent), and vomiting (13 per cent). This symptom
`complex was considered to be due to a physiolog(cid:173)
`ic response to mediators released from T cells after
`the initial OKT3 treatment, with resulting effects on
`temperature con trol, bronchial smooth-muscle tone,
`and the gastrointestinal tract. In one patient who was
`in a state of fluid overload before treatment, chills,
`bronchospasm , wheezing, shortness of breath, anxi(cid:173)
`ety, increased blood pressure, and pulmonary ede(cid:173)
`ma developed after the first dose of OKT3. The pa(cid:173)
`tient was treated promptly and successfully with
`fluid reduction and steroids. The trial in one patient
`in the OKT3 group was discontinued because of
`renal-artery thrombosis. OKT3 was discontinued
`in four other patients because of high fever, rash
`and pruritus, thrombocytopenia, or profound weak-
`
`OKT3
`
`STEROIO..'i
`
`Reversal of rejection (according 10
`different criteria)
`Serum creatinine level plus clinical indexes
`Serum crca!inine level alone
`One-year follow-up
`Patient survi val
`Actual
`Life table
`Kidney survival
`Actual
`Life table
`
`58162 {94)
`55/62 {89)
`
`45160 (75)
`37/60 (62)
`
`53/62 (85)
`-(85)
`
`52158* (90)
`(90)
`
`36153 (68)
`-(62)
`
`25152 (48)
`(45)
`
`-Two patient$ were lost ro follow.up.
`tNS denotes not significant.
`
`D1scuss10N
`The efficacy of reversal of rejection by OKT3 (94
`per cent) was significantly better (P = 0.009) than
`that with conventional steroid treatment (75 per cent),
`a nd t he high reversal rate with OKT3 was obtained
`with a significan t reduction in the concomitant dos(cid:173)
`ages of steroids and azathioprine. Once the reversal
`of rejection was achieved, patients in both groups
`were treated simila rly with prednisone and azathio(cid:173)
`prine maintenance immunosuppression, and they were
`treated with high-dose steroids or antithymocyte glob(cid:173)
`ulin for repeated episodes of rejection. Both groups
`had similar subsequent rates of repeated r~jection
`and consequen t kidney loss, so that the number of
`kidneys saved as a result of a superior reversal rate
`with OKT3 was reflected in the
`higher numbers of functioning kid(cid:173)
`neys in this group at one year.
`Thus, in patients selected by virtue
`of having had acute rejection, one(cid:173)
`year kidney survival according to
`life-table analysis was 62 per cent
`for the OKT3-treated group and
`45 per cen t 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(cid:173)
`dence of infections were similar in
`both treatment groups. The main
`
`P VALUE
`
`0.009
`< 0.()()1
`
`047 (NS)t
`
`0.029
`
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`

`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
`
`~ 80
`c
`G>
`0
`~ e; _, 60
`< > > a:
`"' > w z
`
`::> 40
`
`Q 20
`::.:
`
`0
`
`0
`
`100
`
`200
`TIME (Days)
`
`300
`
`400
`
`Figure 2. Life-Table Analysis of Kidney Survival in Patients Ran(cid:173)
`domly Assigned to OKT3 or Steroid Treatment for Acute Renal-
`Allograft Rejection.
`All 53 living OKT3-treated patients were followed for one year. In
`the steroid-treated group, two patients were lost to follow-up, and
`all 52 remaining living patients were followed for one year. The
`end of the treatment period is shown by the vertical bar.
`
`adverse reaction attributable to OKT3 was a symp(cid:173)
`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(cid:173)
`nized by OKT3 and localized in the reticuloendothe(cid:173)
`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(cid:173)
`munoglobulin) , the skin tests before OKT3 adminis(cid:173)
`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(cid:173)
`nary edema have occurred after the initial injection of
`OKT3 for acute renal-allograft rejection in other stud(cid:173)
`ies, and two of those patients died of anoxic sequelae
`(Ortho Pharmaceutical: unpublished data). It is note(cid:173)
`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(cid:173)
`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(cid:173)
`load; as judged by chest filmS"and a weight gain ofless
`than 3 per cent in the week preceding treatment. We
`conclude that the pharmacologic effects of the media(cid:173)
`tors released after the first dose can impose a left ven(cid:173)
`tricular strain and cause pulmonary edema, but only
`in patients with impending left ventricular failure due
`
`to fluid overload; patients should be brought to appro(cid:173)
`priate fluid balance before treatment with OKT3 is
`initiated.
`Other monoclonal antibodies have been used thera(cid:173)
`peutically for acute renal-allograft rejection. 25-27 Al(cid:173)
`though these antibodies have resulted in the removal
`of circulating T cells, they have not produced the strik(cid:173)
`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(cid:173)
`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
`preventing antibody formation or to give sufficient
`amounts ofOKT3 to consume the host antibody and
`establish adequate levels of free OKT3 in the circu(cid:173)
`lation .
`Our results were achieved in patients receiving con(cid:173)
`ventional azathioprine and prednisone therapy. Pre(cid:173)
`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.
`
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`5 of 6
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`342
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`THE NEW ENGLAND JOURNAL OF MEDICINE
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`Aug. 8, 1985
`
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