The
`New England
`Journal of Medicine
`
`Estab l i s h e d
`
`i n 1 8 1 2 as TH E NEW ENGLAND
`
`j O URNA L OF M ED I C IN E AN D S U RGERY
`
`VOLUME 33 8
`
`J ANUARY 1 5 , 1 998
`
`NUMBER 3
`
`ORIGINAL ARTICLES
`Effect of Computed Tomography
`of the Appendix on Treatment of Patients
`and Use of Hospital R esources
`.. ... .. ..... .... 141
`P .M. RAo , ) .T. RH EA, R.A. NO VE LLINE ,
`A.A . MO STAFAVI , AND C.J . M CCABE
`
`P repregnancy Weight and the Risk
`of Adverse Pregnancy Outcomes
`..... .... 147
`5. CNATT!Nli!U S, R. B ERG STROM , L. LIPWORT H ,
`AND M .S. KRAMER
`
`SYT-SSX Gene Fusion as a Determinant
`of Morphology and Prognosis
`. ..... ..... ....... ...... .... ..... 153
`in Synovial Sarcoma .. ...
`A. KAWA I AN D OTH ERS
`
`I.nterleukin-2-Receptor Blockade
`with Daclizumab to Prevent Acute Rejection
`in Renal Transplantation
`....... .. 161
`F. V INCENT I AND OTHERS
`
`Brief Report: A True Hermaphrodite Chimera
`Resulting from Embryo Amalgamation after
`in Vitro Fertilization
`.. . .. ...... .. ....... .......... ... .. .. .. 166
`L. STRAI N, J .C .S. DE AN, M. P.R. H AM ILTO N,
`AND D .T. BoN THRON
`
`IMAGES IN CLINICAL MEDICINE
`Fetal Micturition ....
`R . 0E VESA AND M. TORRE NTS
`
`.. .. 170
`
`REVIEW ARTICLE
`Seminars in Medicine of the Beth Israel
`Deaconess Medical Center: Protective
`and Damaging Effects of Stress
`Mediators ... ......
`.... .. .. .... .. ........
`B.S. M c EWEN
`
`CASE RECORDS OF THE
`MASSACHUSETTS GENERAL HOSPITAL
`A 50-Year-Old Woman with Increasing
`Headache and a Left Abducent-Nerve Palsy .... 18o
`D .H. O' L EARY AND S. DE LA M ONTE
`
`EDITORIALS
`More Precision in Diagnosing Appendicitis ..... .. .. 190
`I . M cCo LL
`
`High Prep regnancy Body-Mass Index -
`A Maternal-Fetal Risk Factor ........ ....
`H . WOLFE
`
`.. . 191
`
`The Clinical Significance of Fusion Oncogenes
`... .. .......... ...
`. .. . .... 1~
`inC~~.. ..... . .. . .. .
`T. H . RABBITTS
`
`Outcome of Assisted Reproductive Technology . 194
`A. VA N STE IRTEGHEM
`
`CORRESPONDENCE
`A Controlled Trial of Double versus Triple Therapy
`............ .. ..
`.. .... . . 196
`for HIV.
`Battling HIV on Many Fronts
`.. . 198
`Stent Placement Compared with Balloon
`Angioplasty for Obstructed Coronary
`Bypass Grafts . .. ..... .. ............ .. .. ........ .... ......... .. .. .. ..... ... 198
`Bone Marrow Necrosis and the Lambert-Eaton
`Syndrome Associated with Interferon Alfa
`Treatment
`.. .. .... .. .. ............ .. .. ........ .. ..........
`Legionnaires' Disease
`.. .. .. .. .. .. .. .. .. .. . .. .. .. .. ...
`Fatal Intoxication with 1,1-Dichloro-
`1-Fluoroethane ................... .. .. .... .. ..... .. ........ .... .. ... .... 201
`Transfer of Peanut Allergy by a Liver Allograft
`.. .. 202
`
`.. .. 199
`.. .. 200
`
`BooK RE V I EWS
`
`............ .. ........ .....
`
`... .. .. ... .... ..
`
`. ............ 171
`
`N O TI CE S
`
`I NF O R MA T I O N FO R A UTHO R S
`
`.. .. 204
`..... 206
`208
`
`0Jlll/ed, pub/is/u:d, n11 d © cop_yrigbtcd, 1998, by THE M.-\SSACH USETTS M EDICAL SOCif.TY
`
`p
`E
`
`RETURN TO
`CIRCULATION DESK
`
`The New England journal
`rnt·? cl i c i nF~
`BI'1L.
`I...JC b<Oin D i (:·?go:::o
`Receiv e d on: 01-20-98
`
`(;ht:d Wt:~kl y
`puon pru::c
`ling otliccs.
`,-0803.
`
`N
`
`E w
`s
`p
`A
`p
`E
`R
`
`BIOEPIS EX. 1038
`Page 1
`
`

`

`INTE RL EUKIN-2-RECEPTOR BLOCKADE WITH DACLIZUMAB TO PREVENT REJECTION IN RENAL TRANSPLANTATION
`
`INTERLEUKIN-2-RECEPTOR BLOCKADE WITH DACLIZUMAB TO PREVENT
`ACUTE REJECTION IN RENAL TRANSPLANTATION
`
`FLAVIO VINCENTI, M.D., ROBERT KIRKMAN, M.D., SUSAN LiGHT, M .D., GINNY BUMGARDNER, M.D., PH.D.,
`MARK PESCOVITZ, M .D., PHILIP HALLORAN, M.D., PH.D., JOHN NEYLAN, M.D., ALAN WILKINSON, M .D.,
`HENRIK EKBERG, M.D., PH.D., RoBERT GASTON, M.D., LARs BACKMAN, M.D., PH.D.,
`AND JAMES BURDICK, M.D., FOR THE DACLIZUMAB TRIPLE THE_RAPY STUDY GROUP*
`
`ABSTRACT
`Background Monoclonal antibodies that block the
`high-affinity interleukin-2 receptor expressed on al(cid:173)
`loanti gen-reactive T lymphocytes may cause selec(cid:173)
`tive immunosuppression. Daclizumab is a genetical(cid:173)
`ly engi neered human lgG1 monoclonal antibody that
`bi nds specifically to the a chain of the interleukin-2
`receptor and may thus reduce the risk of rejection af(cid:173)
`ter renal transplantation.
`Methods We administered daclizumab (1.0 mg per
`kilogram of body weight) or placebo intravenously
`before transplantation and once every other week af(cid:173)
`terward, for a total of five doses, to 260 patients re(cid:173)
`ceiving first cadaveric kidney grafts and immuno(cid:173)
`suppressive therapy with cyclosporine, azathioprine,
`and prednisone. The patients were followed at regu(cid:173)
`lar intervals for 12 months. The primary end point
`was the incidence of biopsy-confirmed acute rejec(cid:173)
`tion within six months after transplantation.
`Results Of the 126 patients given daclizumab, 28
`(22 percent) had biopsy-confirmed episodes of acute
`rejection, as compared with 47 of the 134 patients
`(35 percent) who received placebo (P = 0.03). Graft
`survival at 12 months was 95 percent in the da(cid:173)
`clizumab-treated patients, as compared with 90 per(cid:173)
`cent in the patients given placebo (P = 0.08). The pa(cid:173)
`tients given daclizumab did not have any adverse
`reactions to the drug, and at six months, there were
`no significant differences between the two groups
`with respect to infectious complications or cancers.
`The serum half-life of daclizumab was 20 days, and
`its administration resulted in prolonged saturation of
`interleukin-2a receptors on circulating lymphocytes.
`Conclusions Daclizumab reduces the frequency of
`acute rejection in kidney-transplant recipients. (N Engl
`J Med 1998;338:161 -5.)
`~ 1998, Massachusetts Medical Society.
`
`A CUTE rejection is a strong risk factor for
`
`chronic rejection in recipients of renal
`grafts from cadaveric donors.1 This fact
`has prompted the development of new
`immunosuppressive agents designed to reduce the
`incidence and severity of acute rejection. 2·6 All these
`agents, however, achieve reductions in the frequency
`and severity of acute rejection at the price of gener(cid:173)
`alized immunosuppression, with its attendant risks
`of opportunistic infection and cancer.
`One potential target for more specific immuno(cid:173)
`suppressive therapy with monoclonal antibodies is
`
`the interleukin-2 receptor.? The high-affinity inter(cid:173)
`leukin-2 receptor is composed of three noncovalent(cid:173)
`ly bound chains: a 55-kd a chain (also referred to
`as CD25 or Tac), a 75-kd {3 chain, and a 64-kd
`y chain.? This receptor is present on nearly all acti(cid:173)
`vated T cells but not on resting T cells. The interac(cid:173)
`tion of interleukin-2 with this high-affinity receptor
`is required for the clonal expansion and continued
`viability of activated T cells. A variety of rodent
`monoclonal antibodies directed against the a chain
`of the receptor have been used in animals and
`humans to achieve selective immunosuppression by
`targeting only T-cell clones responding to the al(cid:173)
`lograft.8·13 Daclizumab, a molecularly engineered
`human IgGl incorporating the antigen-binding re(cid:173)
`gions of the parent murine monoclonal antibody,
`offers the potential for greater therapeutic use of in(cid:173)
`terleukin-2-receptor blockade.14·17 We compared the
`efficacy of daclizumab with placebo for the preven(cid:173)
`tion of acute rejection in renal-transplant recipients.
`
`METHODS
`
`Study Design
`
`We performed a randomized, double-blind, placebo-controlled
`trial at 11 transplantation centers in the United States, 3 in Can(cid:173)
`ada, and 3 in Sweden. Adults receiving first renal allografts from
`cadaveric donors were eligible for the study. Patients were exclud(cid:173)
`ed if they were receiving multiple organ transplants or had a pos(cid:173)
`itive crossmatch for T-ceU lymphocytes. The protocol was ap(cid:173)
`proved by the institutional review board or ethics committee at
`each participating center, and all patients gave written informed
`consent.
`
`Immunosuppressive Treatment
`
`All patients received cyclosporine, azathioprine, and predni(cid:173)
`sone. The first dose of cyclosporine was given during the period
`from 12 hours before to 24 hours after transplantation .
`Daclizumab (Zenapax, Hoffmann-LaRoche ) or placebo was
`
`From the University of California, San Francisco (F.V. ); Brigham and
`Women's Hospital, Boston (R.K. ); Hoffmann-LaRoche, Nutley, N.J.
`(S. L. ); Ohio State University, Columbus (G.B. ); Indiana University, Indi(cid:173)
`anapolis (M.P. ); the University of Alberta, Edmonton, Alta., Canada
`.); the University of California, Los
`(P.H. ); Emory University, Atlanta (J.
`Angeles (A.W.); Malmo University Hospital, Malmo, Sweden (H.E.); the
`University of Alabama, Birmingham (R.G.); Sahlgrenska Hospital , Goth(cid:173)
`enburg, Sweden ( L.B. ); and johns Hopkins University, Baltimore (J.B. ).
`Address reprint requests to Dr. Vincenti at the Transplant Service, Univer(cid:173)
`si ty of Califo rnia, San Francisco, 505 Parnassus Ave., Rm. M884, Box
`01.16, San Francisco, CA 94143 -0116.
`*Other members of the Dacli zumab Tripk Therapy Study Group are
`listed in the Appendix.
`
`Vol um e 338 Number 3
`
`161
`
`BIOEPIS EX. 1038
`Page 2
`
`

`

`The New England Journal of Medicine
`
`administered intravenously over a period af-;15 minutes. Each pa(cid:173)
`tient received five doses of either daclizumab·~ mg per kilogram
`of body weight, to a maximum of l 00 mg per dose) or placebo
`(0.2 mg of polysorbate 80 per milliliter in 67 mM phosphate
`buffer). The first dose was administered within 24 hours before
`transplantation, with subsequent doses given two, four, six, and
`eight weeks after transplantation .
`
`Primary and Secondary End Points
`
`The primary end point of the study was the incidence of biop(cid:173)
`sy-confirmed acute rejection within the first six months after
`transplantation. All patients with an unexplained rise in the serum
`creatinine concentration or one or more symptoms of acute re(cid:173)
`jection (fever, pain over the graft, or a decrease in urinary volume)
`were required to undergo a renal biopsy within 24 ho urs after the
`initiation of antirejection therapy, which consisted initially of in (cid:173)
`travenous methylprednisolone (7 mg per kilogram per day ) for
`three days. The histologic diagnosis of rejection was based on the
`presence of acute tubuli tis or vasculitis and was made by the pa(cid:173)
`thologist at each institution. Patients were considered to have
`presumptive rejection if they received a course of antirejection
`therapy in the absence of histologic confirmation of rejection .
`The diagnosis of any subsequent episodes of rejection in patients
`presenting with renal dysfunction was based on clinical criteria,
`such as the absence of evidence of nephrotoxicity or of urinary
`tract obstruction or infection, with a biopsy for confirmation per(cid:173)
`formed at the investigator's discretion .
`Secondary end points included patient survival and graft sur(cid:173)
`vival at one year, the time to the first episode of acute rejection,
`the number of acute rejection episodes per patient, the need for
`antilymphocyte therapy (OKT3 or polyclonal antithymocyte glob(cid:173)
`ulin ) because of glucocorticoid-resistant rejection (defined as the
`absence of a response to intravenous methylprednisolone pulse
`therapy), graft function (as indicated by the serum creatinine con(cid:173)
`centration and glomerular filtration rate ), and the cumulative
`dose of prednisone in the first six mo nths after transplantation.
`
`Pharmacokinetic Measurements
`
`Blood samples were collected immediately before and after (for
`trough and peak concentrations, respectively) the first and fifth
`infusions of daclizumab or place bo and on days 70 and 84 after
`transplantation . A sandwich enzyme-linked immunosorbent assay
`was used to measure daclizumab in scrum_l s
`In 20 consecutive patients at one U.S. center (University of
`California, San Francisco), lymphocyte analysis was performed to
`determine the saturation of the interleukin-2-receptor a chain,
`with the use of methods reported previously_17
`
`Glomerular Filtration Rate
`
`The glomerular filtration rare was measured in all patients with
`functioning grafts six months after transplantation. Measure(cid:173)
`ments were based on iohexol, radioisotope, or inulin clearance.
`
`Statistical Analysis
`
`Differences _in categorical variables between the two groups
`were determined with the use of the Mantel-Haenszel test (with
`stratification according to center). Differences in the time to the
`first biopsy-confirmed episode of rejectio n wen: determined with
`the use of the log-rank test (with stratification according to cen(cid:173)
`ter). The log-rank test was also used to analyze the time to graft
`failure (or death with a functioning graft) because of the small
`number of events reported. Kaplan-Meier estimates of the prob(cid:173)
`ability of patient su rvival and graft survival and the cumulative
`probability of biopsy-confirmed rejection were plotted over time.
`Differences in the number of presumptive or biopsy-confirmed
`rejection episodes per patient in the first six months were ana(cid:173)
`lyzed with a normal regression model. The serum creatinine con(cid:173)
`centrations, glomerular filtration rates, and cumulative doses of
`prednisone administered during the first six months after trans-
`
`162
`
`January 15 ,- 1998
`
`plantation in the two groups were compared with the usc of the
`Wilcoxon rank-sum test. Logistic-regression analysis was used to
`determine the effects of various factors on the probability of bi (cid:173)
`opsy-contirmcd rejection . Proportional-hazards analysis was used
`to determine the effects of various factors o n the rime to biopsv(cid:173)
`confirmed rejection. The results of lymphocyte and interleuki n-
`2-receptor assays were compared with the use of Student's t-tesr.
`All statistical tests were two-sided.
`All patients randomly assigned to a treatment group were in (cid:173)
`cluded in the primary analyses of efficacy and safety, according to
`the intention -to-treat principle. Values arc reported as means ~SD .
`
`RESULTS
`A total of 260 patients were enrolled in the study:
`134 patients were assigned to the placebo group,
`and 126 to the daclizumab group. The two groups
`were similar with respect to age, sex, race, cause of
`end-stage renal disease, presence or absence of pan(cid:173)
`el-reactive anti-HLA antibodjes, number of HLA(cid:173)
`DR mismatches between donor and recipient, and
`duration of cold ischemia for the graft (Table 1 ).
`All patients received at least one dose of the study
`drug, and 107 of the patients in the placebo group
`(80 percent ) and 107 of those in the daclizumab
`group (85 percent) received all five doses. Graft
`function was delayed in 39 patients in the placebo
`group (29 percent) and 27 patients in the daclizu (cid:173)
`mab group (2 1 percent). The early use of prophy(cid:173)
`lactic antilymphocyte therapy for delayed graft fun c(cid:173)
`tion led to the discontinuation of the study drug in
`nine patients in the placebo group (7 percent) and
`nine in the daclizumab group (7 percent).
`
`Efficacy
`Daclizumab prophylaxis resulted in a significant
`reduction in the incidence of biopsy-documented
`acute rejection during the first six months after
`transplantation (22 percent, vs. 35 percent in the
`placebo group; P = 0.03; odds ratio, 0.5; 95 percent
`confidence interval, 0.3 to 0.9 ) (Table 2 ). The pro(cid:173)
`portion of patients with presumptive or biopsy-con(cid:173)
`firmed acute rejection and the number of rejection
`episodes per patient were also lower in the dacli zu (cid:173)
`mab group, and the time to the first rejection vvas
`longer. There was a trend toward a reduction in the
`number of patients with two or more rejection epi (cid:173)
`sodes and the number receiving antilymphocyte prep(cid:173)
`arations for severe rejection in the daclizumab grou p.
`The beneficial effect of daclizumab was not influ(cid:173)
`enced by delayed graft function, initial use of other
`antilymphocyte therapies, or exclusion of patients
`who did not receive all five infusions of the studv
`drug (data not shown).
`The patient-survival rates at one year were 98 per(cid:173)
`cent in the daclizumab group and 96 percent in the
`placebo group (Table 3 ). The graft-survival rates in
`the daclizumab and placebo groups were 95 and 90
`percent, respectively. None of the patients in the da(cid:173)
`clizumab group but three of those in the placebo
`group died of infections: one each of aspergillosis,
`
`BIOEPIS EX. 1038
`Page 3
`
`

`

`INTERLEUKIN-2-RECEPTOR BLOCKADE WITH DACLIZUMAB TO PREVENT REJECTION IN RENAL TRANSPLANTATI ON
`
`TABLE 1. B ASE- LI NE CHARACTEIUSTICS OF RENAL-ALLOGRAFT
`RECIPIENTS . *
`
`TABLE 3. CAUSES OF DEATH AND RENAL-G RAFT
`F AILURE AT O NE YEAR IN THE PLACEBO
`AND D ACLIZUMAB GROUPS .
`
`CHARACTERISTIC
`
`yr
`.-\ge -
`Sex- no. o f patimts (%)
`Male
`Female
`!bee o r ethnic group -
`no . of patients (%)
`White
`Black
`Other
`Cause of renal fJ ilure -
`no. of patients (%)
`Glomerulo nephritis
`Diabetes mellitus
`Hereditary or polycystic kidney disease
`Hypertensio n
`Other
`Panel-reactive serum antibodies -
`no. of patients (% )t
`0- 10%
`11-49%
`50- 100%
`No. of HLA-DR mismatches-
`no. of patients (%):j:
`
`0
`I
`2
`Graft cold-isc hemia time -
`
`hr
`
`PLACEBO
`IN=1341
`
`DACLIZUMAB
`(N=126l
`
`47 :':: 13
`
`47 :':: 13
`
`8 1 (60)
`53 (40 )
`
`74 (59 )
`52 (4 1)
`
`8 1 (60 )
`27 (20 )
`26 ( 19 )
`
`40 (30 )
`29 (22 )
`20 ( I S)
`19 (14)
`26 (19 )
`
`84 (67 )
`24 ( 19 )
`18 ( 14)
`
`33 (26 )
`32 (25 )
`24 (19)
`18 ( 14)
`19 ( IS )
`
`121 (90 )
`10 (7 )
`3 (2)
`
`ll 3 (89 )
`12 (10)
`1 ( 1)
`
`22 (16)
`62 (46 )
`40 (30)
`21:'::9
`
`19 (15 )
`49 (39)
`50 (40 )
`22:'::8
`
`*Plus-minus values are means :':SO. Percentages may not sum to 100
`because of rounding.
`tPanel -reactive antibodies are anti -HLA antibodies that have a cytotoxic
`dfect on lymphocytes obtained from a panel of donors from the general
`population.
`:j:Data were missing for some patients.
`
`TABLE 2. A CUTE REJECTION EPISODES IN THE FI R.ST SIX MONTHS
`AFTER RE NAL T RANSPLANTATION IN THE PLACEBO
`AND D ACLIZUMA!l GROUPS.
`
`REJECTION
`
`One or more biopsy-confirmed
`episodes- no. of patients (%)
`One or more biopsy-confirmed or
`presumptive episodes -
`no. of
`patients (%)
`Two or more biopsy-confirmed or
`no. of
`presumptive episodes -
`patients (%)
`Mean 110. of episodes/ patient
`Time to tirst episode -
`days *
`Episode requiring antilymphocyte
`therapy- 110. of patients (%)t
`
`PLACEBO
`IN=134l
`
`DACLIZUMAB
`IN= 1261
`
`P VALUE
`
`47 (35)
`
`28 (22 )
`
`0.03
`
`52 (39)
`
`32 (25 )
`
`0.04
`
`18 ( 13 )
`
`9 (7)
`
`0.08
`
`0.6
`30:':: 27
`19 ( 14 )
`
`0.3
`73:'::59
`10 (8 )
`
`0.01
`0.008
`0.09
`
`*Plus-minus val ues are means :':SO.
`t Antilymphocyte therapy consisted of OKT3 or polyclonal anti thy·
`mocyte globulin .
`
`CAUSE
`
`PLACEBO
`IN=134l
`
`0ACLIZUMAB
`IN = 126l
`
`no. of patients 1%)
`
`Death
`Infection or lymphoma
`Cardiovascular cause
`Pulmo nary embolism
`Intracerebral bleeding
`Suicide
`Graft fai lure
`Death
`Rejection
`Technical cause
`Primary nonfunction
`
`5 (4)
`3 (2)
`I (1)
`1 (1)
`0
`0
`13 ( 10)
`5 (4 )
`3 (2)
`4 (3)
`1 ( I )
`
`3 (2)
`1 (1)
`0
`0
`1 ( I )
`1 ( I )
`6 (5)
`3 (2)
`1 (1)
`2 (2)
`0
`
`coccidioidomycosis, and pseudomonas sepsis. One
`patient in the daclizumab group died· of lymphoma.
`The mean serum creatinine concentrations six
`months after transplantation were the same in the
`two groups (1.7±0.7 mg per deciliter [150::!:::60 J.Lmol
`per liter] ). The mean glomerular filtration rate was
`55::!:::23 ml per minute in the daclizumab group and
`52±22 ml per minute in the placebo group. The av(cid:173)
`erage daily doses of prednisone and cyclosporine did
`not differ between the groups at any time during the
`study, nor was there a difference in the mean trough
`whole-blood cyclosporine concentrations at any time.
`
`Adverse Events
`The administration of daclizumab was not associ(cid:173)
`ated with any immediate side effects. There was no
`significant difference in reported adverse events be(cid:173)
`tween the two groups (Table 4) . One patient in the
`placebo group and two patients in the daclizumab
`group had lymphoma during the first year after
`transplantation.
`
`Pharmacokinetic Data
`Pharmacokinetic data were available for 92 pa(cid:173)
`tients in the daclizumab group. The mean serum
`half-life of daclizumab was 20 days.
`
`Circulating Peripheral-Blood Lymphocytes
`and lnterleukin-2 a-Chain Receptor
`There were no differences in absolute lymphocyte
`numbers between the placebo and daclizumab groups
`before transplantation or for six months afterward.
`Circulating CD3+ cell concentrations and T-cell sub(cid:173)
`groups were not measured, because they were not
`affected by daclizumab therapy in an earlier study.17
`There was a significant decrease in the percentage
`of circulating lymphocytes that stained with anti-
`
`Volum e 338 Numb e r 3
`
`163
`
`BIOEPIS EX. 1038
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`

`The New England Journal of Medicine
`
`on activated T cells. Use of the drug thus spares oth(cid:173)
`er immunocompetent cells.?
`Only 10 percent of daclizumab is composed of
`murine sequences, which are from the antigen-bind (cid:173)
`ing regions of the parent antibody. These sequences
`are inserted into human immunoglobulin with the
`use of molecular biologic techniques.14 Our study
`highlights the advantages of this type of antibody,
`including its prolonged serum half-life, approaching
`that of human IgG, and the absence of functional
`immunogenicity associated with its use.I 5,I6,I9,2o
`The exact mechanism or mechanisms of action of
`daclizumab are not known . A likely mechanism is that
`it binds to circulating lymphocytes with interleuk.in-2
`a-chain receptors but does not activate the receptors,
`and the cells therefore have no fi·ee interleuk.in-2
`a-chain receptors available tor activation by interleu (cid:173)
`k.in-2. In addition, the decline in the percentage of
`circulating lymphocytes expressing CD25 (measured
`by staining with 7g7 antibody) without an accompa(cid:173)
`nying decrease in the absolute number of lympho(cid:173)
`cytes suggests that the expression of interleukin-2 re(cid:173)
`ceptors is down-regulated or the shedding of the
`daclizumab-bound interleuk.in-2 a chain is increased.
`In conclusion, when added to therapy with cyclo(cid:173)
`sporine, azathioprine, and prednisone, daclizumab
`reduces the frequency of acute rejection and im (cid:173)
`proves short-term graft survival in renal-transplant
`recipients.
`
`Supported by a grant from Hotlinann- LaRoche.
`
`We are indebted to D1: Thomas A. Waldmann for his contribu(cid:173)
`tioll to the developmm t of dac/izumab, and to Ms. Peggy Millar for
`her assistance in the prepamtion of the manuscript.
`
`APPENDIX
`In addition to the authors, the to llowing investigators participated in the
`Daclizumab Triple The rapy Study Group: Victol'ia Gmcml Hospital, Hali(cid:173)
`fax, N.S., C1111ada- B. Kibert; Huddi11ge Hospital, Huddiugc, Swedm (cid:173)
`G. Tyden ; U~tillcrsity of MimJCSotn, Mi>mcapolis - A. Matas; Beth lsmc!
`Deaco1tess Medical Ccutcr, Bostuu - M. Shapiro; Tampa Gmcml Hospital,
`Tampa, Fla. - G. Chan; Vnnco!II'CI' Gmcml Hospital, VmJCO!II'll; B.C.,
`Canada- P Keown; Ut~i11ersity of Califomia, Sau Fm11cisco- M. Lantz;
`UuiPnsity of Alberta, Edmomo11, Alta., Ca11ada - K. Solez; and Hoff'
`mmm-LaRochc, Nutley, N.J. - A. Lin , I. Patel, K. Nieforth , A. Wolitzkv,
`and). Hakimi .
`
`REFERENCES
`
`1. Ferguson R. Acute rejection episodes - best predictor of lon g-term pri ·
`mary cadaveric renal transplant survival. Clin Transplant 1994;8:328-31.
`2. Sollinger HW. Mycophenolate moktil fo r the prevention of acute rejec·
`tio n in primary cadaveric renal allograft recipients. Transplantation 1995 ;
`60:225 -32.
`3. Vincenti F, Laskow DA, Neylan )F, Mendez R, Matas A). One-year fol ·
`low· up from an open -label trial of FK506 in primary kidney transplanta·
`tio n: a report of the U.S. Multicenter FK506 Kidney Transplantation
`
`TABLE 4. ADVERSE EVENTS AT SIX MONTHS
`IN THE P L>.CE!lO AND DACLIZUMAB G ROUPS.
`
`ADVERSE EVENTS
`
`Serious event•
`Fever
`Sepsis and bacteremia
`Pneumonia
`Fungal infection
`Fungemia
`Local infec tion
`Local intectiont
`Cellulitis and wound
`infection
`Urinary tract intCction
`Other
`Any viral infectiont
`Viremia
`Local infection
`Cytomegalovirus
`infection
`Viremia
`Tissue infection
`
`PLACEBO
`IN=134l
`
`0ACLIZUMAB
`IN=126l
`
`no. of patients (%1
`
`13 ( 10 )
`16 ( 12 )
`9 (7 )
`4 (3)
`27 (20 )
`2 ( I )
`25 (19 )
`70 (52 )
`4 (3 )
`
`44 (33 )
`38 (28 )
`32 (24 )
`12 (9 )
`21 (16)
`14 (10)
`
`10 (7)
`4 (3 )
`
`6 (5 )
`II (9 )
`4 (3 )
`3 (2 )
`21 ( 17)
`0
`21 ( 17 )
`59 (47 )
`7 (6 )
`
`34 (27)
`36 (29 )
`29 (23)
`12 ( 10)
`20 ( 16)
`IS ( 12 )
`
`12 ( 10)
`3 (2 )
`
`*Serious adve rse events were defined as complications
`other than death or rejection that prolonged or required
`hospitalization and were possibly or probably rdated to the
`study drug.
`tSome patients had more than one type of infection .
`
`CD25 antibody starting 10 hours after transplanta(cid:173)
`tion and lasting up to four months in the daclizu(cid:173)
`mab group (data not shown). Similarly, there was a
`significant decrease in the percentage of circulating
`lymphocytes that stained with the fluorescein-conju(cid:173)
`gated antibody 7g7, which binds to an interleuk.in-2
`a-chain-receptor epitope distinct from the epitope
`recognized by daclizumab and reflects total interleu(cid:173)
`kin-2a-receptor expression (data not shown) .
`
`DISCUSSION
`We found that the patients receiving daclizumab
`in addition to maintenance therapy with three im(cid:173)
`munosuppressive agents had a lower frequency of
`biopsy-confirmed acute rejection in the first six
`months after transplantation than the patients re(cid:173)
`ceiving placebo with the three immunosuppressive
`agents. In addition, the time to the first episode of
`acute rejection was significantly prolonged, and the
`mean number of episodes per patient significantly
`reduced in the daclizumab group. These results were
`obtained without a concomitant increase in infec(cid:173)
`tious complications or cancers. The efficacy of da(cid:173)
`clizumab is probably related to its selective target,
`the a-chain component of the high-affinity interleu(cid:173)
`k.in-2 receptor, which is present almost exclusively
`
`164
`
`Januar y 15, 1998
`
`I Group. Transplantation 1996;6 1:1576·81.
`
`4. Morris RE . Mtchanisms of action of new immunos u ppress iv~ drugs.
`Kidney lnt Suppl 1996;5 3:S·26- S-38.
`5. Kahan BD. Sirolimus: a new agent lor clinical renal transplanta tion.
`
`j Transplant Proc 1997;29:48 -50.
`
`6. Gruber SA, Chan GLC, Canafax OM, Maras A). Immunosuppression in
`renal transplantatio n. II. Corticosteroids, antilymphocyte globulin, and
`OKT3. Clin Transplant 1991;5:219-32 .
`
`BIOEPIS EX. 1038
`Page 5
`
`

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`8. Kupicc-Wcglinski JW, Diamantstein 1~ Tilney NL, Strom TB. Therapy
`with monoclonal antibody to intcrkukin 2 receptor spares suppressor
`T ...:dis ~1nd prevents or reverses acute allograft rejection in rats. Proc Nat!
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`9. R«d MH , Shapiro ME, Strom TB, et al. Prolongation of primate renal
`allogr.lft survival by ;:mti ·Tac, an anti-human lL-2 receptor monoclonal an (cid:173)
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`10. Soulillou I-P, Cantarovich D, Lc ,V(autl' B, et al. Randomized con(cid:173)
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`( 33 B3.1 ) as compared with rabhit anti thymocyte globulin tor prophy(cid:173)
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`11. Kirkman R.L, Shapiro ME, Carpenter CB, et al. A randomized pro(cid:173)
`spective tri al of anti -Tac monoclonal antibody in human renal transplanta(cid:173)
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`12. van Gelder T, Zictsc R, Mulder AH, et al. A double-blind, placebo(cid:173)
`controlled study of monoclonal anti-intcrkukin-2 receptor antibody
`(BT563 ) administration to prevent acute rejection after kidney trlnsplan(cid:173)
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`13. Reding R, Vraux H , de Ville de Goyer I, ct al. Monoclonal antibodies
`in prophylactic immunosuppression after liver transplantation: a random-
`
`ized controlled trial comparing OKT3 and anti-1L-2 receptor monoclonal
`antibody LO-Tact-1. Transplantation 1993;55:534-4 1.
`14. Queen C, Schneider WP, Sel ick HE, et al. A humani zed antibody that
`binds to the interleukin 2 receptor. Proc Nat! Acad Sci U S A 1989;86:
`10029 -3 3.
`15. Hakimi J, Mou ld D, Waldmann TA, Queen C, A.nasetti C, LightS. De(cid:173)
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`JR, eds. Antibody therapeutics. New York: CRC Press, 1997:277-300.
`16. Hakimi J, Chizzonire R, Luke DR, et al. Reduced immunogenicity
`and improved pharmacokinetics of humanized anti -Tac in cynomolgus
`monkeys. J [mmunol 1991 ;147:1352-9.
`17. Vincenti F, Lantz M, Birnbaum J, et al. A phase l trial of humanized ~
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`18. Fayer BE, Soni PP, Binger MH, Mould DR, Satoh H. Determination
`of humanized anri -Tac in human serum by a sandwich enzyme linked im(cid:173)
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`
`Sunset, Canadian Rockies
`
`ARTH UR H. COHEN, M.D.
`
`Volume 338 Number 3
`
`165
`
`BIOEPIS EX. 1038
`Page 6
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