`Vol.32, No.6
`TRANSPl.A.NTATION
`Printed in U.S. A.
`Copyright© 1981 by The Williams & Wilkins Co.
`TREATMENT OF ACUTE RENAL ALLOGRAFT REJECTION WITH
`OKT3 MONOCLONAL ANTIBODY1
`
`A. BENEDICT COSIMI, ROBERT c. BURTON, ROBERT B. COLVIN, GIDEON GOLDSTEIN,
`ROBERT H. RUBIN, FRANCIS L. DELMONICO, MICHAEL P. LAQUAGLIA, NINA TOLKOFF-RUBIN,
`
`JOHN T. HERRIN, AND PAUL S. RUSSELL
`
`Transplantation-lmmunclogy Unit of General Surgical Services, Massachusetts General Hospital; Departments of Surgery,
`Pathology, Medicine, and Pediatrics, Harvard Medical School, Bosten, Massachusetts; and Ortho Pharmaceutical
`
`Corporation, Raritan, New Jersey
`
`laboratory revealed significant cross-reactivity of some of them
`Eight cadaver donor renal allograft recipients, who
`
`with lymphocytes of subhuman primates. In order to evaluate
`
`had received azathioprine and prednisone from the day
`
`of transplantation, were treated with OKT3 monoclonal
`the possible clinical role of monoclonal antibody as an immuno
`antibody (reactive with all mature peripheral blood T
`suppressive agent, we previously investigated in cynomolgus
`In all
`cells) at the time of diagnosis of acute rejection.
`renal allograft recipients the effects ofOKT4 antibody (6). This
`antibody is reactive with human T cells having major helper/
`
`
`
`cases, loss of essentially all detectable peripheral blood
`
`OKT3-reactive cells was noted within minutes after the
`inducer and T-T collaborative functions (7, 8). By using flow
`initial 1-to 5-mg i.v. in.fusion. Chills and fever invariably
`cytometry for monitoring of peripheral blood lymphocytes, we
`
`occurred following the first or second in.fusion of mono
`defined the dosage and timing ofOKT4 antibody administration
`required to provide in vivo coating of this specific T cell
`clonal antibody, but were not noted during the subse
`quent 10-to 20-day course of therapy, suggesting rapid
`population now in 10 cynomolgus recipients. With a dosage
`cell lysis as the etiology of this toxicity.
`range of 0.5 to 1.0 mg/kg/day, coating of all reactive cells was
`
`The established rejection episode was reversed in all
`cases within 2 to 7 days without addition of any therapy
`observed and residual circulating Ab was usually detectable 24
`other than OKT3 antibody and despite continued low
`hr after administration. When OKT4 therapy was started before
`ering of the steroid dosages. During the subsequent 3-to
`transplantation, allograft survival was extended to as long as 7
`12-month follow-up period, further rejection episodes
`weeks after a 1- to 2-week course ofthe.rapy (control survival 8
`occurred in five of these patients, two of these were
`to 11 days).
`
`
`irreversible with conventional therapy so that six of the
`Encouraged by the effectiveness, ease of administration, and
`lack o( toxicity in this in vivo model, we have begun a trial of
`
`
`eight allografts continue with excellent renal function.
`
`
`These preliminary observations suggest that homoge
`monoclonal antibody therapy in human renal allograft recipi
`
`neity, limited dosage requirements, and ease of in vitro
`ents. Although the ultimate goal is to evaluate only selected T
`monitoring of dosage effects should markedly simplify
`
`the use of monoclonal antibody to T cell populations in
`cell subset suppression, in order to expose the patients in this
`
`human allograft recipients. This second generation of
`initial study to the least risk of ineffective immunosuppression,
`we have tested 0 KT3 antibody which is reactive with all mature
`
`
`
`antilymphocyte preparations offers the potential for not
`
`
`of only increased effectiveness but also the possibility
`human T cells (9, 10).
`
`manipulating specific T cell subsets.
`
`.,.
`
`Although some heterologous antisera to human lymphocytes
`have proved to be effective in delaying or reversing allograft
`rejection (1, 2), the preparation of these agents has been difficult
`using conventional immunization techniques. Even the purified
`IgG fraction from animals immunized with lymphocytes con
`tains not only a heterogeneous group of antibodies to T lym
`phocytes, but also antibodies reactive with other normal cells
`as well as extraneous antibodies reflecting the animal's previous
`. �unological activity (3). Therefore, techniques of developing
`· 'more'specific reagents· have been sought.
`Based upon the recent demonstration by Kohler and Milstein
`(4) that monoclonal antibody to a specific membrane determi
`nant can be reliably produced using cell hybridization tech
`niques, Kung et al (5) have produced a panel of monoclonal
`antibodies specifically. reactive with human lymphocyte sub
`populations. A phylogenetic screen of these reagents in our
`1 This work was supported by United States Public Health Service
`Grant HL/ AM-18646 and by funds provided by the Ortho Pharmaceu
`tical Corporation. Presented at the Seventh Annual Scientific Meeting
`of the American Society of Transplant Surgeons, Chicago, illinois, June
`5 to 7, 198l.
`
`MATERIALS AND METHODS
`Eight cadaver donor renal recipients, who had received aza
`thioprine and prednisone from the time of transplantation, were
`treated with OKT3 monoclonal antibody at the time of diag
`nosis of acute rejection. Allograft rejection was suggested in
`these patients by deterioration in renal function and was con
`firmed in all patients by histopathological evaluation of tissue
`obtained by percutaneous needle biopsy.
`In the attempt to identify the most effective and least toxic
`combination of conventional and OKT3 therapy, se:v.eral dosage
`schedules were pursued. In the first two patients, azathioprine
`was administered in a dosage of 10 mg/kg on the day of
`transplantation and then maintained at 1 to 2 mg/kg/ day unless
`the white blood count fell below 3000/mm3. Prednisone was
`begun at a daily dosage of 2 mg/kg. Beginning on the 5th
`postoperative day, the dosage was decreased by 10 mg/day to
`0.8 mg/kg/day, after which the dosage was more slowly tapered
`to the maintenance dosage of 0.25 mg/kg/day. Following con
`firmation of the diagnosis of rejection, OKT3 antibody was
`administered by bolus i.v. injection in a total daily dosage of 1
`to 2 mg for 10 days. In the next two patients, the azathioprine
`was reduced to 0.75 mg/kg/day and prednisone dosage to 0.6
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`TRANSPLANTATION
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`Vol. 32, No. 6
`
`mg/kg/day during OKT3 therapy which was ad.ministered i.v.
`
`patients, the azathioprine and prednisone dosages were further
`
`in a total daily dosage of 1 to 3 mg for 14 days. In the last four
`reduced to 0.4 mg/kg/day during OKT3 therapy. In these
`patients OKT3 was administered daily for 14 to 20 days at a
`dosage of 4 to 5 mg/day (Fig. 1). After discontinuing OKT3
`therapy, the azathioprine dosage was again increased to 1 to 2
`mg/kg/day in the last six patients.
`
`Prior to transplantation, during azathioprine and prednisone
`therapy, and at frequent intervals after institution of OKT3
`antibody therapy, peripheral blood lymphocytes from buffy
`coat preparations were analyzed for OKT3-reactive cells using
`flow cytometry (JJ). Recipient serum was monitored by incu
`bating sequentially diluted sera with normal human peripheral
`blood lymphocytes, followed by staining with fluoresceinated
`goat anti-mouse antibody, in order to detect and maintain a
`circulating level of OKT3 antibody. Effectiveness of therapy
`was judged by reversal of rejection defined as the day after
`which consistent improvement in renal function occurred. Per
`cutaneous renal biopsies were performed on all patients after
`OKT3 therapy.
`Toxicity was studied by daily monitoring of recipient com
`plete blood count, blood urea nitrogen, and creatinine, weekly
`assays of hepatic function and urine protein excretion, and
`careful observation for any clinical evidence of serum sickness.
`Serial urine, salivary, and buffy coat specimens were cultured
`for viral activity as previously described (12).
`RESULTS
`The clinical course of a representative patient treated with
`OKT3 antibody is depicted in Figure 1. Following cadaver
`donor renal transplantation in this 41-year-old male, the serum
`creatinine level fell to normal levels by the 4th post-transplant
`day. Subsequently, the onset of rejection was suggested by the
`rising serum creatinine level which occurred in conjunction
`with decreased urinary output, weight gain, hypertension, and
`low-grade fever. Allograft biopsy confirmed the diagnosis on
`the 7th post-transplant day and the initial 5-rng dose of OKT3
`antibody was infused i.v. after an i.d. skin challenge was ob
`served to produce no reaction. Approximately 45 min later, an
`
`episode of shaking chills with fever to 101 C occurred. In
`
`addition, the patient complained of shortness of breath and
`diffuse wheezes were noted over the lung fields. These symp
`toms rapidly responded to acetaminophen and antihistamine
`therapy. The patient had no further chills, fever, or other
`adverse reactions with subsequent OKT3 infusions.
`Sequential monitoring of peripheral blood lymphocytes was
`
`begun 15 min after the initial injection. As noted in Figure 1,
`
`there was essentially complete loss of OKT3-reactive cells from
`the peripheral circulation, a condition which persisted through
`out the 14-day course of therapy. That this was not attributable
`
`to masking or modulation of OKT3 antigen was indicated by
`
`the failure of fluorescein conjugates of OKT4 and OKT8 mono
`clonal antibodies, which bind to other T cell antigens (11), to
`
`react with the residual cells. In addition, detectable antibody
`
`excess was present throughout the course of therapy during
`which a total dosage of 70 mg of OKT3 antibody was adminis
`tered.
`The serum creatinine level continued to rise for several days
`after institution of therapy but the patient's clinical condition
`rapidly improved with diuresis, weight loss, and improved con
`trol of blood pressure being noted within 36 hr of initiation of
`
`RR.
`C.D. Renal Allograft
`
`3
`
`2
`
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`20
`25
`5
`10
`15
`DAYS POST TRANSPLANT
`FIGURE l. Clinical course of renal allograft recipient treated for
`acute rejection with OKT3 monoclonal antibody. A dramatic and
`sustained depletion of peripheral blood OKT3-reactive cells and return
`of normal renal function occurred despite rapid tapering of aw.thioprine
`and steroid dosages.
`
`treatment. Continuous improvement in renal function began 72
`hr after OKT3 treatment was initiated with the serum creati
`
`nine eventually stabilizing at 1.3 mg/100 ml As depicted in
`
`Figure 1, the azathioprine and steroid dosages were rapidly
`tapered during this period. A second allograft biopsy performed
`on the last day of therapy showed essentially complete resolu
`tion of the histopathological findings of rejection (Fig. 2).
`The initial results of treatment of the eight patients studied
`arc summarized in Tables 1 and 2. In every instance, the
`rejection episode for which OKT3 the.rapy was instituted was
`reversed with steady improvement in allograft function begin
`ning after 2 to 7 days of therapy. In the first three patients and
`the last patient treated, a subsequent rejection episode occurred
`beginning 2 to 6 weeks after cessation of OKT3 therapy while
`the patients were being maintained on azathioprine and pred
`nisone. These episodes were easily reversed in three of these
`patients with increased steroids. The second rejection episode
`in patient 3, however, could not be reversed despite increased
`
`steroids, local irradiation, and actinomycin D therapy. She
`
`2 of 5
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`BI Exhibit 1025
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`December, 1981
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`COSIMI ET AL.
`
`537
`
`returned to dialysis 2 months after transplantation. She subse
`quently developed severe cytomegalovirus infection and expired
`3 months after transplantation.
`Patient 4 is of particular interest because of the development
`during therapy of an antibody response to the OKT3 reagent.
`During the initial 10 days of therapy, peripheral blood T cell
`monitoring of this patient revealed essentially complete loss of
`cells reactive with OKT3 antibody, and allograft function stead
`ily improved from a peak serum creatinine of 8.1to2.9 mg/100
`ml. During the final 4 days of OKT3 therapy, however, large
`numbers of OKT3-reactive cells were repeatedly demonstrable
`in the patient's peripheral blood and no serum excess of OKT3
`could be achieved even after the dosage of monoclonal antibody
`had been increased from 2 to 5 mg/day. At the time, the steadily
`falling serum creatinine again began to rise and allograft biopsy
`revealed extensive evidence of acute rejection. The immuno
`suppressive protocol was immediately changed to conventional
`therapy with high-dose steroids, local irradiation, and actino
`mycin D; but the rejection process continued, necessitating
`allograft nephrectomy 31 days after transplantation. Evaluation
`of serial serum samples from this patient by flow cytometry
`documented the appearance of anti-OKT3 antibody initially on
`day 10 of therapy with the titer peaking 5 days after therapy
`was discontinued. Characterization of these antibodies will be
`reported in detail elsewhere. No evidence of serum sickness or
`anaphylaxis was noted at any time in this patient.
`Therefore, six of the eight allografts continue with excellent
`renal function 3 to 12 months after OKT3 treatment. All of the
`patients treated with OKT3 antibody developed chills and fever
`
`1''1GURE 2. Histopathological picture of renal allograft biopsies be
`fore (left) and after (right) OKT3 monoclonal antibody therapy. Almost
`complete disappearance of the interstitial mononuclear infiltrate and
`reversal of endothelial damage is noted after treatment.
`
`2
`3
`4
`5
`6
`
`Weight
`
`Male
`Female
`Male
`Male
`Female
`
`matched
`
`0
`1
`1
`1
`2
`2
`
`1
`0
`
`(months
`12
`12
`Sb
`3"
`6
`6
`
`4
`3
`
`TABLE 1. Cadaver donor renal allograft recipients treated for acute rejection with OKT3 monoclonal antibody
`Follow·uf
`HLA antigens
`Sex
`Etiology of renal disease
`Patient Age
`(kg)
`Female 55
`16
`IgA nephropathy
`52
`N ephrosclerosis
`76
`59
`50
`I ntcrstitial nephritis
`41
`Chronic glomerulonephritis
`70
`41
`Chronic glomerulonephritis
`78
`Dysplasia + focal sclerosing
`39
`55
`glomerulonephritis
`Chronic glomerulonephritis + diabetes
`52
`7
`56
`Male
`8
`40
`51
`Polycystic renal disease
`Female
`0 Expired with cytomegalovirus infection after second rejection episode.
`
`b Maintained on dialysis after loss of allograft during second rejection episode.
`
`TABLE 2. Results of treatment of acute rejection with OKT3 monoclonal antibody
`Total OKT3
`Days to
`Post·
`Prerejection
`Post-therapy
`Patient transplant
`creatinine Peak
`creatinine reversal creatinine Mg
`day of
`(mg/lOOml)
`rejection
`6
`1
`1.6
`1.9
`16
`2
`1.6
`8
`3
`4
`9
`5.0
`7
`5
`1.6
`6
`6
`2.9
`3.0
`7
`6
`8
`9
`10.4'
`•Reversed with conventional immunosuppression.
`6 Irreversible using conventional immunosuppression.
`< On hemodialysis.
`
`5.4
`4.8
`4.3
`8.1'
`5-8
`8.5
`8.1'
`11.3"
`
`4
`2
`2
`2
`2
`5
`4
`7
`
`1.3
`1.6
`0.9
`2.9
`1.3
`0.9
`1.2
`u
`
`13
`20
`18
`34
`
`70
`57
`90
`100
`
`Days
`
`Subsequenl
`rejection
`episode
`
`10
`10
`15
`14
`14
`14
`17
`20
`
`Yes"
`Yesn
`Yesb
`Yes6
`No
`No
`No
`Yes0
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`to as high as 102 C within 1 hr of the first injection, and several
`were noted to have diffuse wheezing during this period. No
`reactions to subsequent injections were noted and no other
`evidence of toxicity could be identified.
`The effective removal of OKT3-reactive cells (mature T
`lymphocytes) from the circulation within minutes after infusion
`of OKT3 antibody was clearly documented by flow cytometry
`analysis in each case. This dramatic lysis of cells occurred only
`with the first injection, the OKT3-reactive population then
`remaining depressed (except in patient 4) throughout the course
`of therapy.
`
`Vol. 32, No. 6
`long-term allograft survival can be
`improved
`Whether
`achieved with such therapy remains to be established; however,
`some observations regarding the addition of monoclonal anti
`body to conventional therapy can be made. In the first four
`patients, the attempt was made to use the minimum total
`irnmunosuppression which would produce reversal of the rejec
`tion episode. Thus, the dosage of OKT3 antibody administered
`was limited to that (1 to 2 mg/day) which maintained a barely
`detectable serum antibody level. In each case, except patient 4
`who developed anti-OKT3 antibodies, all clinical manifestations
`of rejection were abolished. However, post-therapy allograft
`biopsies showed persistent cellular infiltration and recurrent
`rejection requiring conventional high-dose steroid therapy ap
`DISCUSSION
`peared within 2 to 6 weeks. All of these patients subsequently
`A central problem in transplantation remains that of incom-
`suffered significant oral infection secondary to herpes simplex
`pletely controlled rejection. Intense, nonspecific suppression of virus and cytomegalovirus pnewnonitis was documented after
`the second rejection episode in two of the patients, one of whom
`the recipient's immune system is produced with currently used
`·agents but the level of clinical success and toxicity has changed
`subsequently died. These observations appear to emphasize the
`little over the past decade. The only significant addition to this previously proposed concept that a modestly high-dose "net
`regimen has been the gradual acceptance of heterologous anti-
`state of immunosuppression" over a prolonged period of time is
`lymphocyte preparations such as antilymphocyte globulin, an-
`probably of greater risk to patients than a limited, more inten
`tithymocyte globulin (ATG), etc. (13), with which a more
`sive course of therapy (12). In the next four patients, therefore,
`selective suppression of the recipient's cellular immune re-
`the dosage of OKT3 antibody was sharply increased in an
`sponses is anticipated. However, with currently available attempt to reverse more definitively the rejection activ.ity dur
`ing a limited period of therapy. In addition, as in our studies
`agents, prepared by routine immunization techniques, only 5 to
`10% of the total dose administered represents the actual ther- with ATG (14), we have continued to try to limit the dosages of
`apeutic product. As hybridoma technology bas developed, the azathioprine and prednisone administered during the period in
`possibility of producing anti-T cell monoclonal antibodies with which the patients received OKT3 antibody. To date, the
`effecti�ness similar to currently used ATG preparations but
`clinical course in these patients has been much more satisfac
`which are active in much smaller quantities has been realized. tory.
`Furthermore, the feasibility of using antibodies to suppress
`Unacceptable in vivo toxicity of monoclonal antibody admin
`selected T cell subsets rather than the entire population can
`istration has not been observed. The chills, febrile response,
`now be tested.
`and occasional wheezing noted on the first day of treatment
`The results of our studies have begun to delineate the in vivo have been found to be readily controlled with antihistamine
`effects of such reagents. We have observed significant immu-
`and acetaminophen therapy. These symptoms have been noted
`nosuppression in subhuman primate renal allograft recipients with ATG treatment as well (15) and have been thought to be
`receiving relatively minute quantities of monoclonal antibody
`(total recipient dosage: 17 to 56 mg compared with 50 to 100
`secondary to release of endogenous pyrogens following exten
`sive lysis of peripheral blood lymphocytes. The observations in
`mg/kg/ day (14) when using heterologous ATG preparations)·
`the patients treated with OKT3 antibody would tend to support
`Moreover, the OKT4 antibody administered to these recipients
`such an explanation, for the chills and fever were noted only
`has been shown to be directed only to the helper/inducer T cell
`subset, reacting with approximately 50 to 60% of human pe-
`after the first infusion concomitant with the dramatic drop in
`the number of circulating T lymphocytes. Subsequent infusions
`ripheral blood T cells and 45 ± 9% of cynomolgus T cells. These were tolerated without similar incidents. It is hoped that later
`observations demonstrate not only the immunosuppressive po- morbidity, primarily infection, can be minimized if an appro
`tency of monoclonal antibody..but also that effective prQtoc�� .,,priate dosage of monoclonal antibody can be defined which will
`may be developed in which the requirement for agents, which . maximize control of rejection without the addition of other
`produce indiscriminate T cell depression, might be markedly agents. It might then be anticipated that long-term morbidity
`reduced.
`would be less than with conventional therapy, since it is gen-
`In our previous clinical evaluation of equine ATG, we have
`erally accepted that serious complications are most likely to
`found the most definitive means of demonstrating effectiveness occur when large doses of steroids are required to reverse
`was in studies in which ATG alone was added to the immuno.
`· ·:
`··rejection activity.
`.
`.
`,. ·
`. , , ,
`suppressive protocol at the time of diagnosis of acute rejection
`In conclusion, these observations suggest that the homoge-
`(2). Since only a single agent is being used to reverse a readily neity, limited dosage requirements, and ease of in vitro moni
`defined event, it is possible to elucidate immediately the effect
`toring of the effects of monoclonal antibody upon T cell popu-
`of the added therapy without the need for long-term random-
`lations in the peripheral blood will simplify their application to
`ized trials. Thus, we have pursued a similar model for the patient management. Although, to date, only a reagent reactive
`evaluation of monoclonal antibody. We have selected OKT3 with all peripheral blood T cells has been evaluated in patients,
`antibody rather than antibody to a T cell subpopulation in
`the possibility of manipulating selected T cell subsets is now at
`order to reduce the likelihood of inadequate suppression in this hand.
`initial trial. Our most important clinical observation in the
`patients treated to date has been the initial reversal in all cases
`of the established rejection episode without addition of any
`therapy other than OKT3 antibody and despite continued
`lowering of the steroid dosage.
`
`1. Thomas F, Thomas J, Flora R, Mendez-Picon G, Peace K, Lee
`
`LITERATURE CITED
`
`HM. Effect of antilymphocyte-globulin potency on survival of
`cadaver renal transplants. Lancet 1977; 2: 671.
`
`4 of 5
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`2. Shield CF, Cosimi AB, Rubin RH, Tolkoff-Rubin NE, Herrin J,
`Russell PS. Use of antithymocyte globulin for reversal of acute
`allograft rejection. Transplantation 1979; 28: 461.
`3. Skamene E, Russell PS. A quantitative study of the binding of ALS
`to various cell types. Clin Exp Immunol 1971; 8: 195.
`4. Kohler G, Milstein C. Continuous cultures of fused cells secreting
`5. Kung PC, Talle MA, DeMaria ME, Butler MS, Lifter J, Goldstein
`antibody of predefined specificity. Nature 1975; 256: 495.
`
`G. Strategies for generating monoclonal antibodies defining hu
`man T lymphocyte differentiation antigens. Transplant Proc
`1980; 12: 141.
`6. Cosimi AB, Burton RC, Kung PC, et al. Evaluation in primate
`renal allograft recipients of monoclonal antibody to human T
`cell sub-classes. Transplant Proc 1981; 13: 499.
`7. Reinherz EL, Kung PC, Goldstein G, Schlossman SF. Flll'ther
`characterization of the human inducer T cell subset defined by
`monoclonal antibody. J Immunol 1979; 123: 2894.
`8. Thomas Y, Sosman J, Irigoyen 0, et al. Functional analysis of
`
`human T cell subsets defined by monoclonal antibodies. I. Col
`laborative T-T interactions in the immunoregulation of B cell
`differentiation. J Immunol 1980; 125: 2402.
`9. Kung PC, Goldstein G, Reinherz EL, Schlossman SF. Monoclonal
`
`539
`COSIMI ET AL.
`antibodies defining distinctive human T-cell surface antigens.
`Science 1979; 206: 347.
`10. Chang TW, Kung PC, Gingras SP, Goldstein G. Does OKT3 mono
`clonal antibody react with an antigen-recognition structure on
`
`human T cells? Proc Natl Acad Sci USA 1981; 78: 1805.
`11. Cosimi AB, Colvin RB, Blll'ton RC, et al. Use of monoclonal
`antibodies to T-cell subsets for immunologic monitoring and
`treatment in recipients of renal allografts. N Engl J Med 1981;
`12. Rubin RH, Cosimi AB, Hirsch MS, et al. Effects of antithymocyte
`305: 308.
`globulin on cytomegalovirus in renal transplant recipients. Trans
`plantation 1981; 31: 143.
`13. Cosimi AB. The clinical value of anti-lymphocyte antibodies.
`Transplant P:roc 1981; 13: 462.
`14. Cosimi AB, Shield CF, Peters C, Burton R, Scott G, Russell PS.
`Prolongation of allograft survival by cyclosporin A. Surg Forum
`1979; 30: 287.
`15. Cosimi AB, Wortis HH, Delmonico FL, Russell PS. Randomized
`clinical trial of ATG in cadaver renal allograft recipients: Impor
`
`tance of T-cell monitoring. Surgery 1976; 80: 155.
`Received 8 June 1981.
`Accepted 10 September 1981.
`
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