Nuclear Medicine Communications 9, 919-930 (1988)
`
`Human immunological response to mouse
`
`
`monoclonal antibodies in the treatment or
`diagnosis of malignant diseases
`
`M.J.P.G. VAN KROONENBURGH and E.K.J. PAUWELS
`
`Department of Diagnostic Radiologij, Division of Nuclear Medicine, University Hospital Leiden, 2300
`RC Leiden, Tile Netlierlands
`
`Received 8 March 1988
`
`Summary
`An overview of the literature is presented concerning the formation, detection, incidence and
`effect of the human immunoglobulin response on immunoscintigraphy. The following conclu­
`sions are drawn. The production of human anti-mouse antibodies (HAMAs) is associated with
`a diminished therapeutic response; adequate prevention of HAMA production is not yet poss­
`ible; high HAMA titres give rise to rapid clearance of MoAb into the liver and marked reduction
`of tumour uptake which results in reduced image quality on immunoscintigraphy; alteration
`of antibody biodistribution is likely to be related to the 111 vivo formation of antibody-antibody
`complexes which could interfere with image quality when sequential imaging is carried out.
`
`Introduction
`
`Monoclonal antibodies have been used for more than a decade in biomedical research.
`One of the most exciting and promising areas of research is the use of specific mono­
`clonal antibody radionuclide conjugates for diagnostic imaging (immunoscintigraphy)
`and therapy for malignant diseases. When these monoclonal antibodies (MoAbs),
`most of which are developed from mouse hybridomas, are injected into the patient,
`they are recognized as foreign globulins.
`The resulting immune response leads to the development of human anti-mouse
`antibodies (HAMAs), which can be of practical significance. Once HAMAs have been
`induced, they are able to neutralize the effects of the MoAbs. Since repeated injections
`lead to rising HAMA concentrations, the efficacy of this approach may be short-lived.
`As this is regarded as a major complication of the use of MoAbs for clinical purposes,
`it is essential to establish the scope of the problem of the production of HAMAs.
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`This paper attempts to present an overview of the literature concerning the forma­
`tion, detection and incidence as well as the effect of the human immunoglobulin
`antibody response on immunoscintigraphy.
`
`Findings in the literature
`
`Human anti-mouse antibodies (HAMAs)
`When a normal individual is exposed for the first time to a foreign antigen, there is
`a lag phase that may last as long as 10-12 days before antibodies appear in the serum.
`This primary immune response consists in general of IgM antibodies. Subsequent
`encounters with the same antigen usually evoke an enhanced secondary or memory
`response characterized by marked production of IgG (1).
`Every antibody has fundamentally the same structure in that it consists of a heavy
`and a light chain; it also contains a variable and a constant region which may act as
`antigenic determinants. The antigenic constituents of the variable region of an im­
`munoglobulin are known as its idiotype. The part of the variable region which forms
`its specific binding site is called its paratope. Thus, it is possible to distinguish between
`anti-idiotypes directed against idiotypes within the binding site (anti-paratopic) and
`those directed against idiotypes outside the binding site. Only those binding to the
`antigen-binding site inhibit the interaction between that binding site and the antigen.
`Antibodies directed against the constant region are called anti-isotopic antibodies.
`Jerne (2) postulated a network of interacting antibody molecules and lymphocytes in
`which idiotypes of antibody molecules are recognized by anti-idiotopic (AB2) antibodies.
`This AB2 response is probably a very important part of the human immunological
`response. The immune system may be regulated at least in part by a network of
`interactions between idiotypes and anti-idiotypes. He also suggested that AB2 antibodies
`may exert a strong inhibitory effect on B cell clones during the immune response. Of
`interest is the fact that injection of these AB2 antibodies into the patient can also give
`rise to HAMAs (3). Moreover, AB2 antibodies already present in the body have been
`shown to be potent enhancers or inhibitors of the immune system.
`It is known that healthy individuals possess antibodies against various animal
`proteins (4) and the patients with various malignancies are able to produce a range
`of antibodies (5). There are many reports in the literature concerning the presence of
`pre-treatment anti-mouse antibodies (6-15). Naturally occurring anti-mouse activity
`was demonstrated in the serum of 990 of 1008 healthy blood donors by Thompson
`et al. (10). The aetiology of these pre-existing HAMA levels could be vaccination in
`the past, animal handling or dietary exposure. Another plausible explanation came
`from Shawler e� al. (16), who suggested that such HAMA levels are probably related
`to the sensitivity of the assay and represent nothing more than background levels
`caused by non-specific human immunoglobulin. The HAMA levels found by Ritter
`et al. (17) in normal serum were equivalent to the level of endogenous anti-human
`immunoglobulin (rheumatoid factor) also found in normal serum [18). It is therefore
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`reasonable to suppose that pre-existing HAMA levels may merely reflect a facet of
`the nonnal immune system. The question of when an HAMA level should be considered
`indicative of HAMA production should therefore be dependent upon the upper limit
`of normal. Carrasquillo et al. (19] consider a patient HAMA-positive when the percen­
`tage binding is at least 3 s.o. greater than the mean for normal individuals. The variety
`of methods and techniques currently in use for detecting the human anti-mouse
`antibody response in serum, i.e. radioimmunoassays (RIA), enzyme-linked im­
`munoabsorbent assays (ELISA), haemagglutination tests (HAT) and immunofluor­
`escence assays (IF), makes it difficult to estimate the mean value for normal individuals.
`According to the literature, HAMAs are first detected after day 2 (20]. However,
`the moment of first detection is highly variable, as illustrated by Goodman et al. [14]
`who even found the first detectable HAMA level 233 days after treatment. Therefore,
`in other studies more patients might have been found to be HAMA-positive if serum
`samples had been taken at a later stage. The antiglobulin response consists mainly
`of IgG antibodies, although IgM antibodies have also been observed [7, 9, 11, 15,
`21-23]. The rapid elevation of the antiglobulin level reported by several authors (7,
`9, 11, 12, 24, 25] is consistent with the kinetics of a secondary immune response, but
`in general HAMA production occurs 2-3 weeks after MoAb injection; the levels
`subsequently decrease gradually in the course of several weeks. However, as men­
`tioned above, HAMAs have been detected for up to 300 days after MoAb administra­
`tion; in fact, in one case an AB2 response persisted [26] for more than 770 days. The
`fact that antiglobulin levels do not recur indicates that feedback inhibition of the
`globulin response probably does not occur (9].
`The first investigations of the specificity of the antiglobulin response suggested that
`the response was directed mainly (95%) against the constant region of the MoAb
`(anti-isotopic), while a minority of the antibodies was directed against the variable
`region (anti-idiotopic) of the MoAb (7, 11, 27]. However, in man, 50% of the patients
`receiving the 17-lA monoclonal antibody against a colon carcinoma antigen exhibited
`an anti-idiotopic AB2 response [28]. Recently, more authors have found that a relatively
`high percentage of the responses is anti-idiotopic (14, 15, 26, 29]. The difference in
`results is not yet understood. It is possible that a large percentage of AB2 is followed
`by anti-anti-idiotopic antibodies (AB3), which could hamper detection of the AB2;
`another explanation is that the AB2 response is dependent on the type of MoAb.
`Shawler et al. (15] suggest that multiple infusions of a single MoAb will result in a
`marked specific response, while infusion of two or more monoclonal antibodies may
`induce only anti-isotopic antibodies.
`
`Variables which influence the development of ltuman anti�mouse antibodies
`Of primary interest is the group of variables that determine why some individuals
`develop an antiglobulin response during immunoscintigraphy or immunotherapy
`while many others do not. Shawler et al. [15] were unable to correlate the lack of
`response to a large number of clinical parameters, and it still remains difficult to
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`predict on the basis of clinical data which patients will develop antibodies. Although
`the development of HAMAs is not related to skin-test positivity [8, 11], the outcome
`of lymphoproliferative assays [30] or previous therapy, there are some variables that
`presumably do influence HAMA production.
`
`Table 1. Incidence of HAMAs in patients receiving labelled antibodies for
`immunoscintigraphy.
`
`Autlwrs
`
`Larson et nl. [38)
`Carrasquilloetnl. [50)
`Reynoldsetnl. [51)
`Engelstad etnl. [22)
`
`Reynolds ct nl. [32]
`Carrasquilloctnl. [52)
`Rosenetnl. [21]
`
`Reynoldsclnl. [32]
`Murray ctn/. (13]
`
`Yenr
`
`1983
`1983
`1985
`1986
`
`1986
`1987
`1987
`
`1986
`1987
`
`Mo Ab
`
`Pnt/HAMN Frequency (o/o)
`
`96.5
`96.5
`96.5
`96.5
`TlOl
`TlOl
`TlOl
`672.3
`ZME018
`
`6/3
`3/3
`37/12
`6/3
`
`20/6
`410
`6/6
`
`30/15
`1717
`
`50
`100
`32
`50
`30
`0
`100
`
`50
`41
`
`'No. of evaluable patients in the study/incidence of HAMAs.
`
`In the first place, it has been observed (31] that HAMAs are seldom encountered
`in patients with B cell malignancies but are frequently found in patients with T-cell
`· or solid tumours. The variation in the incidence of HAMAs (see Tables 1 and 2)
`probably depends on the immunocompetence of the subjects. This is illustrated by
`the fact that out of six patients with chronic lymphocytic leukaemia none exhibited
`an immune response to MoAb TlOl (an anti-human T-cell monoclonal antibody)
`whereas five out of ten patients with cutaneous T-cell lymphoma had measurable
`HAMA activity [15]. Moreover, the immune system of patients with less advanced
`disease might be expected to be more competent so that the likelihood that HAMAs
`will develop would be greater. Theoretically, it is feasible that healthy humans should
`have a 100% response rate to murine MoAbs. In the second place, mouse whole
`antibody is more immunogenic than the Fab fragment [32]. However, it has been
`shown that repeated administration of the murine Fab fragment will also lead to a
`high frequency of HAMA positivity [15, 19, 20, 24, 26]. In addition, the development
`of HAMAs may be dose-dependent [9, 20, 21, 28, 30, 33]. Eight out of nine patients
`who were given less than 200 mg MoAb developed HAMAs compared with only one
`out of nine receiving higher doses, suggesting that larger doses of MoAb could induce
`tolerance for murine immunoglobulin (20]. Essentially the same observation was re­
`ported by Oldham et al. [9], who found mea·surable increases in anti-globulin response
`after administration of 50 mg doses and a loss of demonstrable antiglobulin at higher
`doses. Herlyn et al. (26] were not able to confirm this correlation but found instead
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`Table 2. Incidence of HAMAs in patients undergoing immunotherapy.
`
`Authors
`
`Year
`
`MoAb
`
`Pat/HAMA*
`
`Freq11c11cy (o/o)
`
`Milleretal. (53]
`Miller ct al. [7]
`Miller et al. [27]
`Sears et al. [24]
`Koprowski ct nl. [28]
`Sears eta/. [20]
`Sears cf nl. {29]
`Herlyncfa/. [26]
`Herlyn ct nl. {26]
`Sears cf al. (33]
`Sindelar ct nl. (25]
`Lobuglio ct nl. (39]
`Frodincta/. [23)
`Douillardetn/. (60]
`Steplewskiefn/. [61)
`Dillman ct nl. (54]
`Dillman eta/. [56]
`Dillman ct al. [57]
`Bunn ct al. (58]
`Foonefa/. [12)
`Dillman ct al. [36]
`Schroffeln/. [11)
`Shawler ct al. (15)
`Bertram et nl. (30)
`Rosen el nl. (21]
`Miller cl al. [40]
`Meeker et al. (3]
`Ball eta/. (55]
`Linch ct nl. (37)
`Carrasquillo et al. (19]
`Goodman eta/. (14]
`Oldham et al. (9)
`Houghton ct nl. [59)
`Press ct a/. (31)
`
`1981
`1981
`1983
`1982
`1984
`1984
`1985
`1986
`1986
`1986
`1986
`1986
`1986
`1986
`1986
`1982
`1983
`1983
`1983
`1984
`1984
`1985
`1985
`1986
`1987
`1982
`1985
`1983
`1983
`1984
`1985
`1984
`1985
`1987
`
`Leu-1
`Leu-1
`Leu-1
`17-lA
`17-lA
`17-lA
`17-lA
`17-lA
`17-lA
`17-lA
`17-lA
`17-lA
`17-lA
`17-lA
`17-lA
`TlOl
`TlOl
`TlOl
`TlOl
`TlOl
`T101
`TlOl
`T101
`TlOl
`T101
`Anti-idio
`Anti-idio
`PM81, PMN29
`UCHTl,2
`48.7
`96.5; 48.7
`9.2.27
`R24
`1F5
`
`111
`1/0
`7/4
`
`4/3
`29/10
`18/9
`20/10
`42/21
`37/32
`65/35
`25/23
`20/17
`8/8
`20/11
`4/3
`2/0
`6/4
`2/0
`5/4
`13/0
`8/2
`24/7
`16/5
`13/3
`515
`1/0
`11/5
`3/1
`1/1
`8/5
`4/4
`8/3
`12/12
`411
`
`100
`0
`57
`75
`34
`50
`50
`50
`86
`54
`92
`85
`100
`55
`75
`0
`66
`0
`80
`0
`25
`29
`31
`23
`100
`0
`45
`33
`100
`62
`100
`38
`100
`25
`
`•No. of evaluable patients in the study/incidence of HAMAs.
`
`a positive correlation between the number of injections and the occurrence of HAMAs.
`In addition to the dose of MoAb and the number of injections, the time interval
`between injections (treatment schedule) has also been associated [19, 20) with HAMA
`production. Finally, differences in response may be related to pre-existing antiglobulin
`level [11) or the route of-administration. Reynolds et al. [32) suggest that there is no
`apparent difference in HAMA development when an antibody is given subcutaneously
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`or intravenously. It is interesting that interstitial administration of MoAbs increased
`anti-mouse activity [22], whereas a similar dose of the MoAb given intravenously
`could not be associated with increasing HAMA levels.
`
`Effect of lmman anti-mouse antibodies
`Radioimmunotherapy studies indicate that immune complexes may form in the pres­
`ence of circulating free antigen. HAMA may also form complexes with the injected
`MoAb, probably in direct proportion to the HAMA concentration [34, 35]. On the
`other hand, Oldham et al. [9] showed that only one out of eight patients exhibited
`HAMA-MoAb complexes. The consequences of complex formation, should it occur,
`are likely to depend upon the patient, the type of malignancy and the MoAb used.
`The formation of complexes of MoAbs and the circulating target cells has been as­
`sociated with serum sickness, renal toxicity and various adverse reactions that could
`inhibit effective antibody therapy or imaging [9]. Although Bertram ct al. [30] described
`a patient with an anaphylactoid reaction associated with the development of HAMAs,
`it should be noted that patients with HAMAs generally exhibit no toxicity whatsoever,
`presumably because of the blocking effect of the antibody [36, 37].
`The bioavailability of a MoAb for a tumour depends on the MoAb dose, the levels
`of circulating antigen and antigen expression of the tumour, the kinetics of antigen
`modulation and the presence of HAMAs. It has been demonstrated by Linch et al.
`[37] that therapeutic failure is attributable to the appearance of anti-mouse antibodies
`and not to antigenic modulation. The development of antibodies against mouse im­
`inunoglobulin Jed to a marked decrease in the levels of circulating mouse immuno­
`globulin (24, 39]. Free antibodies could no longer be detected after the development
`of HAMAs [27]. HAMAs are able to consume antibodies, thus preventing the binding
`of these antibodies to cellular antigens [3, 15, 24, 27, 30, 36, 37]. It is therefore obvious
`that anti-mouse antibodies eventually neutralize the therapeutic effect of MoAbs.
`Once an immune response begins, further infusions of antibody are not capable of
`inducing tumour regression. However, the results of Oldham ct al. [9] indicate that
`murine antibody can be given in repeated doses to immunologically intact patients
`with a solid tumour without eliciting a therapeutically limiting anti-globulin response.
`Miller et al. [27] showed that host antibodies cquld block the binding of anti-Leu-1 to
`target cells in vitro. Similarly, host antibodies may neutralize the in vivo and in vitro
`effects of MoAbs, probably by increasing the removal of these antibodies and/or by
`blocking.
`Some MoAb clinical trials have led to the suggestion that an immune response
`against the murine immunoglobulin could be beneficial (28]. This is based on the
`report of Miller et al. (40], who described very successful treatment of a patient with
`progressive lymphocytic lymphoma, and on the theoretical consideration that second
`(AB2) and third (AB3) order antibodies with tumour-binding activities will ultimately
`induce an immune attack by the host against the tumour. It is possible that the AB2
`antibody will trigger an active anti-tumour response in the regulatory immune network
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`[3). It has been reported that the anti-idiotopic response correlates with clinical re­
`sponses [3, 26, 28, 40), but according to Lowder ct nl. [41) and Sindelar ct nl. [25) there
`is no relation between AB3 and clinical response. While anti-idiotypes may be used
`in the future to advantage for therapeutic purposes, they also limit the more straightfor­
`ward use of mouse antibodies for immunosuppression.
`The production of HAMAs will cause changes in the pharmacokinetic behaviour
`of MoAbs. It is postulated that HAMAs stimulate the removal of MoAbs by the
`reticuloendothelial system. Patients with detectable HAMA levels cleared the labelled
`mouse antibody much more rapidly than those without HAMAs [27, 38). Rosen et
`nl. [21) reported that the HAMA response is most probably responsible for the en­
`hanced antibody clearance rates seen after retreatment. This effect has been observed
`using radiolabelled MoAbs. Radiolabelled MoAbs are currently in use for diagnostic
`imaging of tumours. Low doses ( < 10 mg) of MoAbs are labelled with radioisotopes
`suited for external gamma scintigraphy. In most cases a single injection of the
`radiolabelled MoAb is adequate for tumour imaging. However, when sequential im­
`aging is performed multiple injections are necessary. In that case the uptake in the
`liver can be significantly higher on the second occasion and the tumour uptake could
`be less marked [38) which could result in reduced image quality [42-45).
`Another effect, which has been described extensively [46), is positive interference
`of the HAMAs with the effectiveness of two-site immunoassays. These artefacts have
`been observed in both monoclonal and polyclonal sandwich-type immunoassays.
`
`Prevention of /111111nn n11ti-mousc antibodies
`Many investigators hope that human monoclonal antibodies or recombinant chimeric
`antibodies, obtained by chemical coupling of the mouse variable region to the human
`constant region by genetic engineering, will be the key to preventing the immunogenic­
`ity associated with immunoglobulins. Although it has been suggested that human
`monoclonal antibodies could reduce the immune response, the work of Shawler et
`nl. (15] implies that such antibodies might still induce anti-idiotype antibodies. The
`immunogenicity in man of human monoclonal as well as chimeric antibodies has not
`yet been tested.
`Because of the relationship between immunocompetence and the likelihood of
`HAMA development, Miller et nl. [27] tried to prevent the occurrence of HAMAs by
`giving cyclophosphamide during MoAb treatment. The result was not successful. The
`use of concurrent therapies, such as chemotherapy [47], radiotherapy or immunosup­
`pressive drugs [48], to suppress the response or produce immunologic tolerance has
`had some effect in reducing HAMA levels. The initial administration of large doses
`of highly purified monoclonal antibodies might induce tolerance [20], while the proper
`dose and treatment schedule could mimic the effects of HAMA production [21, 30].
`Goodman et nl. [14] reported that a loading dose, that produces high plasma concen­
`trations, followed by a maintenance dose every 48 h resulted in a lack of HAMA
`development. The application of plasmapheresis or affinity columns to lower the
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`amounts of free antigen or eliminate the HAMAs formed [3, 7, 19, 21, 49] has been
`reported to be successful [21]. Other more speculative approaches to the prevention
`of HAMA development are skin antigen desensitization and, theoretically, the use of
`immunoconjugates with toxin, radioactivity or drug molecules that would bind to
`and destroy the HAMA-producing B cells [15].
`
`Conclusions
`Analysis of the factors that play an important role in the development of HAMAs is
`complicated by such problems as the relatively small number of reports, the variety
`of diseases treated and the lack of uniformity in the design of these trials. This makes
`it difficult to predict the type of host anti-mouse immunoglobulin response to be
`expected. Although data regarding HAMA production are limited, some conclusions
`can be drawn.
`First, the production of HAMAs is associated with a diminished therapeutic
`response.
`Secondly, adequate prevention of HAMA production is not yet possible. All avail­
`able methods for prevention, except for that based on an increase in the dose of
`MoAb, are not very practical at the moment.
`Thirdly, as far as immunoscintigraphy is concerned, the most important conse­
`quence of high HAMA titres is the rapid clearance of MoAb into the liver and marked
`reduction of tumour uptake, which results in reduced image quality [38, 42-45].
`Fourthly, it is likely that the alteration of antibody biodistribution is related to the
`in vivo formation of antibody-antibody complexes (35] and that this alteration could
`interfere with image quality when sequential imaging is performed, even when carried
`out several months after the initial investigation [38].
`
`Acknowledgement
`This paper has been prepared under the auspices of the joint Task Group on Clinical
`Utility of Labelled Antibodies of the European Association of Nuclear Medicine.
`
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`immune fragments. Ca11cer Treatment Rep 1984; 68: 317-28.
`20. Sears HF, Herlyn D, Steplewski Z, Koprowski H. Effects 'of monoclonal antibody immuno­
`therapy on patients with gastrointestinal adenocarcinoma. J Biol Response Modifiers 1984; 3:
`138-50.
`21. Rosen ST, Zimmer AM, Goldman-Leikin R, Gordon LI, Kazikiewicz JM, Kaplan EH, Var­
`iakojis D, Marder RJ, Dykewicz MS, Piergies A, Silverstein EA, Roenigk HH, Spies SM.
`Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an
`1-131-labeled monoclonal antibody: an Illinois Cancer Council Study. f Clin Oncol 1984; 5:
`562-73.
`22. Engelstad BL, Spitler LE, Del Rio MJ, Ramos EC, Rosendorf LL, Reinhold CE, Khentigan
`A, Huberty JP, Corpuz SW, Lee HM, Okerlund MD, Hattner RS, Scannon PJ. Phase 1
`immunolymphoscintigraphy with an In-111-labeled antimelanoma monoclonal antibody.
`Radiology 1986; 161: 419-22.
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`9 of 12
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`VAN KROONENBURGH and PAUWELS
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`928
`23. Frodin JE, Biberfeld P, Christensson B, Philstedt P, Sundelius S, Sylven M, Wahren B,
`Koprowski H, Mellstedt H. Treatment of patients with metastasizing colo-rectal carcinoma
`with mouse monoclonal antibodies (Moab 17-lA): a progress report. Hybridom11 1986; 5
`(Suppl. 1): 151-61.
`24. Sears HF, Atkison B, Mattis J, Ernst C, Herlyn 0, Steplewski Z, Hayry P, Koprowski H.
`Phase-I clinical trial of monoclonal antibody in treatment of gastrointestinal tumours. Lancet
`1982; ii: 762-5.
`25. Sindelar WF, Maher MM, Herlyn 0, Sears HF, Steplewski Z,Koprowski H. Trial of therapy
`with monoclonal antibody 17-lA in pancreatic carcinoma: preliminary results. Hybrido11111
`1986; 5 (Suppl. 1): 125-32.
`26. Herlyn 0, Sears H, Iliopoulos 0 el 11/. Anti-idiotopic antibodies to monoclonal antibody
`C017-1A. Hybrido11111 1986; 5 (Suppl. 1): 51-8.
`27. Miller RA, Oseroff AR, Stratte PT, Levy R. Monoclonal antibody therapeutic trials in seven
`patients with T cell lymphoma. Blood 1983; 62: 988-95.
`28. Koprowski H, Herlyn 0, Lubeck M, OeFreitay E, Sears HF. Human anti-idiotype antibodies
`in cancer patients: is the modulation of the immune response beneficial to the patient?
`Proc N11t Ac11d Sci USA 1984; 81: 216-19.
`29. Sears HF, Herlyn 0, Steplewski Z, Koprowski H. Phase II clinical trial of the murine
`monoclonal antibody cytotoxic for gastrointestinal adenocarcinoma. Cancer Res 1985; 45:
`5910-13.
`30. Bertram JH, Gill PS, Levine AM, Boquiren 0, Hoffman FM, Meyer P, Mitchell MS. Mono­
`clonal antibody T101 in T cell malignancies: a clinical, pharmacokinetic and immunologic
`correlation. Blood 1986; 68: 752-61.
`31. Press OW, Appelbaum F, Ledbetter JA, Martin PJ, Zarling J, Kidd P, Thomas ED. Mono­
`clonal antibody lFS (anH-CD20). Serotherapy of human B cell lymphomas. Blood 1987; 69:
`584-91.
`32. Reynolds JC, CarrasquiUo JA, Keenan AM, Lora ME et 11/. Human anti-murine antibodies
`following immunoscintigraphy or therapy with radiolabeled monoclonal antibodies. j N11c/
`Med 1986; 27: 1022-3 (abstract).
`33. Sears HF, Herlyn D, Steplewski Z, Koprowski H. Initial trial use of murine monoclonal
`antibodies as immunotherapeutic agents for gastrointestinal adenocarcinoma. Hybrido11111
`1986; 5 (Suppl. 1): 109-15.
`34. Del Vecchio S, Reynolds JC, Carrasquillo JA, Lora ME, Larson SM. Human anti-murine
`antibody (HAMA) concentration and HAMA murine antibody (antibody-antibody) com­
`plexes. ] Nuc/ Med 1987; 28: 614 (abstract).
`35. Reynolds JC, Del Vecchio S, Lora ME, Carrasquillo JA, Larson SM. Antibody-antibody
`complexes are related to human anti-murine antibody (HAMA) levels. N11c/ Med 1986; 26:
`21-2 (abstract).
`36. Dillman RO, Shawler DL, Dillman JB, Royston I. Therapy of chronic lymphocytic leukemia
`and cutaneous T-cell lymphoma with TlOl monoclonal antibody. j C/i11011col1984; 2: 881-91.
`37. Linch DC, Beverley PCL, Newland A, Turnbull A. Treatment of a low grade T cell prolifer­
`ation with monclonal antibody. Cli11 Exp /1111111111011983; 51: 133-40.
`38. Larson SM, Brown JP, Wright PW et 11/. Imaging of melanoma with 1-131 labeled monoclonal
`antibodies. J Nucl Med 1983; 24: 123-9.
`39. Lobuglio_AF, Saleh M, Peterson L, Wheeler R, Carrano R, Huster W, Khazaeli MB. Phase
`I clinical 'trial of C017-1A monoclonal antibody. Hybridoma 1986; 5 (Suppl. 1): 117-23.
`40. Miller RA, Maloney DG, Warnke R, Levy R. Treatment of B cell lymphoma with monoclonal
`anti-idiotype antibody. N Engl/ Med 1982; 306: 517-22.
`41. Lowder JN, Meeker TC, Campell M, Garcia CF, Gralow J, Miller RA, Warnke R, Levy R.
`
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`10 of 12
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`BI Exhibit 1064
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`Human immunological response to mouse monoclonal antibodies
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`929
`
`Studies on B lymphoid tumors treated with monoclonal anti-idiotype antibodies: correlation
`with clinical responses. Blood 1987; 69: 199-210.
`42. Senekowitsch R, Bode W, Reidel G, Glaessner H, Moelkerstadt S, Kriegel H, Pabst HW.
`Improved radioimmunoscintigraphy of human mammary carcinoma xenografts after injec­
`tion of an anti-antibody. N11cl Med 1987; 26: 13-19.
`43. Larson SM, Carrasquillo JA, McGuffin RW ct nl. Use of 1-131 labelled murine Fab against
`a high-molecular weight antigen of human melanoma: preliminary experience. Rndiology
`1985; 155: 487-92.
`44. Pimm MV, Perkins AC, Armitage NC, Baldwin RW. The characteristics of blood-borne
`radiolabels and the effect of anti-mouse IgG antibodies on localization of radiolabeled
`monoclonal antibody in cancer patients. ] Nucl Med 1985; 26: 1011-23.
`45. Hyams D, Reynolds JC, Carrasquillo JA, Perentesis P, Larson SM, Morin M, Simpson D,
`Schlom J, Colcher D. The effect of circulating anti-murine antibody on the phMmacokinetics
`and biodistribution of injected radiolabeled monoclonal antibody.] Nttcl Med 1986; 27: 189
`(abstract).
`46. Zweig MH, Csako G, Benson CC, Weintraub BD, Kahn BB. Interference by anti-immuno­
`globulin G antibodies in immunoradiometric assays of thyrotropin involving mouse mono­
`clonal antibodies. C/i11 Chem 1987; 33: 840-4.
`47. Chatenoud L, Baudrihaye MF, Chkoff N, Kreis H, Goldstein G, Bach J-F. Restriction of
`the human in vivo immune response against the mouse monoclonal antibody OKT31. J.
`[1111111111011986; 137: 830-8.
`48. Ledermann JA, Begent HJ, BodenJA, Searle F, Bags ha we KD. Suppression of the anti-mouse
`antibody response to a monoclonal antitumour antibody in rabbits with cyclosporin A. In:
`Advances in the application of monoclonal antibodies in clinical oncology. London: Royal
`Postgraduate Medical School, 1987: 46 (abstract).
`49. Zim