J Clin Pathol 1982;35:369-315
`
`Review article
`
`Monoclonal antibodies in oncology
`
`KAROL SIKORA
`
`From the Ludwig Institute for Cancer Research, The Medical School, Hills Road, Cambridge CB2 2QH
`
`SUMMARY Molecular biology has made tremendous strides over the last five years. The new biology
`
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`
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`allows us to prepare monoclonal antibodies to defined antigens; to detect, isolate and clone
`
`specific genes; and to insert these genes into defined sites in different cells giving new functions
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`
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`to old organisms. These revolutionary developments have been followed closely by research­
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`
`
`ers, businessmen, politicians and philosophers, as well as by those involved in the clinical
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`
`
`care of patients. Although our understanding of human molecular biology is increasing rapidly,
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`
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`it is the development of monoclonal antibodies that has the most immediate application in the
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`
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`clinic. There have been several reports of their use in the diagnosis, localisation and treatment of
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`human malignant disease. This review describes developments that are likely to have direct relevance
`
`to patient care in the near future.
`
`What is a monoclonal antibody?
`
`The immunological response to any foreign antigen
`is polyclonal: many different clones of B lympho­
`cytes are stimulated to produce antibodies. These
`antibodies have different molecular structures and
`in turn recognise different molecular conformation
`patterns on the stimulating antigen-the antigenic
`determinants. Ct
`is this complexity of antibody
`response that makes the antigen-antibody interaction
`difficult to analyse at a molecular level. This is
`particularly so with complex antigens such as the
`tumour cell surface. Monoclonal antibodies occur
`naturally in patients with myeloma. Here neoplastic
`transformation occurs in a clone of B lymphocytes
`with the result that large quantities of identical
`immunoglobulin molecules are produced. It was by
`using myelomas that the chemical structure of the
`immunoglobulin molecule was discovered.1 However.
`the antigens to which most myeloma immuno­
`globulins are directed are usually unknown and
`are unlikely to be important. In 1975 Kohler and
`Milstein2 constructed a hybrid myeloma (hybridoma)
`which produced a monoclonal antibody directed
`against a specified antigen. Mice were immunised
`with the antigen (sheep red cells) and their spleen
`lymphocytes collected. The lymphocytes were fused
`with an established myeloma
`line and hybrids
`selected by growth in selective tissue culture medium.
`
`Accepted for publication 18 November 1981
`
`I •
`
`The resultant hybrids were rapidly growing (a
`property conferred by the myeloma) and yet
`contained new immunoglobulin genes (from the
`lymphocytes of the immunised mouse). The hybri­
`domas were cloned by diluting the cells and growing
`up colonies from single cells. These cloned hybri­
`domas now contained only one set of new immuno­
`globulin genes (Fig. I). After growing in tissue
`culture the supernatant containing the secreted
`antibody was tested for activity against the im­
`munising antigen. Using this system, antibodies can
`be isolated which define single antigens in a complex
`mixture such as the molecules on tumour cell
`surfaces. These molecules can now be compared to
`those appearing on non-malignant cells from the
`same tissue of origin.
`
`Do tumour antigens exist?
`
`There is considerable evidence that the immune
`system responds to antigens on tumour cells, both in
`experimental animal systems and in human neo­
`plasia. These tumour antigens are defined by assays
`which utilise the various modes of immune response
`to them. It is important to distinguish the antigens
`present on the tumour cell surface that are unique
`to tumours and are not shared with normal cells.
`There are several documented examples of such
`antigens within experimental tumour systems.3 4
`Until the development of the monoclonal anti­
`body technology, it has been impossible to sort out
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`370
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`Tumour cell surface
`(complex antigen)
`A.-nA ,.,
`
`man can actually recognise the tumour cell surface.a 9
`Whether immune mechanisms are able effectively to
`destroy tumour cells in vivo remains in question.
`
`Sikora
`
`-:V
`/µ Q,, 1 �
`
`Production of monoclonal antibodies to human
`tumours
`
`FUSION SYSTEM
`Currently there are three systems in which anti­
`tumour monoclonal antibodies can be raised; mouse,
`rat, and human. For human tumours, mice and rats
`have the obvious advantages of responding to a wide
`variety of antigens and are thus the choice for an
`exhaustive analysis of tumour cell surface com­
`ponents. This wide response may be a disadvantage
`in that xenogeneic immunisations often result in
`antibodies directed against histocompatibility anti­
`gens and blood group substances.
`It is now possible to fuse human lymphocytes
`directly from patients with tumours, either with
`mouse or rat myelomas, so obtaining mixed species
`hybrids which produce human monoclonal anti­
`bodies. The frequency of hybridisation and the
`quantity of human immunoglobulin produced by
`interspecies hybrids is considerably less than in
`mouse-mouse or rat-rat fusions. A further problem
`is the preferential loss of human chromosomes in
`rodent-human hybrids which results in frequent
`loss of immunoglobulin production. There are now,
`however, several human myeloma ·lines available
`which are suitable for fusion.1011 Such lines must
`be rapidly growing and have an appropriate genetic
`selection mechanism to enable the parent myeloma
`to be killed in the hybridoma mixture. Once estab­
`lished, human-human hybrids show no apparent
`preferential loss of chromosomes and thus the
`stability of the hybrid is assured. The quantity of
`immunoglobulin secreted by these human-human
`hybrids is usually of the order of I µ,g/ml which is
`one tenth of the output of the corresponding mouse
`hybridoma system. There are several advantages in
`using human lymphocytes to produce monoclonal
`antibodies. The spectrum of the human immune
`response which serologically defines tumour-specific
`antigens can be examined. There is abundant
`evidence that patients with cancer at some time in
`the natural history of the tumour have
`in their
`serum antibodies which recognise their own tu­
`mours.12 The titre of these antibodies is low and so
`far there have been no good studies on the chemical
`nature of the determinants recognised by such anti­
`bodies. By obtaining the antibodies in monoclonal
`form and in sufficient quantity such chemical studies
`are possible. Lymphocytes from cancer patients
`can be collected from several sites. Peripheral blood
`lymphocytes may not represent a good starting
`
`8
`
`Hybrid
`
`,.L, �
`
`(I ( antibodies
`r',
`r1,
`
`+en•w
`Fig. I Making a monoclonal antibody. A complex
`antigen, such as a tumour cell surface, is used 10
`immunise mice. The spleen cells (S) are removed and
`fused with a myeloma line (M). Hybrids are cloned and
`those antibodies binding to the antigen selected.
`
`the antigenic complexity of human tumour cell
`surfaces. The evidence for the existence of unique
`tumour specific antigens in man analogous to the
`tumour-specific transplantation antigens in animals
`is circumstantial. The natural history of certain
`tumours, the waxing and waning of tumour masses
`the occurrence of spontaneous regression
`and
`suggests that there may be some host control of
`tumour growth.� Similarly, the relation between
`histological evidence of
`tumour
`infiltration by
`immunocompetent cells and prognosis suggests that
`these infiltrating cells have some controlling in­
`fluence of tumour growth.6 Further circumstantial
`evidence comes from the increased incidence of
`malignancy in immunosuppressed patients, although
`here the spectrum of tumour types found is not
`similar to that found in the normal population.7
`Serological analysis and assays of
`lymphocyte
`function have shown that the immune system in
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`Monoclonal antibodies in oncology
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`population from which to perform fusions. More
`likely to be involved in antitumour activity are the
`lymphocytes in the lymph nodes draining a tumour.
`Such lymphocytes can easily be collected in large
`quantities from patients with breast, lung and colo­
`rectal cancer. Another source of lymphocytes for
`fusion comes from the tumour
`itself. Certain
`tumours, for example gliomas, are often heavily
`infiltrated by lymphocytes. These lymphocytes can
`be collected, separated from the tumour and fused
`to a human myeloma line.ts
`
`IMMUNISATION SCHEDULE
`For xenogeneic immunisations the choice of anti­
`genic material and the schedule in which it is used
`for immunisation has varied considerably. Very
`little detailed work has been performed on opti­
`mising these schedules. Sources of tumour material
`for immunisation can come from cell lines grown
`in vitro, pieces of fresh tumour tissue, membrane
`preparations from fresh tissue, or fractionated
`solubilised components from fresh tumour cell
`membranes. These different
`immunisation pro­
`cedures will almost certainly result in different
`spectra of antibodies.
`In the production of human monoclonal anti­
`bodies immunisation is not possible and the choice
`lies in the source of lymphocytes for fusion. There
`is as yet no evidence to suggest that any particular
`source of lymphocytes-peripheral blood, spleen,
`lymph node or intratumour-results in a higher
`frequency of the required antibodies.
`
`SCREENING METHODS
`The production of antibodies against human tumour
`cell surfaces requires the screening of many fusion
`products to find suitable immunoglobulins. Several
`strategies have been developed. The commonest
`method is to immunise mice with a chosen tumour
`cell line, for example a melanoma. The fusion
`products are screened on that melanoma in an
`indirect binding radioimmunoassay (see Fig. 2) and
`the activity of any positive supernatants determined
`on other melanomas as well as on cell lines of
`different types, both normal and malignant (Fig. 3).
`In this way the specificity of the monoclonal anti­
`body is characterised and its ability to distinguish
`tumour cells from their normal counterparts is
`determined.
`Screening can also be performed using primary
`tumour material. Membrane preparations of tumours
`can be used to immunise rodents; the same mem­
`brane preparation can be bound to plastic wells and
`used in a solid phase radioimmunoassay to screen
`the activity of resulting monoclonal antibodies.
`A variant of this screening procedure is to use
`
`371
`
`Radiolabelled
`anti lg
`
`Monoclonal
`antibody
`
`l
`
`n n n n n n
`T urTIOl.r cell membrane
`Direct
`lrdil'Kt
`Fig. 2 Binding assays for monoclonal antibodies. In
`the indirect assay bound monoclonal antibody is detected
`by a radio/abelled anti-immunoglobulin. In the direct
`assay internally labelled-for example, 3H-lysine,
`antibody is used.
`
`tt.rnon lyrrphocyles
`�ipherot blood
`5pte«i
`L yn'f)h nodg
`lntrotumoural
`
`/1�
`
`Radioirnmu"loosm ll!Y!'y1CtistQ!Q9y_ �v.1otoxicit)'..
`Membrcrles ltrvn.noftuorese<ice
`Corr4)l�ment
`K cells
`Whole cells
`llT'fT'UlOl)eroxidase
`Fig. 3 Strategies for making and screening monoclonal
`antibodies to human tumour antigens.
`
`sections of normal and tumour material to look at
`the activity of monoclonal antibodies histologically
`by irnmunofiuorescence on frozen sections or by an
`immuno-peroxidase technique. This latter technique
`has the advantage of allowing retrospective surveys
`of paraffin block material readily available from
`hospital pathology departments. By comparing
`tumour samples from different patients with cancer
`
`Cell ltt
`Fre9\ tumour
`lumou'tne�
`Solubitised lrodions
`
`Mouse
`
`Spleen cells
`
`myeloma
`
`1
`l
`L Fusion with---­
`l
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`372
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`Sikora
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`Antitumour monoclonal antibodies currently
`available
`
`of the same or different tissues, additional infor­
`
`
`
`products.
`Several groups have now produced monoclonal
`
`mation of diagnostic value can be sought.
`
`In the production of human monoclonal antibodies
`
`antibodies to either CEA or other antigens present
`
`screening strategies are less well worked out. One
`
`on colorectal carcinomas. So far these attempts have
`problem is the ubiquitous presence of variable
`been carried out by immunising mice with either
`
`amounts of human immunoglobulin in human
`
`
`purified CEA preparations or colorectal carcinoma
`tumours. The detecting anti-human lg, whether
`cell lines. After fusion, screening on either CEA or
`
`fluorescein coupled or radiolabelled, binds to this
`the immunising cell line has been used to identify
`
`
`resulting in high background levels in tumour
`
`
`interesting supernatants. Accolla and his colleagues16
`
`membrane preparations. This can obscure binding
`raised 400 hybrids from mice immunised with puri­
`
`by relatively small amounts of high affinity mono­
`fied CEA and found two which secreted antibodies
`
`clonal antibody. This problem can be overcome by
`
`reacting specifically with two different antigenic
`
`using cell lines for screening although of course this
`
`determinants present on CEA molecules. The
`
`
`results in selection. A more laborious technique is
`
`
`affinities of these antibodies are relatively high and
`
`
`to radiolabel internally each human immuno­
`
`
`could be used to characterise solubilised CEA
`
`immunochemically. Herlyn et a/17 immunised mice
`globulin produced by the hybrids by incorporating
`and screen a radioactive amino acid such as 3H-lysine
`
`
`with cells grown in vitro. The screening assays
`
`included radioimmunoassay, mixed haemabsorption
`in a direct binding assay.14
`
`assays and immunofluorescence on the immunising
`cell line. Two hybridomas were found which secreted
`
`
`antibodies binding specifically to human colorectal
`
`
`carcinomas, either growing in culture or obtained
`
`
`
`directly from patients. These antibodies do not bind
`COLORECTAL CARCINOMA
`
`Colorectal cancer is a common problem in clinical
`to normal colonic mucosa, to other malignant
`oncology. Diagnosis is often difficult, requiring
`cells or to CEA.
`
`
`extensive endoscopic or radiological investigation.
`The assessment of recurrent disease following
`MELANOMA
`
`primary surgery is usually impossible until large
`Melanoma is a tumour studied frequently by im­
`
`
`
`masses of neoplastic tissue have accumulated. For
`
`munologists. Serology, using panels of patient sera
`the last 15 years much effort has been spent investi­
`and melanoma cells, has been used to construct
`
`gating carcinoembryonic antigen (CEA), an antigen
`
`
`
`large serological matrices. The biochemical separ­
`detected by an antiserum produced in rabbits after
`
`
`ation of thedifferent serologically recognised antigens
`
`immunisation with extracts from colonic cancer.
`has been hampered by the low titres of the sera.
`
`
`This antigen, a glycoprotein with a molecular weight
`
`There are several monoclonal antibodies against a
`of 180 000, is found in several gastrointestinal
`
`variety of human melanoma antigens. Some of these
`tumours, some lung and breast tumours as well as in
`antibodies
`are directed against the human DR
`
`(HLA D locus-related) antigen. In one study,18
`
`
`
`normal fetal colon.ls Considerable interest has been
`aroused in the possibility that the measurement of
`
`
`three out of six hybridoma secreted antibodies were
`CEA in the blood would relate to the tumour load in
`found to bind to the majority of melanoma cell
`
`an individual patient, thus producing both a
`
`lines and to astrocytomas, as well as to all normal
`
`
`diagnostic test and a marker for monitoring progress
`
`and Epstein-Barr virus-transformed lymphocytes
`
`of the disease. A major problem in the use of CEA
`
`tested (the same distribution as the DR antigen).
`
`for these purposes has been the extensive cross­
`
`Two of the remaining antibodies, however, were
`
`reaction between CEA and a variety of similar
`
`
`to found to detect two different antigens common
`
`glycoproteins such an non-specific cross-reacting
`
`melanoma and astrocytoma cells only. The most
`
`antigens (NCA), biliary glycoprotein (BGP) and a
`
`elegant analysis of the use of monoclonal antibodies
`glycoprotein
`found in washings of normal colon
`
`
`in characterising antigenic systems on the surface
`
`
`(NCW). These glycoproteins share antigenic deter­
`of human tumours comes from the work of Dippold
`minants with CEA and therefore confuse the
`
`and his collaborators.19 Mice were immunised with
`the melanoma cell line SK-MEL 28 and the 18
`serological
`
`analysis since different immunisation
`
`and absorption protocols result in the production
`
`antibodies derived were tested on a large panel of
`
`
`
`of different antibodies in the resulting antiserum.
`human cell lines from a variety of tumour types, as
`
`Monoclonal antibodies give more precise informa­
`well as on early cultures of normal tissue. Sero­
`
`tion about the interrelations between these cell
`
`logical studies, in conjunction with immunoprecipi­
`surface components and thus lead to more selective
`
`tation analysis of radiolabelled cell extracts and
`
`and sensitive assays for truly tumour-related
`
`
`antibody inhibition tests with solubilised antigens
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`Monoclonal antibodies in oncology
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`373
`
`Reactive popu/otions
`
`indicated that the 18 monoclonal antibodies
`
`
`
`
`Commercially available monoclonal antibodies to
`recog­
`
`
`lymphocyte differentiation antigens
`
`nised six antigenic systems. Two of the systems are
`with molecular sizes of 95 000 and
`glycoproteins
`Antibody
`150 000 daltons,
`and two systems have characteristics
`
`
`
`of glycolipid antigens. The biochemical nature of
`*OKT 3
`tL17 Fl2
`
`the remaining two antigenic systems has not been
`iNEl-016
`determined.
`
`peripheral blood T lymphocytes, T cell
`leukaemia, mycosis fungoides
`
`helper/inducer T cells, certain leukaemias,
`mycosis fungoidcs, 5ezary syndrome
`
`*OKT 4
`t SK 3
`tSK4
`
`thymic lymphocytes, some thymomas
`suppressor/cytotoxic T lymphocytes,
`certain T cell neoplasms
`immature T cells, certain leukaemias
`
`BREAST CANCER
`•OKT 6
`Xenogeneic monoclonal antibodies have been raised
`
`•OKT 8
`against breast tumour lines, although the number of
`tSK I
`
`antibodies available is less than in colorectal and
`•OKT I 0
`melanoma systems. A monoclonal antibody that
`anti HLA, DR (la) B lymphocytes and B cell neoplasms
`
`may have considerable clinical use is that raised
`ant.i Jg
`(nodular lymphoma, most chronic
`lymphocytic leukaemias, myeloma)
`
`against the human oestrogen receptor.20 It is known
`
`that the presence of oestrogen receptors in breast
`Commercial suppliers:
`
`of cancer tissue is an indicator of the likelihood
`
`•Ortho Pharmaceuticals, Denmark St, High Wycombe, Bucks HPI I
`2ER.
`
`response to hormone treatment. The derivation
`of
`tBecton Dickinson, 490-3, Lakeside Drive, California 94086 USA.
`
`monoclonal antibodies which can be used for im­
`iNew England Nuclear, 2 New Road, Southampton S02 OAA.
`
`munohistological detection of receptors would
`OTHER TUMOURS
`
`
`ability to provide greatly increase the pathologist's
`Monoclonal antibodies have been or are being
`
`
`
`information of prognostic value to the clinician.
`raised against a wide variety of human tumours,
`By using lymphocytes derived from axillary
`
`
`including gliomas, neuroblastomas, sarcomas, lung
`lymph nodes from patients with breast cancer,
`
`cancer as well as bladder, prostrate and testicular
`
`human immunoglobulins which bind to breast
`tumours.
`carcinoma cells have been produced.21 A human
`lgM monoclonal antibody produced in this way has
`Clinical uses
`
`been shown to discriminate between mammary
`carcinoma cells and normal mammary epithelial
`DIAGNOSIS ANO MONITORING
`cells. This antibody also reacted significantly
`
`A major problem in clinical oncology is the measure­
`with
`
`metastatic mammary carcinoma cells in lymph
`
`ment of tumour load in an individual patient.
`Less than 10 % of all cancer patients have disease
`nodes of breast cancer patients with no binding to
`which can be reliably assessed by conventional
`
`stroma of the the normal lymphocytes or to the
`
`
`
`techniques, such as palpation or diagnostic radiology.
`same node.
`
`This hampers the evaluation of different treatment
`
`methods. Certain relatively rare tumours shed
`LYMPHOMA AND LEUKAEMIA:
`A wide range of monoclonal antibodies has been
`
`
`products into the circulation; and the concentration
`of these tumour markers can be related to the total
`raised against myeloid and lymphoid neoplasms.
`tumour cell burden. Examples include a-fetoprotein
`Normal lymphocytes with different biological
`in hepatoma and teratoma; human chorionic
`functions-for example, helper and suppressor
`
`in choriocarcinoma and CEA in
`gonadotropin
`
`effects on antibody synthesis, can be distinguished
`
`
`some colorectal carcinomas. Other tumour-related
`by their surface markers. Not surprisingly neo­
`molecules are also shed into the serum but until
`
`plastic transformation in cells of the lymphoid
`now there has been no way of detecting them. By
`series results in the clonal expansion of a population
`
`using specific monoclonal antibodies in a suitable
`
`of cells bearing a distinct surface marker pattern.
`
`Using conventional serology such patterns have
`
`
`radioimmunoassay, picogram quantities of these
`shed products can be measured. A large panel of
`already been related to prognosis as in the sub­
`
`well characterised monoclonal antibodies will
`
`classification of lymphatic leukaemia into T, B and
`
`
`
`therefore have considerable diagnostic use at several
`
`common ALL types. With monoclonal antibodies a
`stages in the management of cancer patients.
`much finer discrimination can be made and used to
`
`
`Firstly, patients presenting with symptoms sug­
`
`plan therapeutic approaches to these diseases.22
`gestive of malignancy may have no tissue readily
`
`
`to The range of monoclonal antibodies available
`
`
`accessible for biopsy. Investigations now necessary,
`
`different lymphoid subpopulations is outlined in the
`
`are often expensive, time-consuming and cause the
`
`
`
`Table. It should be stressed that these antibodies do
`
`
`patient considerable discomfort. Early carcinoma of
`
`not recognise tumour antigens but clonally expanded
`the pancreas is a good example. The second use of
`normal antigens.
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`374
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`monoclonal antibodies is for regular screening in
`patients with conditions that are known to pre­
`dispose to neoplastic changes, such as ulcerative
`colitis, polyposis coli and certain forms of hepatic
`cirrhosis. Thirdly, the serial monitoring of tumour
`marker concentration
`in an individual patients'
`serum could provide a reliable index of the behaviour
`of the tumour and its reponse to treatment. There are
`several reports of monoclonal antibodies being used
`to detect circulating tumour markers. A monoclonal
`antibody detecting a monosialoganglioside
`from
`colorectal tumour cells has been used to screen serum
`sarnples.23 Blocking activity was found in the serum
`of 24 out of 32 patients with colorectal cancer but was
`not present in the serum of 38 healthy donors and 36
`patients with other cancer types. This sort of observa­
`tion has now been made with several different anti­
`bodies to a variety of tumour types.
`
`HISTOLOGICAL EVALUATION
`Recent advances in oncology have made the therapist
`more dependent on his pathologist colleagues than
`ever before. The oncologist is only too familar
`with
`the problems occuring
`in distinguishing
`certain anaplastic carcinomas from
`lymphomas
`and even teratomas. Immunohistology with mono­
`clonal antibodies can provide considerable diagnostic
`information. In a study of 33 cases of non-Hodgkin's
`lymphoma by a panel of monoclonal antibodies to
`different lymphocyte subpopulations
`information
`was provided that was unobtainable by conventional
`microscopy.24 Using such techniques more can be
`learnt about the different types of lymphoma and
`their response to treatment. Antibodies are also now
`available which can discriminate between different
`histological types of common solid tumour; an
`example is an antibronchial carcinoma antibody
`which binds only to small cell tumours.25 Such
`reagents wiJI be of great value when limited amounts
`of material are available for pathological examination
`as with sputum cytology. A series of monoclonal
`antibodies to various tumour types would be of
`considerable use in evaluating histological material
`from patients presenting with metastatic disease.
`In this way treatable forms of cancer could be
`excluded without the costly and uncomfortable
`exercise of hunting the primary tumour.
`
`TUMOUR LOCALISATION
`The use of radiolabelled polyclonaJ antitumour
`antibodies for tumour detection has been attempted
`with limited success. The major problems have been
`the lack of a suitable antibody giving sufficient
`target to non-target contrast for
`imaging and also
`in reproducibility preparing and
`the difficulty
`purifying antitumour antibodies. The development
`
`Sikora
`
`of monoclonal antibodies has several advantages.
`Firstly, their defined specificity may allow the
`contrast required for effective imaging and, secondly,
`their production is reproducible on a large scale.
`Furthermore, they represent a concentrated form
`of immunoglobulin with defined activity and thus
`the total foreign protein load given to an individual
`patient is much lower. It has been shown that mouse
`monoclonal antibodies to CEA and to teratocarci­
`nomas can localise human tumour deposits
`in
`immunosuppressed mice bearing human tumour
`xenografts.2& 27 There are as yet, however, few
`reports on the use of labelled monoclonal antibodies
`for localisation in man. Mach and his colleagues2s
`injected 14 patients with large bowel and pancreatic
`cancer with 1311-labelled purified mouse monoclonal
`anti-CEA antibody. In eight patients increased
`radioactivity was observed in the region of the known
`tumour deposit. To detect blood pool and secreted
`radioactivity a 99mTechnetium scan was also per­
`formed. After subtraction of 99mTc radioactivity
`from is11 radioactivity a two to tenfold concentra­
`tion of 1s11 activity was found in the tumour sites.
`
`TREATMENT
`Monoclonal antibodies are currently being used by
`several groups in attempts to assess their value as
`therapeutic agents. A T cell specific murine hybri­
`doma monoclonal antibody has been infused into
`patients with T cell neoplasms.29 The antibody used
`reacts with normal human T cell differentiation
`antigens which are present in increased amounts on
`the malignant cells of patients with cutaneous T cell
`lymphomas. Favourable but temporary responses
`were seen in patients with T cell leukaemias and
`with mycosis fungoides, a neoplasm of T helper
`lymphocytes. In another studyso a mouse monoclonal
`antibody directed against a lymphoma-associated
`antigen was given to a patient with lymphosarcoma
`cell leukaemia. Transient decreases in circulating
`tumour cells and the appearance of dead celJs were
`noted after the infusion of 75 mg of antibody. The
`patient had received extensive prior radiation
`therapy and chemotherapy. There are several mecha­
`nisms by which this tumour cell destruction can
`occur. The6C include the activation of complement;
`the triggering of antibody-dependent cell-mediated
`cytotoxicity; and opsonisation resulting in macro­
`phage killing. It is probable that such mechanisms
`alone are unlikely to destroy large tumour masses
`but could deal effectively with well vascularised
`micrometastases.
`Human tumours growing in immune-deprived
`mice have been commonly used targets for thera­
`peutic experiments. By using anticolon carcinoma
`antibodies Herlyn et a/Sl showed that the growth rate
`
`6 of 7
`
`BI Exhibit 1029
`
`

`

`'
`
`Monoclonal antibodies in oncology
`
`375
`11 Accolla RS, Carrel S. Mach JP. Monoclonal antibodies to
`of human colon tumours in these animals was
`CEA and produced by two hybrid cell lines.
`Proc Natl
`
`considerably reduced. A colorectal carcinoma
`Acad Sci 1980;77:563-8.
`
`" Herlyn M, Steplewski Z, Herlyn D, Koprowski H. Colo­
`specific monoclonal antibody has been used to
`
`rectal carcinoma specific antigens: detection by means of
`
`
`explore the possibility of coupling diptheria and
`
`monoclonal antibodies. Proc Not/ Acad Sci 1979·76:
`
`
`ricin toxins to produce specific cytotoxic molecules.32
`1438-42.
`These toxins can be separated into two functionally
`" H�rlyn M, Cl�r� WH, Mastrangelo J, et a/. Specific
`
`1mmunoreact1v11y of hybridoma secreted monoclonal
`
`distinct chains, the A active chain and the B binding
`
`anti melaMma antibodies. Cancer Res 1980·40:3602-9.
`
`chain. The A chains are specific inactivators of
`"Dippold W, Lloyd KO, Lucy TC, et al. Cell surface
`
`protein synthesis within the cell whilst the B chains
`antigens of human malignant melanoma: definition of
`
`are responsible for the binding of toxin molecules
`six antigenic systems with mouse monoclonal anti­
`bodies. Proc Natl Acad Sci 1980;77:6114-8.
`to receptors on cell surfaces. The A chains can be
`••Greene GL, Nolan C, Engler JP, Jensen EV. Monoclonal
`
`and coupled by conventional cross-linking
`separated
`antibodies lo human estrogen receptor. Proc Natl
`agents to the antitumour monoclonal antibody.
`Acod Sci 1980;77:5115·9.
`Such conjugates were shown to be cytotoxic in
`11 Schlom J, Wunderlich D, Teramoto YA. Generation of
`
`human monoclonal antibodies reactive with human
`vitro for colorectal carcinoma cells but not toxic
`mammary carcinoma cells.
`Proc Natl Acad Sci 1980·77:
`'
`
`in the same concentration range for a variety of
`6841-5.
`other human tumour and normal cell lines. The
`
`"Grea�es �F, Robinson JB, Delia D, et al. Comparative
`concept of using the antibody to provide the speci­
`antigenic
`
`phenotypes of normal and leukaemic precursor
`cells analysed with a library of monoclonal antibodies.
`ficity of delivery and the toxin as a warhead clearly
`
`lo: Neth R, ed. Modtrn trends in leukaemia JV. Munich:
`
`
`promises interesting therapeutic possibilities for
`
`JF Lebmans-Verlag, (in press).
`the future.
`
`u Koprowski H, Herlyn M, Steplewski Z, Sears H. Specific
`antigenic in serum of patient with colon carcinoma.
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