J Clin Pathol 1982;35:369-375
`
`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
`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
`to old organisms. These revolutionary developments have been followed closely by research-
`ers, businessmen, politicians and philosophers, as well as by those involved in the clinical
`care of patients. Although our understanding of human molecular biology is increasing rapidly,
`it is the development of monoclonal antibodies that has the most immediate application in the
`clinic. There have been several reports of their use in the diagnosis, localisation and treatment of
`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
`is this complexity of antibody
`determinants. It
`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.' However,
`the antigens to which most myeloma immuno-
`usually unknown and
`globulins are directed are
`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
`
`The resultant hybrids were rapidly growing (a
`conferred by the myeloma) and yet
`property
`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-
`1). After growing in tissue
`globulin genes (Fig.
`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)
`
`Spleen cells
`
`Myeloma
`
`Hybrid
`
`r antibodies
`
`Making a monoclonal antibody. A complex
`Fig. 1
`antigen, such as a tumour cell surface, is used to
`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
`and the occurrence of spontaneous regression
`suggests that there may be some host control of
`tumour growth.5 Similarly, the relation between
`evidence of tumour infiltration by
`histological
`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
`analysis and assays of lymphocyte
`Serological
`function have shown that the immune system in
`
`Sikora
`man can actually recognise the tumour cell surface.8 9
`Whether immune mechanisms are able effectively to
`destroy tumour cells in vivo remains in question.
`
`Production of monoclonal antibodies to human
`tunours
`
`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.'01' 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 1 ug/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
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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.13
`
`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
`line, for example a melanoma. The fusion
`cell
`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
`
`Radiolabetled
`anti Ig
`
`Monoclonal
`antibody
`
`Tumour cell membrane
`
`Indirect
`Direct
`Fig. 2
`Binding assays for monoclonal antibodies. In
`the indirect assay bound monoclonal antibody is detected
`by a radiolabelled anti-immunoglobulin. In the direct
`assay internally labelled-for example, 3H-lysine,
`antibody is used.
`
`Human lymphocytes
`Peripheral blood
`Spleen
`Lymnph nodes
`Intratumoural
`
`Cell line
`Fresh tumour
`Tumour membrane
`Solubilised fractions
`I
`
`louse
`
`I* cells
`
`Spleer
`
`L<
`
`Fusion with
`myeloma
`
`Screening and cloning
`
`Radioimmunoassay
`Immunohistology
`Cytotoxicity
`Membranes
`Immunofluorescence
`Complement
`Whole cells
`Imrnunoperoxidase
`K cells
`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 immunofluorescence 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
`departments. By comparing
`pathology
`tumour samples from different patients with cancer
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`372
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`of the same or different tissues, additional infor-
`mation of diagnostic value can be sought.
`In the production of human monoclonal antibodies
`screening strategies are less well worked out. One
`problem is the ubiquitous presence of variable
`amounts of human immunoglobulin in human
`tumours. The detecting anti-human Ig, whether
`fluorescein coupled or radiolabelled, binds to this
`in high background levels
`resulting
`in tumour
`membrane preparations. This can obscure binding
`by relatively small amounts of high affinity mono-
`clonal antibody. This problem can be overcome by
`using cell lines for screening although of course this
`results in selection. A more laborious technique is
`radiolabel
`internally each human immuno-
`to
`globulin produced by the hybrids by incorporating
`a radioactive amino acid such as 3H-lysine and screen
`in a direct binding assay.14
`
`Antitumour monoclonal antibodies currently
`available
`
`COLORECTAL CARCINOMA
`Colorectal cancer is a common problem in clinical
`oncology. Diagnosis is often difficult, requiring
`extensive endoscopic or radiological investigation.
`following
`The assessment
`disease
`of recurrent
`primary surgery is usually impossible until large
`masses of neoplastic tissue have accumulated. For
`the last 15 years much effort has been spent investi-
`gating carcinoembryonic antigen (CEA), an antigen
`detected by an antiserum produced in rabbits after
`immunisation with extracts from colonic cancer.
`This antigen, a glycoprotein with a molecular weight
`of 180 000, is found in several
`gastrointestinal
`tumours, some lung and breast tumours as well as in
`normal fetal colon.15 Considerable interest has been
`aroused in the possibility that the measurement of
`CEA in the blood would relate to the tumour load in
`thus producing both a
`an individual
`patient,
`diagnostic test and a marker for monitoring progress
`of the disease. A major problem in the use of CEA
`for these purposes has been the extensive cross-
`reaction between CEA and a variety of similar
`glycoproteins such an non-specific cross-reacting
`antigens (NCA), biliary glycoprotein (BGP) and a
`glycoprotein found in washings of normal colon
`(NCW). These glycoproteins share antigenic deter-
`minants with CEA and therefore confuse the
`serological analysis since different immunisation
`and absorption protocols result in the production
`of different antibodies in the resulting antiserum.
`Monoclonal antibodies give more precise informa-
`tion about the interrelations between these cell
`surface components and thus lead to more selective
`and sensitive
`assays
`for
`tumour-related
`truly
`
`Sikora
`
`products.
`Several groups have now produced monoclonal
`antibodies to either CEA or other antigens present
`on colorectal carcinomas. So far these attempts have
`been carried out by immunising mice with either
`purified CEA preparations or colorectal carcinoma
`cell lines. After fusion, screening on either CEA or
`the immunising cell line has been used to identify
`interesting supernatants. Accolla and his colleagues16
`raised 400 hybrids from mice immunised with puri-
`fied CEA and found two which secreted antibodies
`reacting specifically with two different antigenic
`determinants
`present on CEA molecules. The
`affinities of these antibodies are relatively high and
`could be used to characterise solubilised CEA
`immunochemically. Herlyn et al17 immunised mice
`with cells grown in vitro. The screening assays
`included radioimmunoassay, mixed haemabsorption
`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
`to normal colonic mucosa, to other malignant
`cells or to CEA.
`
`MELANOMA
`Melanoma is a tumour studied frequently by im-
`munologists. Serology, using panels of patient sera
`and melanoma cells, has been used to construct
`large serological matrices. The biochemical separ-
`ation of thedifferent serologicallyrecognisedantigens
`has been hampered by the low titres of the sera.
`There are several monoclonal antibodies against a
`variety of human melanoma antigens. Some of these
`antibodies are directed against the human DR
`(HLA D locus-related) antigen. In one study,18
`three out of six hybridoma secreted antibodies were
`found to bind to the majority of melanoma cell
`lines and to astrocytomas, as well as to all normal
`and Epstein-Barr virus-transformed lymphocytes
`tested (the same distribution as the DR antigen).
`Two of the remaining antibodies, however, were
`found to detect two different antigens common to
`melanoma and astrocytoma cells only. The most
`elegant analysis of the use of monoclonal antibodies
`in characterising antigenic systems on the surface
`of human tumours comes from the work of Dippold
`and his collaborators.19 Mice were immunised with
`the melanoma cell line SK-MEL 28 and the 18
`antibodies derived were tested on a large panel of
`human cell lines from a variety of tumour types, as
`well as on early cultures of normal tissue. Sero-
`logical studies, in conjunction with immunoprecipi-
`analysis of radiolabelled cell extracts and
`tation
`antibody inhibition tests with solubilised antigens
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`indicated that the 18 monoclonal antibodies recog-
`nised six antigenic systems. Two of the systems are
`glycoproteins with molecular sizes of 95000 and
`150 000 daltons, and two systems have characteristics
`of glycolipid antigens. The biochemical nature of
`the remaining two antigenic systems has not been
`determined.
`
`BREAST CANCER
`Xenogeneic monoclonal antibodies have been raised
`against breast tumour lines, although the number of
`antibodies available is less than in colorectal and
`melanoma systems. A monoclonal antibody that
`may have considerable clinical use is that raised
`against the human oestrogen receptor.20 It is known
`that the presence of oestrogen receptors in breast
`cancer tissue is an indicator of the likelihood of
`response to hormone treatment. The derivation of
`monoclonal antibodies which can be used for im-
`of receptors would
`munohistological
`detection
`greatly increase the pathologist's ability to provide
`information of prognostic value to the clinician.
`By using lymphocytes derived from axillary
`lymph nodes from patients with breast cancer,
`breast
`human immunoglobulins which bind to
`carcinoma cells have been produced.21 A human
`IgM monoclonal antibody produced in this way has
`been shown to discriminate between mammary
`carcinoma cells and normal mammary epithelial
`cells. This antibody also reacted significantly with
`in lymph
`metastatic mammary carcinoma cells
`nodes of breast cancer patients with no binding to
`the normal lymphocytes or to the stroma of the
`same node.
`
`LYMPHOMA AND LEUKAEMIA:
`A wide range of monoclonal antibodies has been
`raised against myeloid and lymphoid neoplasms.
`biological
`lymphocytes
`Normal
`different
`with
`functions-for example,
`helper and suppressor
`effects on antibody synthesis, can be distinguished
`by their surface markers. Not surprisingly neo-
`plastic transformation in cells of the lymphoid
`series results in the clonal expansion of a population
`of cells bearing a distinct surface marker pattern.
`Using conventional serology such patterns have
`already been related to prognosis as in the sub-
`classification of lymphatic leukaemia into T, B and
`common ALL types. With monoclonal antibodies a
`much finer discrimination can be made and used to
`plan therapeutic approaches to these diseases.22
`The range of monoclonal antibodies available to
`different lymphoid subpopulations is outlined in the
`Table. It should be stressed that these antibodies do
`not recognise tumour antigens but clonally expanded
`normal antigens.
`
`373
`
`Commercially available monoclonal antibodies to
`lymphocyte differentiation antigens
`
`Antibody
`
`*OKT 3
`tL17 F12
`tNEI-016
`*OKT 4
`t SK 3
`tSK 4
`*OKT 6
`*OKT 8
`tSK 1
`*OKT 10
`anti HLA, DR (la)
`anti Ig
`
`Reactive populations
`peripheral blood T lymphocytes, T cell
`leukaemia, mycosis fungoides
`
`helper/inducer T cells, certain leukaemias,
`mycosis fungoides, S6zary syndrome
`
`thymic lymphocytes, some thymomas
`suppressor/cytotoxic T lymphocytes,
`certain T cell neoplasms
`immature T cells, certain leukaemias
`B lymphocytes and B cell neoplasms
`(nodular lymphoma, most chronic
`lvmphocytic leukaemias, myeloma)
`
`Commercial suppliers:
`*Ortho Pharmaceuticals, Denmark St, High Wycombe, Bucks HPI I
`2ER.
`tBecton Dickinson, 490-3, Lakeside Drive, California 94086 USA.
`tNew England Nuclear, 2 New Road, Southampton S02 OAA.
`OTHER TUMOURS
`Monoclonal antibodies have been or are being
`raised against a wide variety of human tumours,
`including gliomas, neuroblastomas, sarcomas, lung
`cancer as well as bladder, prostrate and testicular
`tumours.
`
`Clinical uses
`
`DIAGNOSIS AND MONITORING
`A major problem in clinical oncology is the measure-
`ment of tumour load in an individual patient.
`Less than 10% of all cancer patients have disease
`which can be reliably assessed by conventional
`techniques, such as palpation or diagnostic radiology.
`This hampers the evaluation of different treatment
`Certain relatively
`methods.
`rare tumours shed
`products into the circulation; and the concentration
`of these tumour markers can be related to the total
`tumour cell burden. Examples include a-fetoprotein
`in hepatoma and teratoma; human chorionic
`gonadotropin in choriocarcinoma and CEA in
`some colorectal carcinomas. Other tumour-related
`molecules are also shed into the serum but until
`now there has been no way of detecting them. By
`using specific monoclonal antibodies in a suitable
`radioimmunoassay, picogram quantities of these
`shed products can be measured. A large panel of
`antibodies
`characterised
`will
`monoclonal
`well
`therefore have considerable diagnostic use at several
`the management of cancer patients.
`in
`stages
`Firstly, patients presenting with symptoms sug-
`gestive of malignancy may have no tissue readily
`accessible for biopsy. Investigations now necessary,
`are often expensive, time-consuming and cause the
`patient considerable discomfort. Early carcinoma of
`the pancreas is a good example. The second use of
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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
`samples.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
`distinguishing
`the problems
`occuring
`with
`in
`anaplastic carcinomas from lymphomas
`certain
`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 will be of great value when limited amounts
`ofmaterial 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 polyclonal 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
`difficulty
`reproducibility
`in
`preparing and
`the
`purifying antitumour antibodies. The development
`
`Sikora
`
`of monoclonal antibodies has several advantages.
`their defined specificity may allow the
`Firstly,
`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.26 27 There are as yet, however, few
`reports on the use of labelled monoclonal antibodies
`for localisation in man. Mach and his colleagues28
`injected 14 patients with large bowel and pancreatic
`cancer with l31I-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 131I radioactivity a two to tenfold concentra-
`tion of 131I 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 study30 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 cells were
`noted after the infusion of 75 mg of antibody. The
`patient had received
`prior radiation
`extensive
`therapy and chemotherapy. There are several mecha-
`nisms by which this tumour cell destruction can
`occur. These 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 al31 showed that the growth rate
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`of human colon tumours in these animals was
`carcinoma
`reduced. A colorectal
`considerably
`specific monoclonal antibody has been used to
`explore the possibility of coupling diptheria and
`ricin toxins to produce specific cytotoxic molecules.32
`These toxins can be separated into two functionally
`distinct chains, the A active chain and the B binding
`chain. The A chains are specific inactivators of
`protein synthesis within the cell whilst the B chains
`are responsible for the binding of toxin molecules
`to receptors on cell surfaces. The A chains can be
`separated and coupled by conventional cross-linking
`agents to the antitumour monoclonal antibody.
`Such conjugates were shown to be cytotoxic in
`vitro for colorectal carcinoma cells but not toxic
`in the same concentration range for a variety of
`other human tumour and normal cell lines. The
`concept of using the antibody to provide the speci-
`ficity of delivery and the toxin as a warhead clearly
`possibilities for
`therapeutic
`promises
`interesting
`the future.
`
`References
`
`Glynn LE, Steward MW, eds. Structure and function of
`antibodies. Chichester: Wiley, 1981.
`2 Kohler G, Milstein C. Derivation of specific antibody-
`producing tissue culture and tumour lines by cell fusion.
`Eur J Immunol 1976;6:511-9.
`Old LJ. Cancer immunology: the search for specificity.
`Cancer Res 1981 ;41:361-75.
`4Sikora K, Koch G, Brenner S, Lennox E. Partial purifica-
`tion of tumour specific transplantation antigens by
`immobilised lectins. Br J Cancer 1979;40:831-8.
`5 Everson TC, Cole WH. Spontaneous regression of cancer.
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