MonoclonalAntibodies in Medicine

Adapting antibodies for clinical use

Robert E Hawkins, Meirion B Llewelyn, Stephen J Russell

Techniques for antibody engineering are now over-coming the problems that have prevented mono-clonal antibodies being used routinely in clinicalpractice. With chemical and genetic manipulationantibodies can be linked to bacterial toxins, enzymes,radionuclides, or cytotoxic drugs, allowing targetingof treatment. Antigen binding sites from antibodiesraised in mice can be joined with human IgG toreduce immunogenicity. In vitro gene amplificationand genetic engineering of bacteriophage have pro-duced large antibody gene libraries and facilitatedlarge scale production of human monoclonal anti-bodies with high specificity. The trickle of mono-clonal antibodies into clinical practice may soonbecome a flood.

In our first article we described the early history ofpassive serotherapy, leading up to the discovery ofmonoclonal antibodies.' Once the potential of mono-clonal antibodies was appreciated numerous usefuldiagnostic tests followed. However, it soon becameapparent that murine monoclonal antibodies in theirnative form were unsuitable or ineffective for mosttherapeutic applications. Their fine structure differssignificantly from that of human antibodies and inmany cases the Fc portion is virtually unseen by humanFc receptors and complement proteins, resulting infailure to initiate human defence machanisms (effectorfunctions). Mouse monoclonal antibodies can alsoelicit a strong antimouse protein immune response thatgreatly reduces their circulating half life. Theseproblems should not arise with human monoclonalantibodies, but they are much more difficult to make.'Fortunately, through developments in basic sciencessolutions to these problems are emerging and thepromise of human monoclonal antibody therapy is atlast becoming a reality. The immunogenicity of rodentmonoclonal can now be reduced, to improve theirability to recruit natural effector functions and increasetheir affinity. Many different antibody fragments canbe produced and linked to various effector functions.More recently methods have begun to emerge forgenerating and screening large libraries of humanantibodies entirely in vitro.

In this article we review some of the technicalachievements of antibody engineering. Regardless ofhow a monoclonal antibody is produced, it may bedesirable to tailor it to suit its intended applicationbetter. This can be achieved through chemical orgenetic approaches. Figure 1 shows some of thepossible modifications.

Chemical modification ofmonoclonal antibodiesPROTEOLYTIC CLEAVAGE

Controlled proteolytic cleavage of a purified mono-clonal antibody gives several smaller fragments thatcan be separated chromatographically. Cleavage wasimportant in the early elucidation of antibody structureand structure-function relations but also has thera-peutic implications. Antibody fragments are some-times preferable to intact antibodies as they have ashorter circulating half life and may penetrate tissuesmore rapidly.

Fab(50 kDa)

Fv(25 kDa)

VHHVCHI| CL /

I Single chain FvH 2L Da

Fab fused totoxin

or enzyme

VH VL

CHI CL

Single chain Fvfused to toxin

FIG 1-Antibody fragments. Limited proteolytic cleavage of IgGremoves the Fc portion yielding bivalent F(ab )2 (1 OOkDa) ormonovalent Fab antigen binding fragments. Cloned T genes for Fabcan be expressed in mammalian cells, yeast, or bacteria to producefunctional recombinant Fab molecules. Toxins and enzymes can befused to the recombinant Fab by genetic engineering. Smaller antibodyfragments (Fv) can be produced in bacteria by coexpression of clonedVH and VL genes and stability is increased when VH and VL are linked(genetically) by a short peptide (single chain Fv or scFv). This can alsobe linked to toxins genetically

CHEMICAL COUPLING

Monoclonal antibodies and antibody fragments canbe conjugated chemically to a variety of substances,including plant and bacterial toxins, enzymes, radio-nuclides, and cytotoxic drugs. In this way, an ineffec-tive rodent antibody or antibody fragment may bearmed with a potent effector mechanism. Fragmentscoupled to radioactive elements can also be used for invitro imaging or cancer therapy. However, the chemicalcoupling processes can be inefficient or give rise tounstable products, and repeated cycles of antibodypurification, modification, and repurification are timeconsuming and costly.

Genetic modification ofmonoclonal antibodiesIn contrast to a hybridoma or the protein it secretes

an antibody gene is highly versatile. It can be cut,joined to other genes, mutated randomly or non-randomly, and expressed in various cell types. The

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This is the second of threearticles examining thedevelopment and clinicalapplications ofmonoclonalantibodies.

Medical Research CouncilCentre and Addenbrooke'sHospital, CambridgeCB22QHRobert E Hawkins, CRCsenior clinical research fellowMeirion B Llewelyn, MRCtrainingfellowStephen J Russell, MRCclinical scientist

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genes can be introduced into appropriate plasmidvectors and transfected into mammalian cells, bacteria,insect cells, or even plant cells for protein expression.

ANTIBODY FRAGMENTS

Antibody fragments similar to those generated byproteolytic cleavage can be generated from shortenedversions of the heavy and light chain genes. Themodified genes can then be transfected into bacteria2 ormammalian cells where they produce functional Fv(variable fragment) or Fab (antigen binding fragment)which is then easily purified. Bacteria are unsuitablehosts for producing complete monoclonal antibodiesbecause the Fc domain of antibodies produced in thisway is non-functional.

ANTIBODY FUSION PROTEINS

Genetic engineering has been used to create chimericmolecules in which the variable domain of an antibodyis genetically linked to an unrelated protein. In thisway enzymes, toxins, and cytokines, for example, canbe given novel binding specificities and can be producedin bacteria.3 The approach is made easier when theantibody moiety is expressed as a single chain Fv(scFv) molecule in which the heavy and light chain Vdomains are linked by a short peptide that does notseriously affect antigen binding. The antibody canthen be expressed as a single protein from a single generather than as two chains that must subsequentlyassociate somewhat inside the cell. Several bacterialtoxin-scFv fusion proteins have been produced, andbecause they are smaller than intact antibodies, it ishoped they will prove able to penetrate tumours moreefficiently.

Antibodies can also be expressed on the surface ofcytotoxic effector cells, redirecting them to kill noveltargets. This approach has been used to redirect Tcells4 and has many potential applications to improvecellular immunotherapy.5

HUMANISATION

Chimeric antibodies-Genetic manipulation can alsobe used to make chimeric antibodies-that is, anti-bodies with rodent variable domains for antigen bind-ing and human constant regions for recruiting effectorfunctions.6 The initial stimulus to this research was thedifficulty in producing human monoclonal antibodiesof the desired specificity and affinity. The resultantmolecule (fig 2) is largely human but binds with the

FIG 2-Genetic mdnipulation to produce chimeric (left) or humanised (right) antibodies. The parts ofmouse origin are shown in orange and those of human origin in white. In the humanised version onlythe antigen binding loops are ofmouse origin

specificity of the parent monoclonal. Chimerisationenhances effector functions7 but a significant part ofthe molecule is still of rodent origin and recent humantrials have shown that over half of humans mount anantimouse response after receiving a chimeric anti-body.8CDR grafted antibodies-Structural analysis of anti-

body-antigen complexes shows that the antigen bindingsurface of the antibody is formed by six hypervariableloops of amino acids called complementarity determin-ing regions (CDRs). These loops are mounted onrelatively constant framework regions and by geneticmanipulation can be transplanted (fig 2) from a rodentantibody on to a human framework. This produces aCDR grafted or humanised antibody with the samespecificity as the rodent monoclonal antibody'fromwhich the loops were grafted.9 The process usuallyreduces the affinity of the antibody, but mutations canbe made to restore full binding. Several antibodieshave now been humanised'° and one has already beenused with clear therapeutic benefit."

BISPECIFIC ANTIBODIES

Bispecific antibodies have two antigen binding sites,each with a different binding specificity. Conven-tionally, they have been produced by fusing twohybridoma lines to make a hybrid hybridoma'2 or bychemical cross linking of antibody fragments. Becauseof random pairing of heavy and light chains and ofheavy chain-light chain heterodimers, on average lessthan 1O0% of the IgG secreted by a cell expressing twoantibody genes displays both of the required specifici-ties. Genetic techniques allow the production of con-structs which facilitate the association of non-identicalspecies. For example, one heavy chain has been tailedwith a fos peptide and the other with a jun peptide (fosand jun are nuclear proteins which bind strongly toeach other)." Bispecific monoclonal antibodies havebeen used to cross link cytotoxic effector cells to targetsthat they would not otherwise recognise-for example,tumour cells-and the approach has been used withapparent benefit in the treatment of malignantgliomas.'4 They can also be used to redirect toxins andenzymes to specific cellular targets.

Bispecific antibodies may also show greater targetcell specificity than two monospecific antibodies.Target cells often express a constellation of antigens,each ofwhich is found on certain normal host tissues. Abispecific antibody derived from monoclonal antibodiesagainst two different antigens, expressed singly onseparate host tissues but together on the target, shouldhave more specific targeting properties than eithermonoclonal antibody alone.

Rapid cloning ofantibody genesNo two antibody genes are identical so it might be

expected that cloning each gene would be a tediousprocess. However, with the development of rapidmethods based on the polymerase chain reactioncloning functional, rearranged V genes has becomeroutine.The polymerase chain reaction is a simple and

elegant three step laboratory procedure for producinglarge numbers of faithful copies of a DNA sequence. Inthe first step double stranded template DNA is"melted" into single strands by heating to 95°C. Thistemplate DNA may be derived from any source,including the chromosomal DNA or messenger RNAof a mammalian cell. In the second step the reaction iscooled to allow annealing of oligonucleotide primers tothe single stranded template. The synthetic oligo-nucleotide primers are composed of 15-30 deoxy-nucleotides (dA, dT, dC, and dG) which bind specifi-cally to their complementary sequences on the single

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stranded DNA template. The precise sequence (andlength) of each oligonucleotide can be predeterminedto ensure highly specific binding to chosen targetsequences at an appropriate annealing temperature.The minimal requirement is for two oligonucleotides,each complementary to a different strand of the targetDNA, which flank the template sequence to beamplified. In the third (elongation) step, the templatebound oligonucleotides prime synthesis (catalysed by aheat stable polymerase) of new DNA. Both strands ofthe template are duplicated between the primers,doubling the amount of DNA of interest. The wholecycle (lasting as little as three minutes) is repeatedmany times on an automated heating block andexponentially amplifies the DNA sequence.

Although they differ in the middle, all antibody Vgenes are similar at either end, which allows construc-tion of oligonucleotide sets whose sequences recogniseand bind to the terminals of most V genes and primethe polymerase chain reaction.'5 Oligonucleotide setsare available for amplification of murine or human Vgenes.

It is now possible to amplify and rescue most of theantibody V genes from a diverse population of humanor murine B cells, thereby generating an antibody genelibrary. This method works equally well with any typeof B cell-resting B cells,'6 antibody secreting plasmacells, or memory B cells'7-and the starting materialmay be either RNA or DNA.Whatever the source of the antibody gene library, its

usefulness depends on the availability of a convenientsystem for expressing the genes and selecting thosewhich encode the best antibodies. Until recently, thebest system available was suitable for screening nomore than a million transfected colonies of Escherichiacoli,'8 which is at least two orders of magnitude lowerthan the number of antibodies screened by an intactimmune system. However, with the arrival of phageantibodies (see below),'9 libraries containing at least108 different antibodies can now be screened.

Phage antibodiesFilamentous bacteriophage (hereafter referred to as

phage) are pencil shaped viruses that infect bacteria.They attach to the surface of bacterial cells and injecttheir single stranded DNA genome through the cellwall. The infected bacterium does not die but continuesto divide, distributing copies of the viral genome on toits progeny, which assemble and extrude perfectreplicas of the invading phage. After overnight incuba-tion, one millilitre of the bacterial culture supematantcontains over 10" progeny phage particles.

At one tip of the phage are a few (probably three)copies of a protein (gene III protein). This proteinmediates the initial attachment of the phage to abacterial cell. To make a phage antibody the gene foran antibody fragment is fused precisely to one end ofgene III on the phage genome. When this modifiedphage DNA is transfected into a bacterial cell, the cellproduces and extrudes progeny phage particles thatnot only display the appropriate antibody at their tip(in fusion with the gene III protein) but also contain asingle copy of the antibody gene and are still able toinfect bacteria almost as efficiently as unmodifiedphage. Antibodies displayed on the surface of phageare fully functional and will still bind their antigenspecifically. Phage antibodies with the desired specifi-city can be purified from a mixed population because oftheir ability to bind antigen."Thus a phage antibody is the functional in vitro

equivalent of a resting B cell. It contains an antibodygene and displays the corresponding functional anti-body on its surface. It can be selected for its ability torecognise a particular antigen, whereupon it can beamplified by growth in bacterial culture. It is thensimple to rescue the antibody gene, which can be usedto produce large amounts of soluble antibody (like theplasma cell) or simply stored in the freezer (actingsimilarly to the memory cell).

Phage antibody librariesThe intact humoral immune system is essentially a

large library of antibodies. After challenge withantigen the most suitable antibodies are selected,amplified, and affinity matured. If the whole processcould be reproduced entirely in vitro, production ofhigh affinity human monoclonal antibodies might begreatly simplified.20 With phage antibody libraries (seebelow) this goal is fast becoming a reality and theseshould increase the pace at which antibody therapydevelops.

If a phage antibody can be likened to a B cell, then aphage antibody library is the in vitro equivalent of thehumoral immune system (fig 3). A phage antibodylibrary is constructed by ligating an antibody genelibrary (amplified by the polymerase chain reaction)into the appropriate site on purified phage DNA. Theligated DNA is transfected into bacteria, which thenmanufacture large numbers of phage antibodies, andthose with the desired binding specificies are selectedby using soluble tagged antigen or an antigen coatedsurface. Although still in its infancy, phage technologylooks set to make a major impact on antibody develop-ment.

Phagg Phage displaysystem l.ibrary

Andgiselecd

Anbody gene library clo"nedby polnierase hAdinacdof

.N?tural Na'i.."Nve.uiva lent, , ,.'. B cell

.'., ,^ ,repertoire,

..*.

Antigen specificphage

.. Primas-yresponse-tibdy..

pake,attibo4

mutatl0n I..ilAffinky,

a.ntbodyFIG 3-In vitro antibodies compared with the natural humoral immune system. The phage system allowsall aspects ofthe humoral immune system to be mimicked in vitro

Potential ofphage antibody technologyHUMAN MONOCLONAL ANTIBODIES

Recently, the V genes from the lymphocytes of twohealthy blood donors were cloned and expressed on thesurface of bacteriophage. From this single phagelibrary, consisting of 20 million clones, antibodiesspecific for a variety, of test antigens were selected.'6This "natural" library approach greatly simplifies thegeneration ofhuman antibodies.

Currently, B cell derived heavy chain and light chain(x and X) V genes are amplified separately and mustsubsequently be recombined for expression on phage.By this stage the original pairings between the heavyand light chains have been lost, leaving no option but torecombine the chains randomly before they are trans-fected into E coli for expression and screening. 8 The invitro antibody library is therefore dominated by heavyand light chain pairings that were not present in theoriginal B cells. Alternative methods are beingdeveloped which retain the original pairings and thus

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prepare the library as a faithful copy of the antibodiesexpressed on B cells.2' However, the random combina-torial approach may be an advantage for in vitroproduction of antiself antibodies (see below).

PHAGE "POLYCLONALS"

The natural immune response is polyclonal and thusa cocktail of monoclonal antibodies raised against asingle antigen may be more effective than a singleantibody. It has been so difficult to make humanmonoclonal antibodies that this approach has not beengenerally feasible. With phage antibody libraries, thismay soon change. Already, starting from the bonemarrow of a person infected with HIV, large numbersof human antibodies against HIV have beengenerated.22 Natural libraries will certainly improve interms of both size and their starting genetic material,and thus it should be possible to isolate multiplehuman antibodies to any antigen from a single libraryof sufficient size in a few weeks. Eventually, the wholeprocess may be automated.

Considerable effort is currently being devoted toconstructing large phage antibody libraries, orders ofmagnitude larger than the entire antibody repertoire ofthe human immune system. In time, such libraries maysupply all the antibodies and allow reproducible"polyclonal" human antisera against any antigen to begenerated. By comparison, more conventional methodsof tapping the immune system of an immunised mouseor human may seem inefficient, expensive, time con-suming, and relatively cumbersome.

ANTISELF ANTIBODIES

Humans can legitimately be immunised with avariety of viral and bacterial proteins and their circulat-ing B cells subsequently harvested for production ofmonoclonal antibodies. However, when the goal is toraise human monoclonal antibodies against selfproteins(tumour antigens and lymphocyte markers, forexample) immunisation is inappropriate. Firstly, it isunlikely to be successful since the educated humanimmune system has complex in built control mech-anisms that prevent the production of potentiallydamaging high affinity antiself antibodies. Although aproportion of the normal B cell repertoire is intrinsicallyantiself, these antibodies tend to have relatively lowaffinity, are polyreactive and do not significantlydamage host tissues. Secondly, if the state of selftolerance is broken by immunisation with self proteins,autoimmune disease may result. Phage antibody lib-raries may prove a rich and convenient source of highaffinity human antiself antibodies. Because the originalpairings of heavy and light chains are scrambled, mostof the antibodies in a library differ from those in the Bcells from which they were derived and may thereforebe more likely to have a high affinity for self proteins.Several antibodies against human self proteins havealready been extracted from one large human phageantibody library.'6

AFFINITY MATURATION

Antibodies from natural phage libraries can have lowaffinities,6 but once again phage technology is provid-ing the solution. Larger libraries are expected toprovide higher affinity antibodies, but the phagesystem can also be used for affinity maturation. Afterisolating a low affinity antibody from a primary phagelibrary, the genes can be diversified in several ways andused as the basis for a secondary phage library. Higheraffinity variants of the original antibody can be selectedfrom the secondary library (fig 3). In the immunesystem affinity maturation occurs by random mutationin antibody V genes during B cell division: occasionallysuch mutations result in improved affinity. This processcan now be reproduced in the laboratory by using the

polymerase chain reaction under imperfect conditionsto mutate the antibody gene and create a phage libraryof random mutants. Higher affinity variants can thenbe selected from this library.23

Additional methods of diversifying the initial reper-toire have been developed. For example, the heavychain of a low affinity antibody can be retained in itsoriginal form and recombined with a large library ofcomplementary light chains (or vice versa) to create asecondary "chain shuffled" library.24 Also, any part ofeither chain can be held constant while other parts arediversified by polymerase chain reaction driven re-combination with gene libraries or synthetic oligo-nucleotides.

In vitro affinity maturation on phage can be appliedto any antibody regardless of its original source. Thismay prove useful for improving antibodies that haveshown promise in clinical trials, particularly in view ofthe recent finding that increased affinity of an anti-tumour antibody was associated with improved thera-peutic efficacy.23

Future ofantibody engineeringThe technological trickery of antibody engineering

is advancing more rapidly than it can be tested intherapeutic models. This presents a problem forpharmaceutical companies because in the time it takesthem to scale up production methods for their mostpromising therapeutic monoclonal antibody, both theproduction method and the antibody may have beensuperseded. Notwithstanding, several companies havetaken the plunge, and monoclonal antibodies arebeginning to trickle into clinical practice. This tricklewill probably soon become a flood and, faced with aplethora of cleverly conceived and constructed, butcompleting reagents, clinicians will benefit from anunderstanding of some of the principles of antibodytherapy. The third article in this series tackles thisissue and outlines those areas of medicine in whichantibody therapy is likely to be valuable.

We thank Cesar Milstein, Geoff Hale, Kerry Chester, andGreg Winter for encouragement and critical reading of themanuscript. REH is supported by a Medical ResearchCouncil training fellowship. MBL is funded jointly by MRCand Celltech, SJR is an MRC clinician scientist with additionalsupport from Kay Kendall Research Foundation and LouisJeantet Foundation.

1 Llewelyn MB, Hawkins RE, Russell SJ. Discovery of antibodies. BAf1992;305: 1269-72.

2 Skerra A, Pluckthun A. Assembly of a functional immunoglobulin Fvfragment in Escherichia coli. Science 1988;240:1038-41.

3 Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptorchimeric molecules as functional receptors with antibody-type specificity.Proc NatlAcad Sci USA 1989;86:10024-8.

4 Rosenburg SA. The immunotherapy and gene therapy of cancer. J Clin Oncol1992;lO: 1 80-99.

5 Milstein C, Cuello AC. Hybrid hybridomas and their use in immunohisto-chemistry. Nature 1983;305:537-40.

6 Neuberger MS. Williams GT, Mitchell EB, Jouhal SS, Flanagan JG, RabbittsTH. A hapten-specific chimaeric IgE with human physiological effectorfunction. Nature 1985;314:268-70.

7 Bruggemann M, Williams GT, Bindon CI, Clark MR, Walker MR, Jefferis R,et al. Comparison of the effector functions of human immunoglobulins usinga matched set of chimeric antibodies. JExp Med 1987;166:1351-61.

8 Meredith RF, Khazaeli MB, Plot WE, Saleh MN, Liu T, Allen LF, et al.Phase I trial of iodine-131-chimeric B72.3 (human IgG4) in metastaticcolorectal cancer. JNuclMed 1992;33:23-9.

9 Jones PT, Dear PH, Foote J, Neuberger MS, Winter G. Replacing thecomplementarity-determining regions of a human antibody with those froma mouse. Nature 1986;321:522-5.

10 Russell SJ, Llewelyn MB,H-Hawkins RE. The human antibody library: enteringthe next phage. BMJ 1992;304:585-6.

11 Hale G, Clark MR, Marcus R, Winter G, Dyer MJS, Phillips JM, et al.Remission induction in non-Hodgkin lymphoma with reshaped monoclonalantibody CAMPATH- IH. Lancet 1988;ii: 1394-9.

12 Pastan I, Fitzgerald D. Recombinant toxins for cancer treatment. Science1991;254:1 173-7.

13 Kostelny SA, Cole MS, Tso JY. Formation of a bispecific antibody by use ofleucine zippers. JImmunol 1992;148:1547-53.

14 Nitta T, Sato K, Yagita H, Okumura K, Ishii S. Preliminary trial of specifictargeting therapy against malignant glioma. Lancer 1990;335:368-7 1.

15 Orlandi R, Gussow DH, Jones PT, Winter G. Cloning immunoglobulin

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variable domains for expression bv the polymerase chain reaction. Proc NatlAcadScz USA 1989;86:3833-7.

16 Marks JD, Hoogenboom HR, Bonnert TP, MacCaffertv J, Griffiths AD,Winter G. By-passing immunization: human antibodies from V-genelibraries displayed on bacteriophage. J Mol Biol 1991 ;222:581-97.

17 Hawkins RE, Winter G. Cell selection strategies for making antibodies fromvariable gene libraries: trapping the memory pool. Eur. Inmntnnol 1992;22:867-70.

18 Huse WD, Sastrv L, Iverson S, Kang AS, Alting-Mees M, Burton DR, et al.Generation of a large combinatorial library of the immunoglobulin library inphage lambda. Scietice 1989;246:1275-81.

19 MacCafferty J, Griffiths AD, Winter G, Chiswell DJ. Phage antibodies:filamentous phage displaying antibody variable domains. Nature 1990;348:552-4.

20 Winter G, Milstein C. Man-made antibodies. Nature 1991;349:293-9.21 Embleton MJ, Gorochov G, Jones PT, Winter G. In-cell PCR from mRNA:

amplifying and linking the rearranged immunoglobulin heavy and lightchain V-genes within single cells. Nucleic Acids Research 1992;20:3831-7.

22 Burton DR, Barbas CF, Persson MMA, Koenig S, Chanock RM, Lerner RA.A large array of human monoclonal antibodies to type I human immuno-deficieny virus from combinatorial libraries of asymptomatic seropositiveindividuals. Proc NatlAcad Sci USA 1991;88:10134-7.

23 Hawkins RE, Russell SJ, Winter G. Selection of phage antibodies by bindingaffinity: mimicking affinity maturation. I Mol Biol 1992;226:889-96.

24 Marks JD, Griffiths AD, Malmqvist M, Clackson TP, Bye JM, Winter G. By-passing immunisation: building high affinity human antibodies by chainshuffling. Bio/Technology 1992;10:779-83.

25 Schlom J, Eggensperger D, Colcher D, Molinolo A, Houchens D, Miller LS,et al. Therapeutic advantage of high-affinity anticarcinoma radioimmuno-conjugates. Cancer Res 1992;52:1067-72.

(Accepted 19 October 1992)

Medical Education

Student selection

Stella Lowry

Medicine is often seen as a difficult university subjectto enter, with medical schools choosing only the creamof students from many eager applicants. Certainlymany schools spend considerable time, effort, andmoney on their selection process, but are they reallygetting a good return on this investment? Do we get thesort of medical students and doctors that we want? Arewe even clear about what we want? Does it matter,anyway?

What do we want?If medicine was simply a degree course like any other

there would be little need for elaborate selectionprocesses. Minimum scholastic achievement could bedefined before entry to ensure that students had a fairchance of keeping up with the course, but places couldthen be awarded by lottery.Most people, however, see the medical course as a

vocational training. Applicants are expected to makemedicine their career. Candidates are asked "Why doyou want to be a doctor?" not "Why do you want tostudy medicine?" This is in sharp contrast with otherdegree courses. We do not, for example, expect allgraduates in English to write or teach for a living. Nordo we insist that graduates from other facilities should"repay" society by obtaining any employment, muchless in a specified field. A spattering of students who

How many yo'ung people like these will apply to and be accepted by medical schools?

study medicine for its own sake might even enhancethe educational climate in many of our medical schools.

If we assume, however, that medical education willcontinue, for now, to be about training doctors theselection process becomes one of choosing people whowill make good doctors. This immediately raises theproblem of defining a good doctor. Is there really anessential common core of knowledge, skills, andattitudes that all doctors should have? In a professionlike medicine there may well be niches for all-regardless of their particular interests, skills, andweaknesses. Specific aptitudes are doubtless importantin selecting people for specialist training, but theirrelevance at the undergraduate stage is much lessobvious.

Is there an end product?If we could clearly identify the aims of under-

graduate medical education we could begin to decidehow best to select medical students. The GeneralMedical Council defines the principal objective of basicmedical education as providing "the knowledge, skillsand attitudes which will provide a firm basis for futurevocational training."'The only immediate requirement is to produce a

graduate who can function as a preregistration houseofficer. This should enable an essential core of factualknowledge and clinical skills to be defined that alldoctors should have mastered by the end of the course.They will then have to embark on a protractedpostgraduate education in their chosen specialty. Allmedical graduates should therefore have the skills toenable them to continue learning beyond university.

In recent years the trend has been for medicalschools to select only the most academically giftedapplicants, with standard offers of places oftendepending on acquiring three "A" grades at A level.This attitude is now changing, more schoolsacknowledging that people with only moderateacademic achievement can cope well with the courseand often have more to offer in terms of personal skills,attitudes, and experience. Dr John Foreman, subdeanof University College and Middlesex School ofMedicine, University College, London, recentlyexplained the school's reasons for setting low mini-mum requirements for entry: "Our standard offer of C,C, C is the lowest in the country.... We stronglybelieve C, C, C reflects the level of academic abilityneeded to follow the course. It gives us the scope toadmit people below the academic average for medicine,

This is the second in a series ofarticles examnining theproblems in medical educationand their possible solutions

British Medical Journal,London WCIH 9JRStella Lowry, assistant editor

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