H y b rid o m a technology has p ro d u c e d m o n o clo n al an tib o d ies directed ag ain st antigens on the tu m o u r cell surface. M any tu m o u r antigens have been identified as potential targets for antibody-directed th erap y b u t m ost are also expressed by norm al tissues an d are tum our- related molecules occurring at greater concentrations in tu m o u rs (K ohler
et al., 1975).
The ability to grow hum an tum ours as xenografts in n u d e mice has p ro v id e d a u sefu l m odel for the stu d y of a n tib o d y lo calisatio n in tu m o u rs. The su p erio rity of specific over non-specific an tib o d y w as d e m o n s tra te d in early stu d ie s w h en rad io la b e lle d a n tib o d ie s to carcinoem bryonic antigen (CEA) localised specifically in colon cancers grow ing in mice (Much et a l , 1974) . W ith external gam m a scintigraphic im ag in g it becam e possible to im age tu m o u rs, first in m ice an d su b seq u e n tly in m an w h en deposits of colon cancer w ere im ag ed follow ing intravenous injection of a radiolabelled anti-CEA m onoclonal an tib o d y (G oldenberg et a l , 1974; G oldenberg et a l , 1978). It w as hoped th a t m onoclonal an tib o d ies w o u ld rev o lu tio n ise the d iag n o sis an d treatm ent of hitherto untreatable tum ours and initial pilot studies w ere
encouraging (Miller et al., 1982; Sears et ah, 1982). How ever, it has become clear that there are problem s w ith antibody targeting in m an th at differ from the m ouse xenograft model.
The success of antibody-directed tu m o u r detection and th erap y depends on the ability of the antibody to localise specifically in a tum our. The tu m o u r to n o rm al tissue u p tak e ratio sh o u ld be h ig h an d an ad eq u ate dose of antibody needs to be delivered to the tum our. The fu n d am e n ta l problem w ith an tib o d y targ e tin g in m an is th a t after intravenous adm inistration of antibodies, only a very sm all proportion, about 0.005%, localises to tum ours. This differs from the anim al m odel w here accum ulation of antibody in xenografts is 100-1000 tim es greater (Schlom, 1986). It is difficult to deliver adequate am ounts of antibody to achieve a tum ouricidal effect w ith o u t dam aging o th er n o rm al tissues such as bone m arrow , liver and kidney. In a d d itio n to im p ro v in g delivery of im m unoconjugate to tum our, a further challenge has been to overcom e the hum an anti-m ouse antibody response (HAMA) (Schroff et ah, 1985). Tum ours are rarely cured by a single treatm ent and strategies to overcom e HAMA have been sought to allow adm inistration of repeated therapies.
2.9.2 Therapeutic strategies
Most tum ours are poorly im m unogenic in the host and n atu rally occurring antibody responses are not effective. Limited success has been rep o rte d follow ing the a d m in istratio n of an ti-id io ty p e an tib o d ies to tum ours such as lym phom as which express unique antigens (Miller et ah,
1982) b u t results in solid tu m o u rs are generally d isap p o in tin g . The m ec h an ism of actio n is n o t u n d e rs to o d b u t p ro b a b ly in v o lv e s recruitm ent of n atu ral effector m echanism s including cytotoxic T cells, com plem ent and antibody-dependent cellular cytotoxicity.
For th erap y and im aging antibodies are usually conjugated to a radioactive isotope m ost com m only iodine-131. This em its p rad iatio n capable of penetrating about 1mm, about 40 cell diam eters, w hich helps to overcom e the disad v an tag es of u n equal an tib o d y d istrib u tio n w ith in tu m o u rs. In anim al m odels, injection of radioim m unoconjugates has p ro d u ce d grow th delay of h u m an xenograft tu m o u rs including colon carcinom a (Buchegger et aL, 1989), neuroblastom a (C heung et ah, 1986) and lung cancer (see below). In hum ans, radiolabelled antibodies have been successfully used in the treatm ent of hepatom a and lym phom a w ith response rates in the order of 40% (Lenhard et aL, 1985; O rder et aL, 1985). H ow ever in trials w ith colorectal cancer, m elanom a and neuroblastom a only lim ited responses have been seen w hich are not sustained.
Antibodies have also been conjugated to cytotoxic agents and high potency toxins such as ricin, a protein synthesis inhibitor derived from beans. In a clinical stu d y w here ricin A chain w as conjugated to an antim elanom a an tibody som e responses w ere o bserved (Spitler et aL,
1987). By linking antibodies to enzym es w hich can convert a p ro d ru g to its active form, large am ounts of active d ru g can be generated at tu m o u r sites. ADEPT (antibody directed enzym e p ro d ru g therapy) can eradicate xenografts of hum an choriocarcinoma in n u d e mice (Springer et aL, 1991) b u t as yet no responses in patients have been reported.