The studies outlined above show that the choice of isotype is critical to the effectiveness of the antibody at recruiting natural effector functions. However the importance of this should not be over estimated as the nature of the target antigen seems to play an equally important role [7]. Thus when designing a therapeutic strategy it seems likely that the correct combination of target specificity and isotype will produce the optimum results. For depletion of cells in-vivo in man it would seem that the IgG1 isotype is suitable, particularly when combined with specificities such as CAMPATH-1 [15],[18]. However, the in-vitro observation that the other IgG isotypes are also effective with some individuals [31], leads one to speculate that variable results will be seen in-vivo with many antibodies. It may turn out that artificial mutants containing the best features of several isotypes, for example the shortened hinge variants of IgG3 [37], will be the best choice for a range of antigens.
For some applications it may be necessary to use a non-depleting isotype which merely targets the antigen or blocks its function [4],[33] . Whilst at one time IgG4 might have been considered for this role, the observations that, at least in some individuals, IgG4 can be as effective as IgG1 in ADCC may preclude its use [31]. An alternative is to use mutants which have had their functions destroyed and perhaps a suitable example is the aglycosyl variant. The aglycosyl CAMPATH-1 IgG1 allotype G1m(1,17) shown in Figure 5 does not cause complement mediated lysis and in the in-vivo model system in the mouse the aglycosyl IgG1 did not deplete the cells [55]. Similarly an aglycosyl variant of a humanised CD3 antibody no longer induced mitogenic responses from human T-cells in-vitro [51].
What is clear from these studies is that although we have identified some of the important features of antibodies there is still a great deal upon which we have to speculate. However, advances in current technology are allowing a new approach to many questions and we should hopefully find out much more in the near future.
We would like to thank our colleagues Herman Waldmann, John Isaacs and Steve Cobbold for helpful discussions. This work was supported by grants from the UK Medical Research Council and the Wellcome Trust (034817/Z/91/Z) and also with additional support from the Wellcome Foundation. CAMPATH is a registered trademark of the Wellcome Foundation.
Since this article was originally written the development of the CAMPATH-1 antibodies has continued but no longer as a product from Glaxo-Wellcome. For more information see the web pages for the Therapeutic Antibody Centre in Oxford.
I have also completed a more recent review of IgG structure which extends the work described here. See Clark, M (1997), Chemical Immunology 65, 88-110 Antibody Engineering IgG Effector Mechanisms. In addition there is some more online information on this topic including a useful figure marking up the residues referred to in the text of this article.