Tuesday, July 13, 2010

Antigenic modulation

28 years ago I wrote this editorial for the Lancet. It stll has relevance today as you will see in a subsequent post.

Antigenic modulation

The passive serotherapy of cancer has had a long gestation and little success. However, the advent of monoclonal antibodies with their high specificity has awakened interest in the subject. Lately there have been several reports of attempts to treat lymphoid malignant disease with murine monoclonal antibodies, and antibodies to melanoma, neuroblastoma, leiomyosarcoma, teratoma, and colonic and breast carcinomas have been raised. It has also been proposed that monoclonal antibodies might be used to remove T cells before bone-marrow transplantation to prevent graft-versus-host disease, and to remove tumour cells from bone-marrow autografts after high-dose chemotherapy.

All these applications are threatened by the phenomenon of antigenic modulation. This effect was first described by Boyse et al. for the TL antigen of murine thymic leukaemia, and involves the temporary disappearance of the target antigen from the surface of the tumour cell in the presence of antibody. When antibody is removed from the system the cell re-expresses the antigen. The process begins with the complexing of antibody with antigen on the cell surface. One divalent molecule of antibody links with adjacent molecules of antigen, so that the antigen is rearranged into patches and caps before internalisation of the whole complex by pinocytosis.

The speed of the reaction is remarkable. Incubation of the target cell with antibody at 37 deg C for as little as two minutes can prevent complement-dependent cytolysis. Complete clearance of the antigen is not, apparently, necessary to render the antibody ineffective, and mere persistence of the antigen on the surface of the cell does not mean that that cell will be susceptible to antibody-induced killing or clearing. Simple rearrangement of antigen and antibody in the lipid bilayer seems to hinder the deposition of complement components sufficiently to protect the cell surface. In some systems antigenic modulation takes place so quickly that it appreciably protects the cell even against simultaneous attack by antibody and complement.

A further contribution to chronic antigenic modulation in vivo arises from the
metabolic response to the combination of antibody with cell surface antigen. A surge of intracellular cyclic AMP is succeeded by reduced delivery of antigen to the cell surface. Antibodies kill tumour cells by invoking various effector mechanisms such as complement dependent cytolysis, K cell killing, and binding to Fc or C3 receptors on macrophages. All these mechanisms depend on the antibody remaining on the cell surface in an accessible form for a finite period, and all are susceptible to antigenic modulation.

Most current attempts to bypass this mechanism involve giving the antibody a "warhead" so that these effector mechanisms need not be invoked. It has proved difficult to link cytotoxic drugs to antibody in such a way that the link remains stable in vivo. Labelling the antibody with radioactive isotopes 7 carries the risk of obliterating the antibody combining site. Some groups have tried coupling the biological toxins abrin and ricin to antibody but their safety in vivo remains in doubt.

A more attractive solution has been offered by Glennie and Stevenson. They have constructed a univalent antibody by papain cleavage of one Fab fragment from each immunoglobulin molecule. The resulting antibody cannot cross-link with adjacent antigen molecules and therefore does not cause antigenic modulation. However, it does retain the ability to fix complement. To show its efficacy they have treated the guinea pig prolymphocytic leukaemia L2C with a polyclonal, univalent rabbit antibody against the idiotypic determinants of the surface immunoglobulin. Univalent antibody was more effective in vitro at inducing complement-dependent cytolysis and in vivo it prolonged the life of the guinea pig. In this it was three times as effective as whole IgG. This particular biochemical manoeuvre is effective only for
rabbit IgG but other procedures are available to produce univalent antibody from the immunoglobulin of other species. When they are applied to murine monoclonal antibodies there are immense prospects for successful immunotherapy.


Anonymous said...

Do you know...do the various SMIPs (eg, TRU016) have the ability to avoid the mechanism present with more typical monoclonal antibodies?

Brian Koffman said...

I had no sense of the underlying complexity of the resistance to monoclonal antibodies.
Thanks for explaining