INTRODUCTION – ASSEMBLING AN ATOMIC BOMB
That antibodies have the specificity necessary to deliver targeted therapy was realised shortly after their discovery in the 1890s . During subsequent years, however, it has proved difficult to produce antibody constructs that destroy tumour cells effectively in vivo.
Following the introduction of monoclonal antibodies (MAbs) in the 1970s, several conditions necessary for effective antibody-mediated tumour cell lysis have been identified . These conditions include correct choice of immunoglobulin isotype to activate natural effector mechanisms (including complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC)), correct choice of target antigen as well as other factors described below.
Despite these advances, as single agents, the effects of most MAbs in oncology are often only modest, and with the possible exception of anti-immunoglobulin idiotypic MAbs, none are curative. Consequently, the use of MAbs labelled with radioisotopes, drugs or with potent toxins is being investigated [3; chapters 9,10,11,12,13 in this book]. However, since it is possible to eradicate disease in animals with passive antibody therapy using relatively small doses of MAbs , confidence remains high that it should be possible to do the same in man.
Identified barriers to effective antibody therapy with unconjugated MAbs include:
Circulating free antigen. All cell surface antigens will be found in the circulation at low levels, but high levels will preclude tumour cell uptake. CD23, for example, is shed into the circulation in high quantities in patients with advanced chronic lymphocytic leukaemia (CLL). This problem can be overcome by using higher doses of MAb, but at a potential risk of immune complex disease.
Cell surface antigenic modulation and internalisation. Many cell surface molecules rapidly ‘cap’ and then internalise in the presence of bivalent MAb. This process can occur very rapidly (within minutes) and effectively renders a cell antigen negative – reappearance of cell surface antigen on the other hand may take several hours. Internalisation of MAbs conjugated with either toxins or radioisotopes is necessary, or at least desirable, for efficacy. In contrast, efficacy of most unconjugated MAbs demands the maintained presence of intact MAb at the cell surface (however, if continued signalling via a cell surface molecule is necessary for survival, then removal via modulation might be advantageous) . Modulation limits the number of molecules that can be successfully targeted using regular bivalent MAbs, although this problem may be circumvented by generating monovalent MAbs, either by cell fusion or by genetic manipulation .
Low cell surface antigen density. It is widely believed that high antigen density is necessary for effective MAb action. A certain level of antigen density may be necessary to elicit antibody-mediated cross-linking of the target antigen. However, the empirical evidence for the necessity of high antigen density is lacking and it is clear from the doses of alemtuzumab that ...