PROBLEMS OF DELIVERY OF MONOCLONAL-ANTIBODIES - PHARMACEUTICAL AND PHARMACOKINETIC SOLUTIONS

Monoclonal antibodies to tumour-associated antigens have great theoret ical potential for the specific targeting of radioactivity and anti-ne oplastic agents to rumours. The clinical success of monoclonal antibod y-based cancer diagnosis and therapy depends, however, on solving a nu mber of pharmacokinetic delivery problems. These include: (i) slow eli mination of monoclonal antibodies from the blood and poor vascular per meability; (ii) low and heterogeneous tumour uptake; (iii) cross-react ivity with normal tissues; (iv) metabolism of monoclonal antibody conj ugates; and (v) immunogenicity of murine forms in humans. As a result of extensive pharmaceutical and pharmacokinetic research conducted ove r the past 10 to 15 years, several potential solutions to these delive ry problems have been identified. Blood concentrations of antibody con jugates may be reduced through regional administration, the use of ant ibody fragments, interventional strategies and various pre-targeting t echniques. Tumour uptake may be increased through administration of hi gher doses, or the use of agents to increase tumour vascular permeabil ity. Tumour retention of antibody conjugates may be improved by inhibi tion of metabolism, by using more stable linkage chemistry. Alternativ ely, normal tissue retention may be decreased through the use of metab olisable chemical linkages inserted between the antibody and conjugate d moiety. Very small antigen-binding fragments and peptides that exhib it improved tumour penetration and more rapid elimination from the blo od and normal tissues have been prepared by genetic engineering techni ques. Chimeric (mouse/human) and human monoclonal antibodies have been developed to circumvent the problem of immunogenicity. Future researc h will continue to be focused on improvements in the design of monoclo nal antibodies for tumour targeting, with the ultimate goal of finally uncovering the 'magic bullet' envisioned by Paul Ehrlich almost a cen tury ago.