Engineering antibodies for therapy.

Abstract

For most MAb-based therapies single doses of MAbs or MAb conjugates will not be curative. Rodent MAbs are highly immonogenic in almost all patients. The HAMA response abrogates efficacy and can cause toxicity in organs of clearance, especially for MAb-cytotoxic agent conjugates. Humanization is the most promising generally applicable approach to overcoming the immunogenicity of rodent MAbs. Chimerization reduces immunogenicity in patients significantly, but not completely. Full humanization of rodent antibodies with retention of most of their antigen binding activity is now a routine procedure. The studies with 4D5 (Kelley et al., 1992), however, illustrate that even when antigen binding activity is retained, humanization may affect the overall conformation of the antibody in ways which influence its interaction with cells (for example when the antigen is internalized or involved in signal transduction) and hence its in vivo properties. As yet there are not sufficient data to judge whether full humanization will (in practical terms) completely overcome the immunogenicity problem in patients, but these data will be available within a year. Antibody fragments are the most promising general approach to manipulating the pharmacokinetics and biodistribution of therapeutic MAbs. Such fragments are clearly superior to whole IgGs for tumour detection and will very likely prove superior for tumour therapy also. MAb targeting of highly potent cytotoxic agents to tumours represents a much-needed approach to improving therapeutic ratios in cancer treatment. Radioisotopes and highly potent low molecular weight drugs are the most promising cell-killing agents for MAb targeting, and conjugation technology suitable for clinical use of some of the best of these agents has now been developed. Very encouraging data have already been obtained in clinical studies of haematopoietic malignancies with MAb-isotope conjugates. Tumour loading data from clinical studies suggest that killing of solid tumours in patients will be achievable in the near future with repeated administration of humanized antibody fragments carrying the superior isotopes or highly potent drugs which are now available.