Irreversibly binding anti-metal chelate antibodies: Artificial receptors for pretargeting

Antibodies against metal chelates may potentially be used in biomedical applications such as targeted imaging and therapy of cancer. Highly specific monoclonal antibodies can be developed, but their binding strength needs to be maximized for them to be of practical use. In general, the half-life for dissociation of an antibody-ligand complex is more than an order of magnitude lower than the half-lifetimes for decay of medically useful radiometal ions. Practically speaking, the metal chelate-based ligand will not be bound to its receptor long enough for all of the bound radiometal to decay. A novel approach to this problem is a combination of synthetic chemistry and site-directed mutagenesis, to position a mildly reactive group on the metal chelate adjacent to a complementary reactive group on the antibody when the complex is formed. The partners are chosen to be sufficiently unreactive so that they coexist with other molecules in living systems without undergoing reaction. When the antibody-chelate complex is formed the effective local concentrations of the two groups can be non-physically large, so that a permanent link is formed in the complex even though no reaction occurs when the partners are free in solution.