Drug Targeting Organ-Specific Strategies

In the case of drug–monoclonal antibody conjugates, the entire conjugate may be internalized
after which the drug can be released intracellularly.The drug may also be cleaved extracellularly
and subsequently taken up into tumour cells by diffusion or active transport.
Success with drug–MAb conjugates has been limited thus far because of poor uptake of the
MAb–conjugates especially in solid tumours. Drug delivery is also limited by the number of
drug molecules that can be efficiently carried by each antibody molecule. Furthermore chemical
conjugation is usually a complex procedure that can damage both the MAb and the drug
and MAb–conjugates require intra- or extracellularly active biochemicals and/or enzymes to
cleave the active drug from the antibody. Table 8.2 gives an overview of the various antibody–drug
conjugates that have been developed for cancer therapy to date.
8.5.1.6 Radioimmunoconjugates
8.5 Strategies to Deliver Drugs to Targets within the Tumour (Cells) 215
Another way of using MAbs as therapeutic agents is to couple them to radionuclides (Figure
8.1e and Table 8.3). Radioimmunoconjugates offer many advantages in the treatment of
cancer. Cell killing does not rely on the host’s immune system and occurs by the ionizing effects
of emitted radioactive particles [73]. These radioactive cytotoxic particles are effective
over a distance of several cell diameters, allowing eradication of antigen-negative cells by the
radioimmunoconjugate bound to the adjacent antigen-positive tumour cells. This is useful
considering the heterogeneity of antigen expression in some tumours. Finally, the amount of
radioactive MAb delivered to a tumour can be measured non-invasively by imaging [67].The
most important factors for therapeutic efficacy of radioimmunoconjugates are good penetration,
favourable pharmacokinetics, and a prolonged time of retention in the tumour [74].
Table 8.3. Isotopes used for
radioimmunotherapy in cancer
Radioisotope
Beta-emitters lodine-131
Yttrium-90
Rhenium-188
Rhenium-186
Copper-67
Alpha-emitters Bismuth-212
Astatine-211
Electron capture Iodine-125
8.5.2 Bispecific Monoclonal Antibodies
Another approach to selectively inducing tumour cell killing is by the use of bispecific monoclonal
antibodies (BsMAb). They combine the specificity of two separate antibodies within
one molecule and cross-link an effector killer cell or a toxic molecule with the target cell to
be destroyed [75]. There are three major approaches for creating BsMAbs. They can be obtained
by chemical cross-linking of two MAbs, by fusing two hybridomas [76], or by genetic