Drug Targeting Organ-Specific Strategies

216 8 Strategies for Specific Drug Targeting to Tumour Cells
engineering [77]. Each method has its advantages and disadvantages. Chemical conjugates
have a well-defined linkage and can be produced in high yield. However, there is lot-to-lot
variability in purity and activity. Quadromas, produced by fusing two hybridomas, can also
produce large quantities of BsMAbs. However, in addition to the desired BsMAb, the
parental MAb and every possible combination of heavy and light chain matches and mismatches
are also produced. Furthermore, quadromas are often genetically unstable and require
frequent subcloning.With recombinant fusion proteins, it is possible to make new combinations
of Fab or Fv segments or to combine human and mouse gene segments. Yields and
correct folding of the purified fusion protein can present problems as discussed earlier.
Cytotoxic drugs including toxins such as saporin, ricin A chain, vinca alkaloids, and radioisotopes
have been delivered to tumour cells with BsMAbs that bind to the drug/toxin
with one arm and to a surface molecule on the targeted cell with the other arm.This approach
has proven successful in animals as e.g. shown by Schmidt et al. [78].
Cytotoxic effector cells have also been cross-linked to tumour cells via BsMAb (Figure
8.3). The BsMAb activates the cytotoxic activity of the effector cell on bridging it to the
target cell. Several effector cells, including phagocytic cells, natural killer (NK) cells and T
lymphocytes, can mediate cellular cytotoxity [37,75,79,80].Adequate pre-activation of the effector
cells is an important requirement in these methods of drug delivery. In the case of T
Figure 8.3. Schematic representation of bispecific antobody mediated tumor cell recognition by an
immune effector cell. Summarised are effector cell types, trigger molecules and tumor associated
antigens used as a targed as reported in the literature. From reference [37].