Potential Pitfalls in Tumor Targeting
Upon IV injection, only a small fraction of the homing device–carrier–drug complex is sequestered at the target site. Apart from the compartmentalization of the body (see above: anatomical and physiological hurdles) and consequently the carrier-dependent barriers that result, several other factors account for this lack of target site accumulation (Table 14).
How successful are MAb in discriminating target cells (tumor cells) from non-target cells? Do all tumor cells expose the tumor-associated antigen? These questions are still difficult to answer (Hellstro¨m et al., 1987). Tumor cell-surface specific molecules used for homing purposes are often differentiation antigens on the tumor cell wall. These structures are not unique since they occur in a lower density level on non-target cells as well. Therefore, the target site specificity of MAb raised against these structures is more quantitative than qualitative in nature.
Another category of tumor-associated antigens are the clone-specific antigens. They are unique for the clone forming the tumor. However, the practical problem when focusing on clone-specific antibodies for drug targeting is that each patient probably needs a tailor-made MAb.
The surface “make-up” of tumor cells in a tumor or a metastasis is not constant; neither in time nor between cells in the same tumor. There are many subpopulations of tumor cells and they express different surface molecules. This heterogeneity means that not all cells in the tumor will interact with one, single targeted conjugate. Antigen shedding and antigen modulation are two other ways tumor cells can avoid recognition. Shedding of antigens means that antigens are released from the surface. They can then interact with circulating conjugates outside the target area, form an antigen–antibody complex and neutralize the homing potential of the conjugates before the target area has been reached. Finally, antigen modulation can occur upon binding of MAb to the cell surface antigen. Modulation is the phenomenon that upon endocytosis of the (originally exposed) surface antigen–immunoconjugate complex, some of these antigens are not exposed anymore on the surface; there is no replenishment of endocytosed surface antigens.
Four strategies can be implemented to solve problems related to tumor cell heterogeneity, shed-ding and modulation. (i) Cocktails of different MAb attached to the toxin can be used. (ii) Another approach is to give up striving for complete target cell specificity and to induce so-called “bystander” effects. Then, the targeted system is designed in such a way that the active part is released from the conjugate after reaching a target cell, but before the antigen-conjugate complex has been taken up (is endocytosed) by the target cell. (iii) Not all surface antigens show shedding or modulation. If these phenomena occur, other antigen/MAb combinations should be selected that do not demonstrate these effects. (iv) At the present, injection of free MAb prior to injection of the immunoconjugate is under inves-tigation to neutralize “free” circulating antigen; then, the subsequently injected conjugate should not encounter shedded, free antigen.
In conclusion, targeted (modified) MAb and MAb-conjugates are now studied to assess their value in fighting life-threatening diseases such as cancer. During the last decade, technology has evolved quickly; many different new options became avail-able. Lack of detailed pathophysiological and cell biological knowledge about the behavior of tumors, for instance, slows down progress. It is even possible that the whole concept of MAb-(conjugates) will turn out to be only of limited therapeutic value, because ofproblems such as tumor cell heterogeneity, poor access to tumors and immunogenicity concerns.