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Antibody Recruiting Small Molecules: A New Option for Prostate Tumor Therapy by PSMA Targeting

Finding a cure for most cancer types has been difficult, and, in most cases, unsuccessful. One of the major challenges in current cancer therapy is the differentiation of tumor and healthy cells to enable the sensitive detection of cancer and to avoid the serious side effects of classical (untargeted) chemotherapeutics. Cancer cells are different from normal cells in a number of ways, and one could target these differences for diagnostic and therapeutic purposes. For several applications it has been found to be advantageous to target tumor markers on the cell surface, as these are easy to address with common contrast agents and a number of therapeutics that do often not penetrate cell membranes by passive diffusion. This approach imitates the basic principle of our native defense mechanism against cancer (and other pathogens): the immune system. The approach is therefore related to tumor vaccination. If conjugated to effector molecules such as contrast agents or cytotoxic moieties, ligands for cancer-specific cell-surface receptors can guide marker moieties to a tumor site and allow the sensitive detection of cancer for diagnostic purposes or the specific elimination of cancer cells for therapeutic applications (Scheme 1). This general scheme was inspired by the “magic bullet” concept, pioneered by Paul Ehrlich 100 years ago. Many researchers have used well-known cancer-specific cell-surface epitopes, such as integrins, death receptors, and growth-factor receptors as tumor markers. Besides these cancer-specific receptors, the appropriate specific ligands are a key factor in this concept. They need to bind to the tumor marker with high affinity and have to be suitable for conjugation to effector molecules without losing their binding affinity for the target receptor. This latter point is critical and has led to the development of monoclonal antibodies as tumor-specific “ligands” (Scheme 1 B). Antibodies have several desirable properties: 1) they typically bind their target with high affinity and specificity, 2) they are relatively stable in blood, 3) as macromolecules, they normally conjugate with effector molecules without losing their binding affinity (even “effector molecules” the size of an enzyme can be conjugated), and 4) they can enable an efficient differentiation between healthy and tumor cells through their multivalent binding mode. Another big plus is that they are in principle suitable for the induction of a direct immune response against the targeted tumor cells and can thus be therapeutically useful without the need for conjugation of additional effector molecules. However, in some cases, nonendogenous antibodies cause unwanted immunogenic responses, and their price as well as suboptimal pharmacokinetic properties are often a problem in cancer-related antibody applications. Many researchers have therefore switched to small molecules as modular ligands. These typically have a fast blood clearance, are easy to make by chemical synthesis, and are not immunogenic. However, it is often demanding to reach pharmaceutically relevant affinities and specificities for the targeted tumor cells. Frequently, multimerization is a valuable approach to addressing these drawbacks. In addition, the binding properties of small molecules are often dramatically altered by conjugation to effector molecules of similar or even larger size. Obviously both antibodies and small molecules have advantages and disadvantages, and it is therefore highly attractive to combine the positive features of both agents in one approach. This has been achieved recently by different research groups with small cancer-specific ligands conjugated to an effector group that is able to recruit endogenous antibodies causing an immune response against the targeted cancer cells. This approach nicely combines the favorable pharmacological features of small molecules (the only exogenous component in this Scheme 1. Two approaches to targeting cell-surface epitopes. A) Targeting tumor markers such as membrane proteins by small-molecule modular ligands conjugated to effector molecules X for therapy or diagnosis. A significant difference in receptor density is needed for efficient differentiation between tumor and healthy cells. B) Targeting tumor markers by nonendogenous antibodies. These antibodies might be conjugated to effector molecules X or trigger an immune response that leads to cancer cell death. The multivalent binding mode of antibodies enhances the specificity for cancer cells (high density of tumor markers).