Endoradiotherapy with Peptides - Status and Future Development

Abstract

With the advances in molecular biology and biochemistry new imaging and treatment modalities based on the biological properties of tissues have been developed where important progress has been achieved using antibodies and peptides. This paper will concentrate on peptide vectors. When labeled with therapeutic radioisotopes these agents are suitable for endoradiotherapy and exploit the targeting potential for highly specific treatment which has been realized for antibodies against CD20 or peptides binding to somatostatin receptors. This novel class of pharmaceuticals offers the potential to develop specific therapies beyond the possibilities of current chemotherapy and radiation therapy. Furthermore, these achievements can be seen as proof of principle and encourage more research towards the identification of new specifically binding molecules. Activities towards the development of new biomolecules can be based on biotechnology methods. Rational design uses informations obtained from structure-activity relationship studies and conformational analyses of peptide structures. This approach relies on the identification of lead compounds and screening of various derivatives of these compounds. In contrast to rational design the central idea of black box approaches is to create vast libraries of possible variants of molecules and screen the population for the few compounds that show the property of interest. The attracting feature relies on the huge number of candidate molecules that can be used for further evaluation. After the characterization of the structure-function relationships for the lead compounds found in this process further improvement by rational design of analogs can be performed.

Identification and Characterization of a Peptide with Affinity to Head and Neck Cancer

“…Thus, the identification of novel targets is enabled, and novel molecules can be provided that specifically bind to a given or any unknown target. Phage display has been applied for a variety of purposes, including the mapping of epitopes, the identification of new receptors, the isolation of specific antigens, the production of novel enzyme inhibitors (5), and the identification of high-affinity antibodies and peptides (6). For tumor targeting, peptides have been shown to be useful either as carriers of chemotherapeutic drugs and toxic molecules or as radioactive tracers for noninvasive diagnosis and therapy.…”

Identification of Ligands and Translation to Clinical Applications

“…In phage display libraries, peptide, antibody, or other protein libraries are fused to the carboxy-terminal domain of minor coat protein III or VII on the surface of a filamentous phage (16). The ligand binding to the target is detected using the recombinant receptor molecules or cell lines.…”

“…This approach has been used in various applications, such as in the mapping and mimicking of epitopes, the identification of new receptors and natural ligands, high-affinity antibodies and analogs, the isolation of specific antigens binding to bioactive compounds, the production of novel enzyme inhibitors and DNA-binding proteins, and the probing of cellular and tissue-specific processes. Phage display has been successfully applied for the identification of peptides with a high specificity for target tumor neovasculature or a variety of human tumor cells (16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

“…This step is followed by characterization of the structure-activity relationships for the identified compounds. Subsequently, further improvements can be obtained by mutation analysis or rational design of analogs (16).…”

“…After the identification of lead structures, further improvements can be obtained by mutation and amplification to create a new pool of diverse molecules for further screening rounds. This iterative process of mutation, selection, and amplification to evolve the best-fit molecule is known as "directed evolution" (16).…”