Abstract
Biologics such as monoclonal antibodies (mAb) and soluble receptors represent new classes of therapeutic agents for treatment of several diseases. High affinity and high specificity biologics can be utilized for variety of clinical purposes. Monoclonal antibodies have been used as diagnostic agents when coupled with radionuclide, immune modulatory agents or in the treatment of cancers. Among other limitations of using large molecules for therapy the actual cost of biologics has become an issue. There is an effort among chemists and biologists to reduce the size of biologics which includes monoclonal antibodies and receptors without a reduction of biological efficacy. Single chain antibody, camel antibodies, Fv fragments are examples of this type of deconstructive process. Small high-affinity peptides have been identified using phage screening. Our laboratory used a structure-based approach to develop small-size peptidomimetics from the three-dimensional structure of proteins with immunoglobulin folds as exemplified by CD4 and antibodies. Peptides derived either from the receptor or their cognate ligand mimics the functions of the parental macromolecule. These constrained peptides not only provide a platform for developing small molecule drugs, but also provide insight into the atomic features of protein-protein interactions. A general overview of the reduction of monoclonal antibodies to small exocyclic peptide and its prospects as a useful diagnostic and as a drug in the treatment of cancer are discussed.
Highlights
Recent advances in gene expression, protein production and protein engineering have led to the realized use of macromolecules as therapeutic agents
The independent functional role played by framework and complementary determining region (CDR) in antigen binding led to the development of three different engineered products; (1) Single chain antibody variable domain (Fv), which is a combination of VL and variable heavy chain (VH) linked by a flexible linker (2) Chimeric antibody and (3) humanized monoclonal antibody by CDR grafting [63]
Revealing the feasibility that CDRs alone can initiate biological effects similar to an antibody. These anti-reovirus antibody mimetics were not optimized as inhibitors but the creation of a synthetic antibody loop was an important step in creating new types of therapeutics
Summary
Recent advances in gene expression, protein production and protein engineering have led to the realized use of macromolecules as therapeutic agents. Reducing a large size protein into a smaller molecule or creating a small molecule peptide mimic of the parent protein is an active area of research pursued by several laboratories [4,31,32,33,34,35]. The central philosophy in creating a mini-protein is to identify small structural domains or a scaffold and engineer it for high affinity, specificity and immunogenicity. (1) overview of the structure of antibody which is the basis for much of the progress today, (2) a brief overview of antibodies engineered for clinical use and their limitations and (3) the design and development of anti-erbB peptidomimetics
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