@article {1557, title = {Bispecific antibodies for dual-modality cancer therapy: killing two signaling cascades with one stone.}, journal = {Current Opinion in Drug Discovery \& Development}, volume = {9}, year = {2006}, month = {2006 Mar}, pages = {184-93}, abstract = {

The additive and synergistic therapeutic effects derived from combinations of chemotherapeutic drugs and radiation have established an indispensable paradigm: cancer must be attacked on multiple fronts. However, the increased antitumor efficacy of such combinational regimens is also associated with severe systemic toxicity, as these drugs cannot selectively target tumor cells. Monoclonal antibodies (mAbs), which have exquisite specificity for their antigens, are becoming an increasingly important class of antitumor agents, as they enhance the efficacy of various therapeutic regimens without significantly increasing systemic toxicity. Furthermore, preclinical and early clinical evidence indicate that combinations of antibody-based drugs provide even greater efficacy with minimal side effects. Unfortunately, the research, manufacturing and regulatory costs of mAb development pose a significant barrier to the use of antibody-based combination therapies. An emerging alternative is the use of dual-targeting bispecific antibodies (BsAbs). BsAbs are derived from the recombination of variable domains of two antibodies with different specificities; BsAbs are thus capable of binding both antigens of their parental antibodies. With the recent progress that has been made in antibody engineering technology, BsAbs that simultaneously target two tumor-associated molecules (eg, growth factor receptors) are being heralded for their potential to deliver two therapeutic moieties in a single molecule.

}, keywords = {Animals, Antibodies, Antibody Specificity, Antineoplastic Agents, Combined Modality Therapy, Humans, Immunotherapy, Neoplasms, Signal Transduction}, issn = {1367-6733}, author = {Marvin, Jonathan S and Zhu, Zhenping} } @article {1565, title = {Computation-based engineering of protein and antibody therapeutics.}, journal = {Drug Design Reviews Online}, volume = {2}, year = {2005}, month = {2005}, pages = {419-25}, abstract = {

Recent advances in computation-based protein engineering offer opportunities to introduce or modify the biophysical characteristics of proteins at will. The power of computational design comes from the ability to surpass the combinatorial and physical limitations inherent to laboratory-based high-throughput or trial-and-error methods. As a result, modifications that require significant changes to the amino acid sequence of a protein are now accessible to the protein engineering community. Hydrophobic cores of proteins have been repacked to increase their thermostability. Binding sites in proteins have been modified to increase affinity or alter specificity for proteins, peptides, and small molecules. Enzymes have been designed de novo. Non-natural protein folds have been created. For the most part, these achievements have been applied to proteins that make good model systems in academic settings. How can these computational methods be applied to therapeutically relevant proteins? This review will focus on the ground-breaking achievements of computation-based protein engineering and on recent applications of rational design to improve therapeutic proteins. - See more at: http://www.eurekaselect.com/90585/article/computation-based-design-and-engineering-protein-and-antibody-therapeutics$\#$sthash.kSt3UaNE.dpuf

}, author = {Marvin, Jonathan S and Zhu, Zhenping} } @article {1558, title = {Recombinant approaches to IgG-like bispecific antibodies.}, journal = {Acta Pharmacologica Sinica}, volume = {26}, year = {2005}, month = {2005 Jun}, pages = {649-58}, abstract = {

One of the major obstacles in the development of bispecific antibodies (BsAb) has been the difficulty of producing the materials in sufficient quality and quantity by traditional technologies, such as the hybrid hybridoma and chemical conjugation methods. In contrast to the rapid and significant progress in the development of recombinant BsAb fragments (such as diabody and tandem single chain Fv), the successful design and production of full length IgG-like BsAb has been limited. Compared to smaller fragments, IgG-like BsAb have long serum half-life and are capable of supporting secondary immune functions, such as antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. The development of IgG-like BsAb as therapeutic agents will depend heavily on our research progress in the design of recombinant BsAb constructs (or formats) and production efficiency. This review will focus on recent advances in various recombinant approaches to the engineering and production of IgG-like BsAb.

}, keywords = {Animals, Antibodies, Bispecific, Cytotoxicity, Humans, Immunoglobulin Fc Fragments, Immunoglobulin Fragments, Immunoglobulin G, Immunoglobulin Variable Region, Immunologic, Recombinant Fusion Proteins}, issn = {1671-4083}, doi = {10.1111/j.1745-7254.2005.00119.x}, author = {Marvin, Jonathan S and Zhu, Zhenping} }