Designer Antibodies: A two in one design

Cancer and certain infectious diseases such as HIV-1/AIDS that are characterized by genetic heterogeneity are often difficult to treat with a single therapeutic agent. Combination therapies that target multiple disease-associated molecules are therefore widely deployed. However, numerous issues are raised with these treatments; such as mixtures of antibodies being tested for clinical use, despite high development, manufacturing, and treatment costs. This had lead to the development of a new "two-in-one" designer antibody concept in which the same binding site on an antibody is engineered to recognize two different antigens, both with high affinity.
Currently two antibodies studies by the research team at Genmab (Dutch research firm that develops human therapeutic antibodies) have shown promise. Vascular endothelial growth factor (VEGF) and human epidermal growth factor receptor 2 (HER2), representing well-known tumour targets. VEGF promotes blood-vessel formation for the growing tumour and is targeted by the antibody bevacizumab (Avastin), commonly used to treat colorectal cancer. HER2 is highly expressed by some breast tumours and is targeted by the antibody trastuzumab (Herceptin).

Two for the price of one. An antibody consists of four polypeptides, two heavy and two light chains, that form two "Fab arms."

The Genmab research team generated the two-in-one antibody by expressing the HER2-specific antibody trastuzumab on the surface of filamentous bacteriophage. Random nucleotide sequence was incorporated into the gene segments encoding the antigen-binding loops of the light chain to generate a large phage library. Unlike previous studies in which “Two in one antibodies” were created through the process of simply dual specificity which has been engineered into a naturally occurring and stable antibody isotope should pose no obstacles for manufacturing and has been well validated for clinical use.
Possible outcomes from the development of “Two in one antibodies” include replacement of combination cancer treatments (bevacizumab and trastuzumab) and could be possible used to target two no overlapping epitopes on the same antigen (greater potential in finding targets such as bacteria). The overall potential for high-affinity antibody binding of more than one antigen is intriguing and poses opportunities for future basic research and perhaps clinical development of antibody combination therapy.


Reference:
Article: “Two-in-One Designer Antibodies” accessed on 24th march, 2009. Written by Paul W. H. I. Parren and Dennis R. Burton; Available online at http://www.sciencemag.org/cgi/content/full/323/5921/1567,
Image: “Two for the price of one” accessed on 24th march, 2009. Joost Bakker/GENMAB BV Available online at http://www.sciencemag.org/cgi/content/full/323/5921/1567,