Page 1 of 6 Editorial Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY) For citation purposes: Firer MA. Antibody-drug conjugates in cancer therapy—filling in the potholes that lie ahead. OA Cancer 2013 Jun 19;1(1):8. Competng interests: none declared. Confict of interests: none declared. All authors contributed to concepton and design, manuscript preparaton, read and approved the fnal manuscript. All authors abide by the Associaton for Medical Ethics (AME) ethical rules of disclosure. Novel Therapies Antibody-drug conjugates in cancer therapy—flling in the potholes that lie ahead MA Firer* Abstract Antibody-Drug Conjugates, com- posed of a cytotoxic drug conjugated to a tumour cell targeting antibody are being extensively studied and tested for the treatment of a variety of cancers. Antibody-Drug Conjugate systems hold the promise of more selective drug therapy compared to traditional chemotherapy, with fewer side effects. These important advantages have stimulated excit- ing developments in various aspects of Antibody-Drug Conjugate tech- nology. Although several Antibody- Drug Conjugates have now entered the clinic, a number of biological and technical pitfalls exist that will need to be overcome if Antibody- Drug Conjugates are to fulfil their full therapeutic potential. This paper will discuss the more important of these challenges. Editorial The use of monoclonal antibody- drug conjugates has come a long way since the first attempts in the 1980s to use murine antibody-based anti- body-drug conjugates as therapeutic agents 1 . The concept of antibody- drug conjugates brings together the targeting advantages of antibodies and the cytotoxic potential of chem- otherapy, heralding the promise of targeted accumulation of drug in the tumour cell or tissue. Antibody-drug conjugates are typically comprised of three components: a monoclonal antibody that acts as the cancer cell targeting moiety, a potent cytotoxic agent and a linker molecule to con- nect the two together. Disappointing- ly, the first antibody-drug conjugate constructs, which usually contained doxorubicin or methotrexate as the drug, not only showed little clinical efficacy, but also poor pharmaco- logical parameters and toxicity pro- files 2 . Over the ensuing years, im- provements in monoclonal antibody engineering and production 3 were combined with advances in cytotoxic drug synthesis and selection, linker chemistry and conjugation methods [reviewed in 4 ] that together resulted in many antibody-drug conjugate candidates entering the preclinical development pipeline. Despite this progress, their passage into suc- cessful clinical application has been difficult and slow; only three ADCs have received Food and Drug Admin- istration (FDA) approval for cancer therapy but only two are currently in use. Notwithstanding this sluggish growth, there are now about 30 new antibody-drug conjugates undergo- ing clinical assessment and at least another 12 are in preclinical develop- ment 5 . Figure 1 and Table 1 show the number of different antibody-drug conjugates either approved or cur- rently at different stages of develop- ment. Many of these are being tested in multiple applications. While many pharmaceutical com- panies appear to have embraced antibody-drug conjugates as a source of potentially successful cancer thera- peutics, whether as an extension of immunotherapy or simply as a format for targeted drug delivery, a number of important pitfalls still exist in this field. These will need to be addressed if antibody-drug conjugates are to fulfil their therapeutic potential. What are the most important of these challenges and where do we current- ly stand in overcoming them? Target cell surface-specific molecules One of the basic concepts of ADCs is their ability to deliver the drug payload to the correct cell, which as- sumes the ability to identify unique markers on the target cell surface. A variety of biochemical, immunologic, genetic and proteomic techniques have been used over the years to gen- erate a plethora of cell surface-bind- ing antibodies. Only rarely, however, have these antibodies targeted true tumour-specific antigens, such as clo- notypic membrane immunoglobulins in some B-cell leukaemias 6 . The vast majority of the cell surface targets can only be classed as tumour-asso- ciated cell surface antigens (TAAs) or overexpressed antigens (OEAs) 7 , for example the HER-2 receptor. De- spite their lack of true tumour cell specificity, treatment with antibodies to TAAs and OEAs undoubtedly has made a clinical impact and they save lives 3 . Nonetheless, their use is in- trinsically associated with side ef- fects 8 that limit their efficacy. This situation could change in the near future. The antibodies and ADCs currently in the clinic and many of those in clinical development were dis- covered using more traditional tech- nology streams that began with immu- nization, production of hybridomas and selection of antibody candidates. This approach carries with its inher- ent limitations regarding the scope of antibodies identified. For exam- ple, ‘one-fit-for-all’ high-throughput screening methods tend to favour an- tibodies targeting dominant epitopes 9 , * Corresponding author Email: firer@ariel.ac.il Department of Chemical Engineering, Faculty of Engineering and Ariel Center for Applied Cancer Research, Ariel University, Ariel, 40700, Israel