Anti-Cancer Drug Discovery & Therapy (Track)


Sayed K Goda 

Anti-Doping Lab Qatar Protein Engineering unit Doha, Qatar


Antibody-Directed Enzyme Prodrug Therapy (ADEPT) is a novel strategy to improve the selectivity of cancer treatment (see fig. below). Methotrexate (MTX), a synthetic folate analogue that inhibits dihydrofolate reductase, a key enzyme in the folate pathway, serves as an important component of various chemotherapeutic regimens for the treatment of cancer patients. One major drawback to the clinical use of MTX is an unacceptable level of toxicity. One of the most effective ways to achieve a rapid removal of the excess of these drugs is by glucarpidase degradation. Repeated cycles of ADEPT and the use of wild type glucarpidase in detoxification are essential but are hampered by the human antibody response to the enzyme.  Additionally, glucarpidase has a relatively slow action in detoxification.

Figure: The principle of ADEPT. In the first phase, an antibody-enzyme fusion protein is injected i.v., and allowed to localize to tumors. After clearance of conjugate from circulation, a prodrug is given in the second phase. The enzyme cleaves the prodrug to release the active drug. The extracellularly generated drug can diffuse throughout the tumour and kill antigen positive tumour cells as well as tumor cells not expressing the relevant antigen, thus giving a "bystander" effect


We embarked on a program to produce novel glucarpidases by different technologies to overcome problems assciated with this technology. We successfully produced, by DNA shuffling an ultra-active glucarpidase that degrades MTX with a very high efficency and we are continuing the production of more efficeint forms. We also  isolated two novel glucaripdase producers from soil and clone and molecular charaterised a novel glucarpidase which could be used in the ADEPT techniques for cancer treatment that could overcomes the antibody problems. We introduced a new mutation into the newly isolated enzyme which produced a novel ultra active glucarpidase. All the novel variants of the glucarpidases will be largely produced for a further study and possible clinical trials. The talk will also cover diffeent aspects of our current and future work.