Engineering enzymes and antibodies for cancer therapy
The discovery and pharmacological development of therapeutic proteins such as enzymes and antibodies has been a great asset in the fight against cancer, Professor George Georgiou of University of Texas, Austin, stated during a presentation on May 21 at the Thayer School of Engineering at Dartmouth College.
According to the Warburg effect, cancer cells inherently have a different metabolic pathway in comparison to the normal cells of the human body. Thus, it is hypothesized that inhibiting the acquisition of particular metabolites by cancer cells could have a therapeutic effect. The objective of any cancer therapy is to kill cancer cells without damaging the normal cells, i.e., to achieve a positive therapeutic ratio.
Nevertheless, with the exception of Acute Lymphoblastic Leukemia (ALL), a type of cancer found in children, for which administration of the bacterial enzyme Asparaginase has been shown to have significant therapeutic benefit, no other enzyme drugs for cancer treatment have been successful. This is because non-human enzymes are recognized as foreign by the human immune system and often elicit strong deleterious responses. Moreover, since “the human genome does not encode enzymes with therapeutically relevant catalytic activity or pharmacological enzymes,” there are not many cancer therapeutic enzymes in development.
Resultantly, Professor Georgiou sought engineering human enzymes to display desired therapeutic properties as the best approach that would also avoid the problems of immunogenicity previously found in non-human enzymes.
L-Methionine stress as a result of nutritional restriction by administering patients with liquid diet lacking sulfur containing amino acids was known to be an effective procedure for killing rapidly growing tumors and glioblastomas. However, the lethal effects of immunogenicity involved in this procedure led to the development of L-Methionine degradation using engineered version of Human Cystathionine gamma-Lyase, an enzyme found in humans. After modifications such as PEGylation, the enzyme was shown to be stable, and therapeutically effective at killing cancer cells while also being able to continually circulate within the human body without being excreted by the kidneys.
Similarly, L-Arginine depletion was also found to result in cell cycle arrest and apoptosis or cell death. Since cancer cells lack ASS and OTC, the two major enzymes necessary for arginine biosynthesis, engineered Human Arginase has also shown to be a potential cancer therapeutic agent. Furthermore, the isolation of IgG antibodies to cancer antigens and the enhancement of Fc-mediated effector functions are also hypothesized to play a big role in the cancer therapy.
The use of protein engineering strategies to create modified forms of human enzymes thus not only exhibits new catalytic properties of therapeutic relevance but also the befitting stability and tenacity within humans necessary for the success of therapeutic applications. Ultimately, the ability of this therapeutic regimen to be effective even in small doses and its potential to kill other human tumor cell lines shed a ray of hope to millions of cancer patients and doctors who require a drug with the best positive therapeutic ratio to ensure their success in the monumental battle against cancer.