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Principal Investigator: SANKAR ADHYA
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2023
Award: $1,110,488
Funding agency: National Cancer Institute
Part A. Three lines of investigations are being pursued currently. 1. Use of bacteriophages in treating human diseases because of bacterial infections. We are currently dealing with infections caused by Klebsiella. We have succeeded in defining bacteriophage cocktails that take care of bacteriophage resistance that arises during infection processes. 2. We have succeeded in engineering Klebsiella phages to have multiple tails to increase the host range of a phage to be capable of infecting and killing multiple hosts species. 3. We have succeeded to construct a T7 bacteriophage derivative in which we cloned a peptide antibiotic gene (AMP), which when infects a given host also produces vast amount of the antibiotic. This enables the phage to kill by the action of AMP any mutant bacterial host which becomes resistant to phage. However, the expression of AMP has been poor, which does not kill phage resistant hosts. But when the AMP expression is covalently linked to a soluble protein, the expression was reasonable. Currently, we have made a library of phage carrying random mutations in the peptide anti biotic and screening them for one with more effective anti-bacterial activity. These findings encourage us to pursue the process further. Part B. We are using our previously developed phage display technology using bacteriophage Lambda to make vaccines against infectious diseases as well as against cancer. We already constructed displaying potential antigenic peptides and proteins of CLL leukemia, malaria and Covid 19 virus. We invested a lot of time in engineering, purifying, validating, and testing the authenticity of multiple phage constructs that could potentially be developed as a phage-based vaccine for COVID-19, CLL, and malaria. Currently, we are performing several experiments and analyzing data on testing phage-based vaccines in a mouse model to generate immunity against COVID-19 and glioblastoma. We are currently working in the future experimental plan to demonstrate the efficacy of phage-based COVID-19 vaccine. The goal is the same in both cases: to prepare purified, engineered lambda for animal immunogenecity study. In the first branch of the project, we engineered a phage with the EGFRvIII antigen present in glioblastoma and attached to the D protein of the lambda phage. The other branch of the project involved the same process, but the antigen was a fragment of the covid-19 spike protein. These constructions were made as prophages. The prophages were then induced phage production and phages purified and concentrated. The respective phages are now being tested for immunogenecity in animals.
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