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Enhancing biological drug production through protein secretion

Periodic Reporting for period 1 - SECReTE (Enhancing biological drug production through protein secretion)

Berichtszeitraum: 2018-12-01 bis 2020-05-31

The drug industry of the 21st Century is shifting towards biological drugs - proteins. Protein drugs include hormones such as insulin that are injected to diabetes patients and antibodies that are used to treat cancer and viral infections. Chemists cannot produce such proteins with same synthetic means that they use to manufacture small molecule drugs such as aspirin etc. Instead, biological cells are used as living factories to make such proteins. the gene encoding for the desired protein is inserted into the genome of a cell, and the cell produces the protein, almost for free, as if it were a normal resident of that cell. Yet, producing the protein of interest is but a first step in a long and expensive process. Following the proteins production within the cell, the next step is to isolate a clean preparation of the protein, separating it from thousands of other proteins in the cell. Purity is of prime importance, for example ,it's inconceivable that injection of insulin will actually consist of a mixture of other proteins too. The pharma industry has thus been struggling with the expensive process of isolation of the protein to purity, and the costs of this process have huge effect on drug prices.

Of all normal resident proteins a cell makes, some are kept inside the cell while a selection are actually secreted outside, as they are needed in the extracellular space. Such indeed is the natural fate, within the body, of hormones and some antibodies for example. How do cells know which genes to keep inside and which to secrete? It has long been recognized that a "zip-coding system" operates within cells, and embedded within genes' genetic sequence that instructs which proteins are to be secreted. Recently we made a breakthrough discovery of a new such zip-coding system (Cohen-Zontag PLoS Genetics 2019). This DNA sequence motif is embedded within most secreted protein sequence in many genomes and we showed that it regulates their secretion out of the cell following synthesis.

We have thus realized that if the motif would be imprinted onto the sequence of a gene that encodes for a biological protein drug, the cell will not only produce it, but secrete it to teh extracellular medium. Such secretion may facilitate the isolation and cleaning to purity the preparation of many biological proteins. Yet, we did not discover a single such motif, but rather a large family of many variants in this motif, and the best instance among them, that would maximize secretion of many proteins of interest, was yet to be found. That was exactly the aim of this PoC ERC grant.

During the period of this PoC grant we have worked on best characterizing the motif that maximizes secretion of proteins. We devised a novel methodology to examine in parallel thousands of alternative versions of the motif. We are in advanced stages of implementation of the method.

Towards commercialization of the invention we teamed up with one of the world's largest companies for mass production of biological drugs - Lonza. Through a partnership with Lonza we obtained from them several proteins of key interest in efficient production along with this cellular production systems. We are working with Lonza scientists and engineers to finalize the analysis of the candidates for best secretion capability.

Within the next months we aim to finalize the screen and obtain the best secreting version of the zip-code.

We negotiate with Lonza of a license for utilization of the technology.