Synthetic Biology Offers a Solution to Cell Therapy Source Material Constraints

October 2, 2020

An innovation such as synthetic biology can develop a consistently stable starting cell line for cell therapy source material.

The source material for cell therapy product development is a critical component in the manufacture of cell therapies, but variability in the starting material (human cells) leaves an element of uncertainty and risk in the safety, efficacy, and purity of the end product. An innovation such as synthetic biology poses a potential solution to the challenge of developing a consistently stable starting cell line.

To explore the potential use of synthetic biology and the challenges of sourcing material for cell therapy manufacture, BioPharm International spoke with Mark Kotter, PhD, founder and CEO of bit.bio, a UK-based biotechnology company specializing in synthetic biology.

In bit.bio’s viewpoint, the development of cell therapies, e.g. to fight cancer, is currently limited by the lack of a reliable source of human cells. The company’s ultimate goal, therefore, is to develop a platform capable of producing consistent batches of every human cell type, which will enable widespread manufacture of cell therapies at scale and reduced cost. Having consistent starting material would also potentially improve the safety and effectiveness of cell therapies and extend their application to other indications, beyond immune and cancer therapy, Kotter notes.

BioPharm: How can this goal of having a platform to produce consistent batches of human cells be achieved?

Kotter: Human induced pluripotent stem cells (iPSCs) provide an excellent source of starting material. They exhibit an indefinite capacity to proliferate while maintaining the potential to differentiate into any cell type. But stem cell differentiation using classical differentiation methods is challenging and fraught with inconsistency and complex protocols that are difficult to reproduce and scale.

Cellular reprogramming is able to overcome one of the bottlenecks of their application: the long and complex protocols required to generate a new cell type. This synthetic biology paradigm involves activating a new cell-type program directly, skipping the usual intermediate steps that occur during development. As a result, stem cells convert directly into any desired cell type, such as those of the liver, brain, or immune system.

However, until recently, reprogramming of cells including iPSCs has been very inefficient with low yields. bit.bio’s proprietary optimized inducible overexpression (opti-ox) technology overcomes gene silencing and, with it, the restrictions of inefficient cellular reprogramming. The precise control of the expression of transcription factors results in deterministic reprogramming of entire human iPSC cultures into the desired target cell type.

In parallel, bit.bio has developed a high-throughput research platform to identify transcription factor combinations that make up cell-type programs. Advanced deep learning algorithms will enable to decode ‘cellular identity’ and discover the programs for every cell type in the human body. This will open avenues for large-scale and cost-effective production of every human cell.

BioPharm: How will this technology address the bottlenecks in cell therapy manufacture?

Kotter: First, our approach provides a unique opportunity to generate not only immune cells but even define the exact sub-type of the cell. We envisage that iPSC lines engineered with the appropriate opti-ox cassette will be expanded until billions of iPSCs have been obtained and at the right moment the cassettes will be activated to precisely program the into the desired T-cell phenotype. Based on our experience with other cells, this will lead to a highly defined and consistent product that has the potential of minimizing off-target effects, which are often caused by impurities in the cultures. The technology will also cut the cost and allow for widespread adoption of cell therapies in otherwise difficult-to-treat diseases.

An additional advantage is that the chimeric antigen receptors (CARs) can be engineered into the cells at the iPSC stage. This will overcome the random integration of CAR genes based on lentiviral transduction. The use of iPSCs enables further synthetic biology applications: deleting endogenous T-cell receptors has the potential of improving safety by preventing graft-versus-host effects, whilst human leukocyte antigen (HLA) masking may help to prevent rejection by the host immune system. The latter would enable the use of cells from a single donor cells for the treatment of many patients.

We hope that with the help of our technology we can expand the application of cell therapies to other indications. For example, it may become possible to use iPSC-derived oligodendrocytes to regenerate the central nervous system, after being damaged by multiple sclerosis attacks, or to use iPSC-derived hepatocytes to treat patients that currently require a liver transplant. Both these cell types are currently difficult to culture from primary samples and address significant unmet clinical needs.

The third revolution of medicine is intelligent. Widespread access to human cells will have unprecedented positive implications in reducing the cost and failure rates of drug development and enable a new generation of cell therapies. At bit.bio we are driven by the shared vision of accelerated biomedical research and new generations of cures by transitioning biology to engineering.

About the author

Feliza Mirasol is the science editor for BioPharm International.