Although he started out in theoretical physics, Swamy Vijayan, PhD, has worked in the biotechnology industry for most of his professional career. His path included a stint at Illumina and the launch of Omniome, a short read sequencing company that was acquired by Pacific Biosciences in 2021. His next gig is in drug discovery as CEO of Zafrens, a company that is developing a multimodal platform that it is betting will shake up the drug discovery market. 

This week, Zafrens announced the close of $23 million in financing led by Prime Movers Lab with participation from BlueYard Capital, KOFA Healthcare, Global Brains, FoundersX Ventures, Alix Ventures, Possible Ventures, Iaso Ventures, Hawktail, and other investors. The funds will help Zafrens optimize applications of its Z-Screen platform and support efforts to advance an internal pipeline of potential new drug compounds. 

In principle, Z-Screen is designed to condense multiple elements of the drug discovery process into a single platform. That means coupling traditional cell-based assays using large-combinatorial chemical libraries with single-cell sequencing and imaging data to assess the molecular and functional underpinnings of complex cellular co-culture interactions. Large CRISPR, CAR-T, mRNA libraries as well as endogenous molecular heterogeneity can be mapped to cell behavior, and cell-cell interactions and secretions.

When Vijayan and his team began working on the platform in January 2022, one of their objectives was to design a flexible platform that wasn’t heavily reliant on automation. This was important, Vijayan told GEN in an interview, because “we wanted to be able to do really high-throughput experiments anywhere in the world and at really high resolution.” They also wanted to expand on the traditional 96-well plates that are a drug discovery staple. Z-Screen boasts 50,000200,000 microwells fabricated onto a small glass or plastic substrate, each of which can house a single cell. Zafrens is not disclosing details about the mechanics of the technology at this time. 

Speaking about the platform in an interview with GEN, Vijayan explained that Z-Screen can be used to combine various cell types and observe how they interact in culture. These kinds of studies make up “the first pillar of our technology [which is] is being able to do really, really high throughput, longitudinal co culture experimentation,” he explained. An example of this might be looking at the interactions between T cells and tumor cells to identify the particular subset of cells that most effectively attack and kill cancer cells or studying B-cell antibodies. 

Zafrens’ second pillar centers on combining genetics and imaging from individual cells. “What this allows us to do is map the functional manifestation of the molecular states of cells,” Vijayan said. Going back to the T cell example, with this data scientists could investigate T-cell activation in detail or assess their resistance to exhaustion. Lastly, the company can evaluate the effects of exposing individual cells to libraries of small molecules or other perturbations in a single experiment. The company uses uniquely barcoded compounds that are attached to beads and cleaved by exposure to light. By imaging the cells exposed to the barcoded compounds, Zafrens captures how they respond to different compounds. Because the company also sequences the cells, they can also gather genomic-level information about the impact of drug compounds such as any off-target effects as well as the molecular pathways involved in the cell’s response. They can also identify relationships between molecules that are responsible for modulating the responses observed.

The market for multimodal drug discovery platforms is growing. In recent years, other companies have unveiled commercial platforms that incorporate different kinds of data into the drug discovery process. Eikon Therapeutics’ platform, for instance, uses super-resolution microscopy imaging to shed light on protein behavior in live cells. Meanwhile, Recursion’s platform combines information from high-dimensional biological and chemical datasets to create maps of biological relationships that help them identify new targets and drug compounds.  

The volume and scale of Zafrens’s data is one of its key differentiators. “By measuring whole-cell transcriptomic, proteomic, and imaging responses when exposed to massive libraries of perturbations and external interactions, Zafrens creates datasets that are orders of magnitude more complex than single-protein binding measurements, revealing causal underpinnings of subtle cell behavior,” said Jason Whitmire, managing partner, BlueYard Capital and board director at Zafrens

It’s a lot of data generated from thousands of cells linking structure to genomic or gene expression profiles and function. At the moment, Zafrens does not use artificial intelligence but Vijayan said that as the company gathers more information, it will eventually begin using AI models to make predictions from its data. Zafrens has begun working on some AI models but these are in their infancy. “We’re still in the process of collecting the volumes of data, characterizing them, validating them, and so on,” he said. “I think in about a year, this will become our most important asset.”

In the months ahead, there are several avenues where Z-Screen might be used. The company has a partnership model in place and is actively working to engage with drug developers. Zafrens could work, for example, with companies that are developing new cell therapies or on antibody discovery programs among other possibilities. 

Currently, the company intends to engage with partners that specialize in some of its internal areas of expertiserapid, HLA-independent, highly-selective TCR discovery, and RNA regulatory small molecules across 3’ UTR regulation, splicing and epigenetic reprogramming. Zafrens is also seeking partnerships focused on CAR-T optimization and bi-specifics discovery or areas where combinatorial libraries of small molecules, genetic perturbations, and cell-cell interactions could produce breakthroughs.

Separately, Zafrens is developing an internal pipeline of RNA-modulatory small molecules and HLA-agnostic TCR libraries to common cancer mutations. It’s also building a capable interdisciplinary team that brings together people with expertise in sequencing, engineering, chemistry, and so on. So far, the company has about 30 people on staff.

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