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A-Alpha Bio Raises $2.8 million in Seed Financing to Develop NGS-Based Protein Interaction Tech

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NEW YORK – A-Alpha Bio, a University of Washington spinout, has raised $2.8 million in seed financing to develop its next-generation sequencing-based method for characterizing protein-protein interactions.

The Seattle-based firm will use the funding to support R&D and validation of its yeast-based AlphaSeq technology, which combines synthetic biology and NGS readouts to provide quantitative data on protein interactions at scale.  

OS Fund led the round, joined by AME Cloud Ventures, Boom Capital, Madrona Venture Group, Sahsen Ventures, the Washington Research Foundation, and other angel investors.

"Our goal is to help pharmaceutical companies characterize protein interactions to improve drug development," A-Alpha Bio CEO and Cofounder David Younger said. "Developing a new protein drug is like trying to find a key to a lock." While existing methods for characterizing protein interactions, such as phage display, can test libraries of "keys" against a single "lock," AlphaSeq is like testing "a pile of locks, where we can screen the library of keys against all of them."

The platform engineers yeast cells to express proteins on their surface and reprograms the yeast sexual agglutination mating system such that protein interaction strength is linked with mating efficiency. When interacting proteins lead to cell fusions, paired barcodes representing binding proteins can be read out by NGS.

AlphaSeq is based on a method of characterizing protein interactions described in a 2017 publication in the Proceedings of the National Academy of Sciences; the firm holds an exclusive license to it. Younger was first author and his doctoral advisors Eric Klavins and David Baker were senior authors on the PNAS study and are involved with the firm's scientific advisory board. Cofounder and CTO Randolph Lopez is a former Illumina engineer. The firm has three other full-time employees.

The seed funding builds on money A-Alpha Bio raised from the National Science Foundation, the Bill and Melinda Gates Foundation, and CoMotion — the University of Washington's tech transfer and commercialization hub. In 2018, NSF awarded the firm a $225,000 Phase I Small Business Innovation Research grant to develop AlphaSeq. In May, it received a grant for an undisclosed amount from the Gates Foundation to support a collaboration with Lumen Biosciences and MassBiologics on AlphaSeq's potential to discover and optimize low-cost therapeutics for intestinal pathogens.

AlphaSeq is a counting approach, like many types of RNA sequencing for transcriptome analysis. "We're looking at an abundance of different paired genetic barcodes to determine relative interaction strength," Younger said.

To get those barcodes to pair, the firm engineers libraries of proteins in yeast haploid cells. "We've knocked out the native protein interactions" that lead mating-type a (MATa) and mating-type alpha (MATalpha) cells to spontaneously fuse "and replaced them with any protein we're interested in" via yeast surface display, Younger said. "So, once we've mixed those, we end up with a population of diploid cells where each diploid was formed because of a particular interaction." Stronger interactions will drive more frequent diploid formations, he added.

A-Alpha's assay uses a recombinase to get the barcodes on the same strand of contiguous DNA. "Once they're paired, we just amplify those fragments with a targeted PCR and throw that on a sequencer," Younger said. The firm mainly uses Illumina's NextSeq platform but is also building a workflow that uses Oxford Nanopore Technologies' sequencers.

A-Alpha has started using nanopore sequencing "mostly for ease and speed of iteration," Younger said. "If we have a couple small proof-of-concept experiments, or are doing assay building, we don't want to have to wait to fill up a full NextSeq run. Getting just a couple million reads is really important for accelerating our timelines."

The interaction counts shown by AlphaSeq have been validated with traditional low-throughput tools such as quantitative ELISAs, Younger said.

AlphaSeq will have to compete with several established protein interaction assays, many of them offered by companies like Thermo Fisher Scientific with its yeast two-hybrid assays, phage display methods, quantitative immunoprecipitation assays, and crosslinking systems. Mass spectrometry-based methods can also analyze protein-protein interactions.

Younger said that compared to yeast two-hybrid assays, AlphaSeq provides quantitative analysis and has fewer false positives. It's also an extracellular approach, which enables it to assess interactions when other compounds are added, such as agonists and antagonists.

"A-Alpha Bio's platform is plug-and-play for partners, facilitating read-outs on drug potency and effectiveness in a much shorter timeframe, solving an important challenge for pharma companies," OS Fund Cofounder and General Partner Jeff Klunzinger said in a statement. "We are confident … the A-Alpha Bio team will be able to accelerate discovery of multi-target protein drugs, such as multi-target antibodies, and small-molecule protein interaction modulators." 

A-Alpha Bio's plan is to partner with pharmaceutical companies and provide contract discovery work. In addition to its collaboration with MassBiologics and Lumen Biotechnologies, it has partnered with Olympic Protein Technologies, a contract research organization, to co-develop a service for characterizing biologics.

The firm has seen some interest from pharma, Younger said, but declined to disclose which companies. Some academic labs have expressed interest in AlphaSeq for applications other than drug development, such as functional proteomics studies.

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