Dr. Aaron Sato: Synthetic Antibody Libraries for the Hardest GPCR Targets

GPCRs account for a substantial fraction of validated drug targets, yet most are drugged by small molecules — antibodies against GPCRs remain notoriously difficult to discover. This conversation explores how synthetic antibody phage display libraries, built on silicon-based DNA synthesis, are rewriting that constraint.

Dr. Aaron Sato, CSO of Twist Biopharma, describes the motif-directed library his team developed by collecting known GPCR-binding sequences from protein, peptide, and antibody ligands and seeding them into the heavy chain CDR3 of a fully human synthetic library. The discussion covers why degenerate oligos had been the bottleneck for library quality, how a "library of libraries" strategy sidesteps the ten-billion-variant ceiling that caps any single phage library, and why the team can now move from a GPCR target to a bivalent IgG ready for functional assays in eight to ten weeks.

For Aaron, this work is personal: he has built his career hunting greenfield targets where others had failed — and GPCRs were the greenfield he had been waiting for.

About the Guest

Dr. Aaron Sato is the Chief Scientific Officer and VP of Protein Engineering at Twist Biopharma, the biologics division of Twist Bioscience. He earned his PhD at MIT in the laboratory of Lawrence Stern, where he studied structure-function relationships of MHC class II proteins by X-ray crystallography. His career has traced the evolution of antibody engineering, with leadership roles at DIAX, Oncomed, Sutro Biopharma, and Lake Pharma before joining Twist. His current focus is building synthetic phage display libraries that drug targets the field has long treated as intractable — GPCRs chief among them.

Scientific Themes of the Conversation

• Silicon-based DNA synthesis and the end of degenerate oligos in library design

• Motif-directed library design — encoding ligand-binding sequences into CDR3 architecture

• The library of libraries as an answer to the diversity ceiling of single phage libraries

• Greenfield target selection as a drug discovery strategy

• Family-level cross-reactivity as an advantage, not an obstacle, in GPCR antibody discovery

• Timelines, automation, and the industrialization of antibody workflows

Key Insights from the Conversation

Silicon DNA synthesis removes the degenerate oligo bottleneck. Traditional synthetic libraries rely on degenerate or trinucleotide mixtures to encode CDR diversity, which limits control over which variants actually appear. Twist's silicon platform produces pools of discrete, designed sequences — a shift in how synthetic libraries are composed.

The motif-directed library encodes prior biological knowledge directly into CDR3. By curating protein, peptide, and antibody motifs known to bind GPCRs and inserting them at the top of the heavy chain CDR3, the library enters each panning campaign already biased toward the target class. The design decision is the library's main differentiator.

A motif-directed library reaches targets its motifs weren't designed for. The same library has produced antibodies against orphan GPCRs and receptors without peptide ligands, because the surrounding CDR diversity provides enough variation to find binders outside the seeded motif content.

Phage display's ~10¹⁰ variant ceiling can be broken by stacking libraries. Any single phage library is capped near ten billion variants. Running multiple libraries in parallel moves the effective diversity toward 10¹² — the idea Aaron calls his library of libraries.

Eight to ten weeks from a GPCR target to a functional IgG is the platform's working tempo, not a best case. By skipping fragment-based screening and going directly to full bivalent IgG, the team hands functional biology teams a molecule that is ready for flow cytometry and receptor assays almost immediately.

Aaron's strategy is deliberately greenfield. He looks for target classes where existing platforms have already failed — not because the biology is easier, but because new technology is rewarded most where the incumbents have stalled.

GPCR family architecture is a discovery advantage. Receptors within a family share sequence and surface topography, so an antibody recovered against one member is often a legitimate starting point for discovery across the family.

Episode Timeline

Timestamps were generated using AI for readability.

00:00 Introduction and sponsor acknowledgment

01:53 The conversation begins

02:29 From MIT crystallography to leading Twist Biopharma

04:21 Twist Bioscience, Twist Biopharma, and the silicon DNA platform

08:12 Using DNA for long-term data storage — a parallel vertical

09:17 Why antibodies to GPCRs have stayed so intractable

09:29 The motif-directed library — encoding receptor motifs into CDR3

12:34 Why one antibody can open up a whole receptor family

14:36 Eight to ten weeks from target to tested bivalent IgG

17:21 The library of libraries — scaling past 10 billion

18:42 Who partners with Twist Biopharma today

22:45 Beyond oncology — inflammation, metabolism, cardiovascular

24:55 Running a protein engineering team through a pandemic

Selected Quotes

About this episode

In this episode of the Dr. GPCR Podcast, I spoke to Dr. Aaron Sato from Twist Biopharma, a vertical within Twist Bioscience. Aaron is currently the Chief Scientific Officer and VP of Protein Engineering. He earned his Ph.D. at the Massachusetts Institute of Technology, where he studied MHC class II structure-function relationships. His path led him to work in an industry where he assumed various responsibilities and roles in the antibody space. Aaron has a proven track record as a biologics leader as he led teams to discover and develop novel first-in-class antibody therapeutics. Dr. Sato published over 30 peer-reviewed papers and contributed to 40 issued patents in the antibody space.

During our time together, Aaron and I discussed how using Twist Bioscience’s proprietary technology to manufacture DNA at a scale, the team saw an opportunity to tackle the challenge of identifying novel functional antibodies targeting GPCRs by incorporating these natural binding partners into Twist’s antibody library design.

We’d like to extend a special thanks to Twist Biopharma for sponsoring this episode of the Dr. GPCR podcast.

Dr. Aaron Sato on the web

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