Functional GPCR Antibodies

From target to optimal development candidates against a challenging GPCR target, in 8 months

GPCRs and ion channels are tough targets. Technical and biochemical challenges, including producing proteins, driving immune responses, and finding hits, have limited antibody drug discovery. 

With technologies intentionally built to break the barriers of conventional discovery, we’re helping partners unlock new opportunities to bring new treatments to patients sooner. 

The Challenge

A GPCR with high homology to the species used for immunization, particularly in the extracellular loops where the desired antibodies needed to bind. 

The Goal

Find antibodies that are: 

  • Functional GPCR inhibitors 
  • Cross-reactive to human and rat homologs 
  • As potent as a clinical benchmark 

The Outcome

125 functional anti-GPCR antibodies, six of which were more potent than a clinical benchmark.

Our Approach


We immunized rats, wildtype mice, and humanized mice using proprietary genetic immunization protocols. Approximately 80% of rats and 30% of mice had cross-reactive titers and were selected for screening. 

Target-specific titers measured by flow cytometry revealed animals producing cross-reactive antibodies.


We screened 2.7 million single antibody-producing cells using a multiplexed live cell-binding assay and identified 618 target-specific hits


We used single-cell sequencing to identify 309 unique antibody sequences from 86 different clonal families. 142 of these antibodies were cross-reactive to the human and rat homologs. 

Bioinformatic analyses demonstrated that the antibodies were derived from mature immune responses with somatic hypermutation observed. The antibody sequences had a high degree of sequence diversity with 35 different VH genes used and CDR3 lengths ranging from 5-24 amino acids

Somatic hypermutation demonstrated by identity to germline. Bioinformatic analysis of 309 target-specific heavy chain sequences compared to germline revealed mature immune responses.
Antibody sequence diversity demonstrated by V gene usage. Bioinformatic analysis of V genes used by 309 target-specific antibody sequences revealed sequence diversity.
Antibody sequence diversity demonstrated by CDR3 Lengths. Bioinformatic analysis of CDR3 lengths of 309 target-specific antibody sequences revealed diverse CDR3 lengths.


We used high-throughput expression and characterization to analyze all 309 unique antibodies. Of these, 125 were functional GPCR inhibitors, and had cross-reactivity to human and rat homologs.

From this panel, we found six antibodies that were cross-reactive and more potent than a clinical benchmark, allowing our partner to select antibodies for validation in an animal model eight months after initiating antibody discovery

Functional antibodies against a GPCR target. Functional characterization of 23 cross-reactive antibodies revealed six with potencies greater than a clinical benchmark.


Together we can make game-changing discoveries.