William Hahn, MD, PhD
Executive Vice President and Chief Operating and Transformation Officer, Dana-Farber
William Rosenberg Professor of Medicine, Harvard Medical School
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Accelerating Therapeutic Antibody Discovery with the PhAST Technology
Project Overview
- Finding novel cancer targets and antibodies against those targets can be slow, laborious, and expensive
- PhAST, a new therapeutic antibody discovery platform developed by Dana-Farber scientists, provides a high-throughput, discovery engine for the rapid discovery of cell surface targets and simultaneous selection of antibodies against those targets.
- The PhAST technology will be developed by a newly established company that originated from the laboratories of Dana-Farber.
Technology
Antibodies that target specific tumor-expressed antigens are now the standard of care for some cancers. However, the identification of new proteins that are differentially expressed on tumors and are amenable to antibody binding remains challenging. Current methods to identify targets and antibodies are slow, laborious, and expensive, often requiring years of work to validate the target-antibody relationship.
To address this bottleneck in developing new antibody-based drugs, a team led by Prof. William Hahn, MD, PhD, executive vice president and chief operating officer at Dana-Farber, and Bärbel Schröfelbauer, PhD, lead scientist, Cancer Surface Profiling, developed the PhAST (Phenotypic Antibody and Simultaneous Target) discovery platform.
PhAST involves the unbiased systematic profiling of the more than 5,000 transmembrane proteins of a cell—the surfaceome—and the discovery of hundreds of antibody/target pairs selective for any cancer type. Through a single round of screening, multiple therapeutic candidates are identified. Instead of many months to discover antibodies against a single target, the PhAST platform allows for the discovery of many targets and antibodies in parallel, shortening the previously lengthy process to two to three months.
The PhAST discovery platform uses a bacteriophage display -based library to select for antibodies that bind with desired cell surface–binding specificity on live cells followed by mass spectrometric identification of the antibody target. This approach allows the discovery of multiple antibody–target pairs specific to the native or cancer-specific state in a single round of screening.
Team Members: William Hahn, MD, PhD, Bärbel Schröfelbauer, PhD, Sarah Hill, MD, PhD, Prafulla Gokhale, PhD
Applications
Because PhAST can be applied to any cell’s ‘surfaceome,’ the technology represents a substantial untapped therapeutic opportunity.
The team has completed PhAST screens in two cancers with significant unmet need, ovarian and pancreatic cancer. The technology revealed known/validated targets as well as new targets.
In ovarian cancer, PhAST screens have been performed on many patient-derived organoids and cell lines. More than 27 ovarian cancer targets have been found including 19 new targets with unique expression patterns, diverse biological functions, and that may be essential for tumor fitness.
Among these ovarian targets is a protein that is highly expressed on the surface of high-grade serous ovarian cancer cells and has roles in adhesion and migration of carcinoma cells. PhAST screens identified 37 potent and developable antibodies against the protein– with at least three now in proof-of-concept studies.
For pancreatic cancer, PhAST screens funded by the Hale Center for Pancreatic Research identified 10 pancreatic targets, including five known and five novel pancreatic targets, one of which is a co-factor of a master signaling regulator. This novel target is found in a subset of late-stage pancreatic tumors but in low numbers in normal pancreas and other tissues and is known to be linked to invasiveness and metastasis.
The PhAST approach may also hold the potential for finding new target/antibody pairs in autoimmune diseases
Opportunities
The PhAST drug discovery platform will be developed in a new company established from the labs of Dana-Farber for discovery of targets and antibodies in cancer and other diseases.
Team Members
Bärbel Schröfelbauer, PhD
PhAST Team Leader, Dana-Farber
Sarah Hill, MD, PhD
Assistant Professor, Department of Medical Oncology and Division of Molecular and Cellular Oncology, Dana-Farber
Prafulla Gokhale, PhD
Director, Experimental Therapeutics Core, Dana-Farber
