When a drug fails, it’s easy to assume that it was the wrong target or formulation or the side effects were too toxic. But it could also be that not enough of the drug got to its intended destination in the first place.
For antibody-based therapies to treat cancer — where it’s common to see failures in solid tumors — it’s essential to find out if the drug wasn’t efficacious or if the tumor tissue was underexposed to it. Unfortunately, modern methods have not allowed scientists to answer that question.
Eben Rosenthal, a surgeon-scientist that treats head and neck cancers at Vanderbilt University Medical Center, and his team wanted to change that by developing the tool themselves. They recently published results using their new platform — called single-cell spatial pharmacobiology (SSP) — in Nature Biotechnology.
“Developing single-cell spatial pharmacobiology to address this question took over a decade and depended on close collaboration among surgeons, oncologists, pathologists, biologists, and engineers,” Rosenthal told DDN.
A window into tumor treatment
To test their new SSP platform, Rosenthal’s team used surgical-window trials, in which newly diagnosed patients test out a new compound before their scheduled surgery. Specifically, they investigated drug delivery of the antibody panitumumab-IRDye800 in Phase 1 trials of patients with head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma.
“We show for the first time that there are specific extracellular matrix [ECM] barriers to drug delivery that are formed by multiple cell/matrix types,” said Rosenthal. Using SSP, their team was able to see the full picture — at the single-cell level — of what happens when an antibody is systemically infused into a patient in the operating room.
Developing single-cell spatial pharmacobiology to address this question took over a decade and depended on close collaboration among surgeons, oncologists, pathologists, biologists, and engineers.
—Eben Rosenthal, Vanderbilt University Medical Center
By combining high-resolution imaging of fluorescently labeled antibodies with multiplexed spatial proteomics, their results showed significant variability in drug-target engagement across different tumor cell types, tissue regions, and individual patients. The overall pattern of results aligned with the binding-site barrier hypothesis, which proposes that large molecules like monoclonal antibodies fail to work because they do not penetrate deeply into a solid tumor and instead bind to the first receptors they meet near blood vessels.
“We are excited to extend SSP to other antibody therapeutics, including immune checkpoint inhibitors, antibody–drug conjugates and multispecific antibodies, to guide more effective treatment strategies,” Rosenthal said. He added that SSP also “makes it feasible now to measure drug-ligand activation, receptor occupancy, and molecular signaling at high resolution in a spatial format.”
Finding the right dose
Rosenthal noted that one surprise along the way came when the team discovered that even extremely low doses — like ten percent of a therapeutics dose — still led to nearly 50 percent saturation of the tumors. “This implies we are giving patients way too much drug,” he explained.
He and his colleagues are now working on studies to show that significantly reduced doses of the FDA-approved antibody panitumumab for colorectal cancer can achieve sufficient tumor target saturation and receptor suppression. “These findings challenge conventional dosing strategies and support optimized, biologically informed dosing in solid tumors to potentially reduce side effects,” said Rosenthal. “This is of critical importance to the new FDA guidance on dosing of biologic drugs released in 2024 for industry.” That guidance served to emphasize moving away from a focus on finding the highest tolerated dose towards exposure-based dosing that identifies the right dose for each individual.
For Rosenthal, this represents a worthy goal. He said the most exciting part of this work is “being able to think about a future where patients get less morbidity from reduced doses and less financial toxicity from gross overdosing of drugs.”
