Abstract
Researchers are looking to improve the design and delivery of antibody–drug conjugates by studying how they interact with and are influenced by the mononuclear phagocyte system.
Buoyed by the success the antibody–drug conjugates (ADC) T-DM1 (Kadcyla; Roche) and SGN-35 (Adcetris; Seattle Genetics), along with promising early data for a third, AbbVie's ABT-414, multiple pharmaceutical companies are busy refining this “guided missile” approach to treating cancer.
There are currently more than 30 ADCs in various stages of clinical development, and the field has seen considerable progress in recent years. For instance, researchers have improved chemical linkers to ensure a more stable connection between antibody and cytotoxic agent.
Various challenges remain, however, including the fact that immune cells may inadvertently remove, or clear, the ADCs before they reach their target. William Zamboni, PharmD, PhD, director of the Translational Oncology and Nanoparticle Drug Development Initiative at the University of North Carolina in Chapel Hill, spoke at the recent 2014 World ADC Summit in San Diego, CA, about the likely involvement of the mononuclear phagocyte system (MPS) in ADC clearance.
The MPS is a network of monocytes, macrophages, and dendritic cells. “These scavengers scarf up particles perceived as foreign,” Zamboni says. “They're slower in going after naked antibodies, but ADCs are engineered with warheads, linkers, and other ‘decorations’ that could make them more vulnerable to MPS recognition and clearance.”
Some ADCs have a narrow therapeutic index—the ratio of toxicity to efficacy—which could be attributed to highly variable MPS function within and between patients, Zamboni notes. Inadvertent engulfing of ADCs by MPS cells could also result in “bystander” toxicity, or the unintended destruction of healthy tissue, as a result of the possible release of any “leftover” drug payload.
Zamboni and his group have developed an array of analytical and phenotypic methods to profile ADCs and other carrier-mediated therapeutic agents. “We can evaluate the rate and extent of drug uptake by MPS cells, and how drugs like ADCs affect this system,” he says. “We also have a technology called MPS-Probe that predicts clearance by measuring MPS function in the blood prior to drug administration.”
“Essentially, we're saying that the MPS could have a central role in the complex pharmacology of ADCs,” Zamboni explains. “Once we understand how this system interacts with ADCs and impacts their delivery and clearance, we can then design better therapeutics.”
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