Prodrug Could Help Curb Skin Toxicity Related to EGFR Inhibiting Cancer Drugs
There may be a way around the harsh skin
toxicity associated with a widely used cancer drug, according to a study
published online this week in Cancer Biology and Therapy by researchers
from City of Hope and the Kimmel Cancer at Jefferson.
Cetuximab (Erbitux) is a monoclonal
antibody that binds to and inhibits the epidermal growth factor receptor (EGFR).
It is widely used to treat colorectal cancer and head and neck cancer. Although
cetuximab and other EGFR inhibitors are associated with a lower rate of side
effects compared with conventional chemotherapy, adverse effects of the drugs
often include a dose-limiting skin rash and gastrointestinal symptoms.
Adverse events in antibody therapy are
frequently due to the binding of antibodies to normal tissue in addition to
tumor tissue, according to Ulrich Rodeck, M.D., Ph.D., professor of Dermatology
and Cutaneous Biology at Jefferson Medical College of Thomas Jefferson
University. By “masking” the antibodies so they preferentially bind to the tumor
tissue, the toxicity may be reduced or avoided.
“We’ve designed a prodrug in which the
antibody is masked by an engineered form of the antigen, preventing it from
binding to antigen on normal tissue,” Dr. Rodeck said. “However, when the
antibody reaches the tumor tissue, enzymes prevalent at tumor sites cleave the
mask off, and the antibody can now engage the antigen at the tumor site.”
The prodrug contains the antigen binding
sites of two different EGFR-specific antibodies: 425 (matuzumab) and C225
(cetuximab). Each antibody is connected via peptide linker to the antigen
recognized by the opposite antibody. The linkers contain sites susceptible to
proteolytic cleavage by metalloprotease 9 (MMP-9), an enzyme that is frequently
overexpressed in epithelial malignancies. Cleavage of the complex leads the
antibodies to become “unmasked” and able to bind to the antigens on the tumor
cells.
“This work provides proof-of-principle
evidence that the concept is feasible, and sets the stage for future studies
using tumors grown in vivo,” Dr. Rodeck said.
This study was led by Dr. Rodeck and John
C. Williams, Ph.D., assistant professor of molecular medicine and director of
the x-ray crystallography program at City of Hope. The first author is Joshua
Donaldson, a graduate student at Jefferson. The print version of the study will
be published in the November 15 issue of Cancer Biology and Therapy.
Media Only Contact:
Emily Shafer
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 9/2/2009