Prodrug could help curb skin toxicity related to EGFR-inhibiting cancer drugs

Sep 01, 2009

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 (). 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 to become "unmasked" and able to bind to the on the .

"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.

The print version of the study will be published in the November 15 issue of Biology and Therapy.

Source: Thomas Jefferson University (news : web)

Explore further: Phase 3 study may be game-changer for acute myeloid leukemia

add to favorites email to friend print save as pdf

Related Stories

Researchers combine nanotubes and antibodies to detect cancer

Nov 17, 2005

By coating the surfaces of tiny carbon nanotubes with monoclonal antibodies, biochemists and engineers at Jefferson Medical College and the University of Delaware have teamed up to detect cancer cells in a tiny drop of water. ...

Recommended for you

Phase 3 study may be game-changer for acute myeloid leukemia

1 hour ago

Moffitt Cancer Center researchers say clinical trials for a new experimental drug to treat acute myeloid leukemia (AML) are very promising. Patients treated with CPX-351, a combination of the chemotherapeutic drugs cytarabine ...

User comments : 0

More news stories

Rising role seen for health education specialists

(HealthDay)—A health education specialist can help family practices implement quality improvement projects with limited additional financial resources, according to an article published in the March/April ...

FDA proposes first regulations for e-cigarettes

The federal government wants to prohibit sales of electronic cigarettes to minors and require approval for new products and health warning labels under regulations being proposed by the Food and Drug Administration.

When things get glassy, molecules go fractal

Colorful church windows, beads on a necklace and many of our favorite plastics share something in common—they all belong to a state of matter known as glasses. School children learn the difference between ...

FCC to propose pay-for-priority Internet standards

The Federal Communications Commission is set to propose new open Internet rules that would allow content companies to pay for faster delivery over the so-called "last mile" connection to people's homes.

SK Hynix posts Q1 surge in net profit

South Korea's SK Hynix Inc said Thursday its first-quarter net profit surged nearly 350 percent from the previous year on a spike in sales of PC memory chips.

Brazil enacts Internet 'Bill of Rights'

Brazil's president signed into law on Wednesday a "Bill of Rights" for the digital age that aims to protect online privacy and promote the Internet as a public utility by barring telecommunications companies ...