One drug, two targets

July 12, 2003

Targeted therapies are the new paradigm in cancer treatment and researchers at Fox Chase Cancer Center in Philadelphia are developing the second generation of these antibody-based drugs. Ongoing research at Fox Chase has demonstrated the ability of recombinantly engineered bispecific monoclonal antibodies to attack two separate targets on a single cancer cell. Most recently, the Fox Chase laboratory of Gregory P. Adams, Ph.D., has done preclinical tests of bispecific molecules carrying a radioactive isotope that can be used to detect or kill a tumor.

"What is unique is that these bispecific antibodies are expected to make the targeted tumor cells more sensitive to the radiation," said Adams, a researcher in the medical science division at Fox Chase Cancer Center. Adams presented his research today at the 94th annual meeting of the American Association for Cancer Research, July 11-14 in Washington, D.C.

Targeted cancer therapies work by attacking a single target on the surface of the cell, either delivering a toxic payload or directly causing it to stop multiplying or die. "Unfortunately, there is a lot of redundancy in cancer cells, making it difficult to kill a tumor with a single hit," Adams pointed out. "We wanted both to refine the tumor specificity of the antibodies and to increase their ability to kill the targeted cells.

"Our targets are members of the epidermal growth factor receptor family, a powerful group of signaling proteins that are found in many commonly occurring cancers. These receptors interact with each other to instruct cells to grow and resist the effects of many cancer cells. Simultaneously targeting pairs of these receptors can increase the specificity of tumor-cell targeting and block their signaling functions, thus making the cells more sensitive to treatment.

"Attaching radioisotopes to this molecule adds insult to injury and gives us a better chance to destroy cancer cells without attacking normal cells," Adams said.

Using mice with grafts of human tumors, studies in Adams' laboratory found that one bispecific molecule, called ALM, achieved highly specific targeting against human breast and ovarian cancers. A second molecule, BLM, led to reduced levels of cell proliferation in human breast cancer cells growing in cell cultures.

Adams also demonstrated how this targeted approach allows more precise detection of cancer cells by using nuclear imaging techniques such as a PET (positron emission tomography) scan.

The Therapeutic Molecules
Cancer therapies using monoclonal antibodies-laboratory-crafted molecules that can bind to specific proteins on cells as the body's natural antibodies do-have been approved by the Food and Drug administration. Examples include Rituxan for lymphoma and Herceptin for advanced breast cancer.

"Although monoclonal antibodies have become accepted tools for cancer treatment and detection, their relatively large size limits their ability to reach target tumor cells," Adams explained. "These antibodies circulate in the bloodstream but can't penetrate deeply enough into the target tissues. Monoclonal antibodies also circulate in the blood too long to carry therapeutic radioactive isotopes without the risk of unacceptable immune suppression."

The smaller therapeutic molecules developed by Adams and his colleagues at Fox Chase Cancer Center and the University of California at San Francisco are actually bioengineered antibody fragments called bispecific single-chain Fv (scFv) fragments. Antibodies are able to bind to new target proteins because of their variability. The Fv in the term scFv stands for fraction variable-the smallest unit of the antibody that retains the binding characteristics of the whole antibody.

"The small size of the bispecific scFv molecules allows them to leave the bloodstream rapidly and reach tumors effectively," said Adams. "This makes the molecules ideal vehicles not only for seeking out cancer cells but for delivering a radioactive death blow."

The Targets
Adams and collaborator James D. Marks, M.D., Ph.D., of UCSF have developed bispecific scFv molecules that target certain epithelial growth factor receptor (EGFR) proteins-a family of receptor tyrosine kinase enzymes involved in cell signaling that promotes growth. The EGFR family of proteins includes EGFR, HER2/neu, HER3 and HER4. The antibody-based drug Herceptin targets HER2/neu.

These receptors trigger a rich signaling network that leads to intense proliferation of cancer cells. On the outside of the cell, areas of these receptor proteins called extracellular domains play a key role in this process.

The first of three targets for the ALM and BLM targeted therapies is the HER2/neu protein. HER2 is overactive in 25 to 50 percent of breast, ovarian, prostate and colorectal cancers. This overexpression is correlated with a poor prognosis in primary breast cancer.

The second target, HER3, is overexpressed in 20 percent of breast cancers, 28 to 47 percent of pancreatic cancers and 81 percent of gastric cancers. Overexpression of HER3 is also found in ovarian, prostate and colorectal cancers and low levels of it are detected in skin, stomach, lung, kidney and brain cancers.

The third target, HER4, is active in normal tissues, such as muscle, heart, pituitary gland and brain, but it is also found breast cancer cells.

The experiments by Adams and his colleagues in mice with human tumor grafts showed that ALM can simultaneously bind to the extracellular domains (ECDs) of both HER2/neu and HER3. The in vitro studies showed that BLM can bind to the ECDs of both HER2/neu and HER4.

Technological Collaborations
For the antibody engineering, Marks' UCSF laboratory provided phage display-derived scFv molecules that targeted the ECDs for the HER2/neu, HER3 and HER4 proteins expressed in Adams' lab.

The isotopes used in Adams' lab for the imaging studies were produced in St. Petersburg, Russia, and were the first of their kind to be imported into the United States. A collaboration with General Electric, focused on developing new agents for PET detection of cancer, supported importation of these isotopes.

The isotopes are positron (beta+) emitters that can be seen with a nuclear imaging device such as a PET scanner. To further collaboration efforts, GE provided support to image the treated mice on Fox Chase Cancer Center's PET/CT scanner (a GE Discovery LS). The PET/CT scanner is normally used to measure physiological activity of human cancer.

"We were surprised by the incredible clarity and sensitivity of the PET/CT scan, which allowed us to see tumor localization of the ALM bispecific antibody within 24 hours of administration to the mice," said Adams. "This demonstrates the potential to use this drug for cancer diagnosis and possibly treatment in humans."

In addition to Marks, Adams' co-authors of this targeted therapy study include staff scientist Matthew K. Robinson, Ph.D., scientific associates Eva Horak and Calvin C. Shaller, scientific assistant Heidi H. Simmons, scientific technician Abohawariat Tesfaye, medical physicist Mohan Doss, nuclear medicine chief Lee P. Adler, M.D., and medical oncology chairman Louis M. Weiner, M.D., vice president for translational research, all of Fox Chase Cancer Center, plus postdoctoral associate Tara Heitner, Ph.D., and graduate student Jennifer L. Garrson, Ph.D., of the University of California at San Francisco.
-end-
Fox Chase Cancer Center, one of the nation's first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic and clinical research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center's web site at www.fccc.edu.

Abstract # R5784:Anti-HER2/HER3 Bispecific Single-Chain Fv Molecules for Cancer Detection and Therapy
To be presented July 13, 9:40-9:55 a.m.,
Immunology 14 Minisymposia on Antibodies and Cellular Response,
Washington Convention Center, Room 207

Fox Chase Cancer Center

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