Second Generation Targeted Antibodies - It’s All in the Binding

Newswise — The overproduction, or 'overexpression', of the epidermal growth factor receptor (EGFR) is one of the most common aberrations in cancer, and subsequently agents that inhibit EGFR are among the most hotly-pursued potential products in the pharmaceutical industry. Now, just weeks after one of the first anti-EGFR antibodies, ImClone's Erbitux (Cetuximab), was approved for use in Europe and the USA, a 'second generation' anti-EGFR antibody is set to enter early-phase clinical trials in Australia. In two articles recently published in the Journal of Biological Chemistry, research teams from the Melbourne Branch of the international Ludwig Institute for Cancer Research (LICR) have elucidated the unique binding properties of an anti-EGFR antibody, called 806, that is able to discriminate between EGFR molecules on cancer cells and EGFR molecules on normal cells.

"There is already one anti-EGFR antibody on the market, and there are several more in clinical trials," says Dr. Andrew Scott, the Head of the LICR Melbourne Branch's Clinical Program. "Although these anti-EGFR antibodies do show some anti-tumor activity in patients, they are far from ideal because they bind to EGFR on both cancer cells and normal cells. As a result, they target normal tissues as well as the tumor, and side-effects, although mild, are common." Perhaps more importantly, the 'first generation' antibodies are limited in their clinical application and their capacity for improvement. "We need to increase the therapeutic efficacy of the available anti-EGFR antibodies," explains Dr. Scott. "What we would like to do is attach a lethal agent to an anti-EGFR antibody, such as a cytotoxic molecule or a radioisotope, so that the agent is targeted directly to the cancer cell. With the 806 antibody, we should be able to both interfere with EGFR signaling and deliver lethal agents to cancers, without causing severe side-effects through the destruction of normal, healthy cells, particularly in the liver and skin."

The 806 antibody was originally discovered at the LICR's New York Branch and has since been developed further through a concerted, international effort by LICR scientists at Branches in New York, San Diego, Stockholm, and Melbourne. The antibody was initially intended to target a mutated form of EGFR and was being developed as a treatment for brain tumors called glioblastomas. However, during comprehensive pre-clinical analyses it was found that the 806 antibody bound not only to the glioblastoma-specific mutant form of EGFR, it also bound to a significant proportion of EGFR positive cancers, but not to any normal tissue. The LICR teams subsequently showed that 806 has a potent anti-tumor activity in animal models of human cancers that overexpress EGFR.

The LICR Melbourne Branch has a longstanding research program in EGFR structure and biology, and in a recent pivotal discovery participated in defining the 3D-structures of the extracellular domains of the EGFR and a related protein, erbB2/HER-2, which is implicated in many breast cancers. The most recent papers describe in detail how EGFR undergoes alterations in its conformation as it is activated, and where the 806 antibody binds to the activated EGFR when the molecule is overexpressed on the surface of a cancer cell. According to Dr. Antony Burgess, the Director of the LICR Melbourne Branch, the elucidation of these conformational changes is crucial to designing more effective cancer therapies. "To rationally design antibodies that improve the targeting to EGFR, or any other cell surface receptor for that matter, you need to have an understanding of how the molecule works. The results from these two papers suggest how we might be able to design more antibodies, like 806, which bind to different conformations of a single molecule, and are thus able to discriminate between normal and tumor cells."

Clinical-grade 806 antibody has been produced within LICR's own biological production facilities for the first early-phase clinical trial. The trial, which will investigate the safety, dose, and tissue distribution of the 806 antibody in patients with head and neck or lung cancers, will commence in Melbourne this year.

The published studies were conducted by scientific teams from: i) the Melbourne Branch of the LICR, Commonwealth Scientific & Industrial Research Organization Department of Health Sciences and Nutrition, and the Walter and Eliza Hall Institute of Medical Research, under the auspices of the Cooperative Research Centre for Cellular Growth Factors, Melbourne, Australia; and ii) the Melbourne and New York Branches of the LICR, Commonwealth Scientific & Industrial Research Organization Department of Health Sciences and Nutrition, and the Walter and Eliza Hall Institute of Medical Research, and the Department of Chemical Engineering, Massachusetts Institute of Technology.

The Ludwig Institute for Cancer Research (LICR) is the largest international academic institute dedicated to understanding and controlling cancer. With ten Branches in seven countries, and numerous Affiliates and Clinical Trial Centers in many others, the scientific network that is LICR quite literally covers the globe. The uniqueness of LICR lies not only in its size and scale, but also in its philosophy and ability to drive its results from the laboratory into the clinic. LICR has developed an impressive portfolio of reagents, knowledge, expertise, and intellectual property, and has also assembled the personnel, facilities, and practices necessary to patent, clinically evaluate, license, and thus translate, the most promising aspects of its own laboratory research into cancer therapies. The Massachusetts Institute of Technology- a coeducational, privately endowed research university-is dedicated to advancing knowledge and educating students in science, technology, and other areas of scholarship that will best serve the nation and the world in the 21st century. The Institute has more than 900 faculty and 10,000 undergraduate and graduate students. It is organized into five Schools-Architecture and Planning, Engineering, Humanities, Arts, and Social Sciences, Management, and Science-and the Whitaker College of Health Sciences and Technology. Within these are twenty-seven degree-granting departments, programs, and divisions. In addition, a great deal of research and teaching takes place in interdisciplinary programs, laboratories, and centers whose work extends beyond traditional departmental boundaries. Fifty-seven alumni, faculty, researchers and staff have won Nobel Prizes.