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Fox Chase Begins Phase I/II Breast Cancer Clinical Trial with Unique Bispecific — Or Two-Target — Antibody

Bispecific Antibody Comes Full Circle: From Concept in a Fox Chase Lab to Trial in a Fox Chase Clinic, By Way of Merrimack Pharmaceuticals, Inc.

Learn more about the origins of bispecific antibody research at Fox Chase (video, 6 minutes).

Philadelphia (July 6, 2009) – It is not often that basic scientists see the results of their work directly affecting patient care, but that is exactly what is happening as Fox Chase Cancer Center becomes one of two sites in the country taking part in a Phase 1/2 clinical trial of MM-111, a bispecific antibody-based therapeutic developed by Merrimack Pharmaceuticals, Inc. The trial will establish safe dosage and pharmacokinetics for the therapeutic in certain forms of drug-resistant breast cancer.

According to Merrimack, the trial has begun enrolling patients at South Texas Accelerated Research Therapeutics (START), a Phase 1 clinical trial program based in San Antonio, Texas. Enrollment will begin at Fox Chase in July.

The general concept behind the new drug was first developed at Fox Chase in collaboration with researchers at the University of California, San Francisco. Both institutions joined to license the intellectual property for the bispecific antibody to Merrimack, which further refined the antibody and made it more suitable for use as a drug in humans.

“From the preclinical studies performed by Merrimack we anticipate that MM-111 will be highly specific for just ErbB2-containing cancer cells,” said Crystal Denlinger, MD, Fox Chase oncologist and head of the trial at Fox Chase. “It is also a rare and wonderful thing to see a trial begin at the place where the concept underlying the drug was initially conceived.”

MM-111 targets cells that exhibit an excess of the ErbB2 on their surface, and therapeutically treats ErbB3 (ErbB2 and ErbB3 are products of two known cancer-related genes, Her2 and Her3, respectively). Together these two proteins form a growth-promoting complex on the surface of many cancer cells, including head and neck cancer and drug-resistant breast cancer.  MM-111 consists of two antibody arms linked by a protein chain; one arm targets ErbB2 with high specificity, while the other serves to block growth-signaling molecules from attaching to ErbB3.

The origin of the double-headed antibody has its roots in a conversation between Louis Weiner, MD, then-chair of medical oncology at Fox Chase, and Greg Adams, PhD, an antibody engineer and Co-Leader of Fox Chase’s Molecular and Translational Medicine Program.  Weiner and Adams took the concept of an anti-ErbB2/ErbB3 bispecific antibody to their long-term collaborator James Marks, MD, PhD, of the University of California, San Francisco. The Adams lab used recombinant DNA technology to engineer the ErbB2 and ErbB3 targets which the Marks lab then used to isolate the antibodies that the Adams lab used to engineer the prototype bispecific antibodies.  The exquisite ability of these prototype bispecific antibodies to target and treat breast cancer cells was then determined in the laboratory by Matthew Robinson, PhD, a Fox Chase associate member.

“Tumors that express the ErbB2-ErbB3 complex are highly aggressive and prone to relapse after initial treatment, so drug-resistant ErbB2-positive breast cancer is an ideal proof-of-concept for these bispecific antibodies,” said Adams. “The antibody literally gets between the two receptors and holds them apart.”

After licensing the intellectual property, Merrimack scientists further refined the concept to create a new drug.  Its antibody arms bind more tightly to their targets and its linker chain is derived from a human protein, which allows the drug to survive in the bloodstream longer. According to Merrimack, MM-111 is the first bispecific antibody binding two different receptors on the same cell to enter clinical development.

According to Denlinger, the Phase 1 study is  open to all cancer patients with drug-resistant tumors that overexpress Her2. This phase of the trial is designed to study drug tolerance and dosage before initiating a Phase 2 study, which is only open to breast cancer patients who overexpress Her2 and have failed treatment with either – or both – traztuzumab (Herceptin) and lapatinib (Tykerb).

Fox Chase Cancer Center, part of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence four consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach.  For more information, call 1-888-FOX CHASE or (1-888-369-2427).

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