IMMUNOMEDICS AND IBC PHARMACEUTICALS REPORT ON A NOVEL
PROTEIN ENGINEERING PLATFORM TECHNOLOGY
- Dock and Lock (DNL) Method has Broad Spectrum of Potential Applications -
Morris Plains, NJ, April 25, 2006 - Immunomedics, Inc. (Nasdaq: IMMU), a biopharmaceutical company focused on developing monoclonal antibodies, and its wholly owned subsidiary, IBC Pharmaceuticals, Inc., today announced the development of a novel platform technology that can be used to generate multifunctional agents for diverse applications. The on-line article entitled "Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting," and authored by E.A. Rossi, D.M. Goldenberg, T.M. Cardillo, W.J. McBride, R.M. Sharkey and C.H. Chang, can be accessed at http://www.pnas.org/papbyrecent.shtml. The print issue will be published in the Proceedings of the National Academy of Sciences of the USA (PNAS) on May 2, 2006.
This new technology may enable the creation of virtually any multifunctional protein for diverse applications. For example, one potential application is to connect multiple antibody fragments with toxic drugs or radioisotopes for disease therapy or imaging. Another possibility is to increase the circulation time of hormones, hematopoietic growth factors, or cytokines in the body by linking them to polymers or albumin. The method could also provide a novel means for selective targeting in gene therapy.
Termed the Dock and Lock (DNL) method, the technology is based on the exploitation of two a-helical peptides that are found in nature to bind specifically with each other. By recombinantly fusing or chemically attaching each peptide to a constituent of interest, these helices provide an excellent linker module for "docking" the two modified components into a quasi-stable structure, which is further "locked" into a stable complex.
"The DNL method can be applied to conjugate, quantitatively and site-specifically, various proteins or non-proteins into stably tethered complexes that retain the full functionalities of the individual components and are suitable for both in vitro and in vivo applications," commented Dr. Chien-Hsing Chang, Executive Vice President of Research at IBC Pharmaceuticals. "A unique feature of the DNL method is that in its simplest format one of the two components is always provided with two copies, which can be very important for increased therapeutic efficacy. Suitable components for this technology include antibody fragments, peptide haptens, polyethylene glycols, human serum albumin, cytokines, DNA vaccines, small interfering RNAs, enzymes, fluorescent proteins and a variety of scaffold-based binding proteins," he added.
To prove the validity of the technology, a new trivalent, bispecific protein, TF2, comprising three stably linked Fab fragments, was generated from two of Immunomedics' humanized antibodies, hMN-14, which binds specifically to carcinoembryonic antigen (CEA), and h679, which recognizes the peptide-hapten, histamine-succinyl-glycine (HSG).
By means of a 'pretargeting' method pioneered by IBC Pharmaceuticals, a bispecific antibody or fusion protein, derived from hMN-14 and h679, is first injected to target to the tumor, followed by giving an HSG-carrying radiotracer that binds selectively to the second arm of the bispecific antibody at the tumor site. Pretargeting studies reported in this PNAS article using TF2 and a technetium-99m-labeled HSG-radiotracer in a CEA-expressing human colon cancer growing in mice demonstrated that 30% of injected radiotracer was bound to tumor within one hour. As a result of the rapid tumor uptake, exceptional tumor-to-nontumor ratios were achieved. At 0.5, 1, and 24 hours after the administration of the radiotracer, the tumor-to-blood ratios were 13, 66, and 395, respectively. These data demonstrate that TF2 is highly stable and capable of in vivo applications. More importantly, other constructs made by the DNL method are also expected to be stable in vivo with retained biological properties.
"We believe the DNL method is superior, in at least five major aspects, to existing technologies that involve the conjugation of two or more biological entities: (1) The technology provides a convenient and facile way of constructing different proteins and non-proteins from modular subunits on demand; (2) the new method has shown good productivity of pure products with defined composition; (3) the resulting conjugates show high stability in vivo; (4) the multifunctional complexes produced can potentially have higher activity than each of their individual components; and (5) the technology generates potentially non-immunogenic molecules use as therapeutics," commented Cynthia L. Sullivan, President and Chief Executive Officer of Immunomedics. "This exciting new technology is another testimony of our core strength in research and development. We continue to build on our strong track record of creating new and innovative products from our laboratories," further commented Ms. Sullivan.
About the Dock and Lock (DNL) Method
The DNL method is a platform technology that utilizes the natural interaction between two proteins, cyclic AMP-dependent protein kinase (PKA) and A-kinase anchoring proteins (AKAPs). The region that is involved in such interaction for PKA is called the dimerization and docking domain (DDD), which always appears in pairs. Its binding partner in AKAPs is the anchoring domain (AD). When mixed together, DDD and AD will bind with each other spontaneously to form a binary complex, a process termed docking. Once "docked," certain amino acid residues incorporated into DDD and AD will react with each other to "lock" them into a stably tethered structure. The outcome of the DNL method is the exclusive generation of a stable complex, in a quantitative manner that retains the full biological activities of its individual components. Diverse proteins, peptides, and nucleic acids are among suitable components that can be linked to either DDD or AD. Since DDD always appears in pairs, any component that is linked to DDD will have two copies present in the final products.
About IBC Pharmaceuticals
IBC is a development-stage biopharmaceutical company focused on the development and commercialization of proprietary pretargeting agents for the detection and treatment of various cancers and other serious diseases. These products are based on IBC's patented technology platform referred to as the "Affinity Enhancement System," or AES. The Company currently has several product candidates in pre-clinical and clinical development, and is extending its pretargeting technology to include bispecific antibodies made by the "dock and lock" method.
Immunomedics is a New Jersey-based biopharmaceutical company focused on the development of monoclonal, antibody-based products for the targeted treatment of cancer, autoimmune and other serious diseases. We have developed a number of advanced proprietary technologies that allow us to create humanized antibodies that can be used either alone in unlabeled or "naked" form, or conjugated with radioactive isotopes, chemotherapeutics or toxins, in each case to create highly targeted agents. Using these technologies, we have built a pipeline of therapeutic product candidates that utilize several different mechanisms of action. Our lead product candidate, epratuzumab, is currently in two pivotal Phase III trials for the treatment of patients with moderate and severe lupus (ALLEVIATE A and B). At present, there is no cure for lupus and no new lupus drug has been approved in the U.S. in the last 40 years. We believe that our portfolio of intellectual property, which includes approximately 90 patents issued in the United States, and more than 250 other issued patents worldwide, protects our product candidates and technologies. Visit our web site at <http://www.immunomedics.com>.