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.
About Immunomedics
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>.