DENVER, April 22, 2009 (GLOBE NEWSWIRE) -- Immunomedics, Inc. (Nasdaq:IMMU), a biopharmaceutical company focused on developing monoclonal antibodies to treat cancer and other serious diseases, today announced the results of four preclinical studies involving new antibody-cytokine conjugates and cytokines site-specifically PEGylated using the Company's and its majority-owned subsidiary, IBC Pharmaceuticals, Inc.'s proprietary Dock-and-Lock method (DNL) for protein engineering.
The first study evaluated the in vitro and in vivo properties of a2b-413 and a2b-457, two DNL-PEGylated interferon-a2b (IFNa2b) molecules constructed with different sizes of polyethylene glycol (PEG), and compared them with approved PEGylated IFNa2b therapeutics, PEG-INTRON and PEGASYS. The two DNL-PEGylated interferons had similar anti-viral activities in vitro, which were higher than PEGASYS but less than PEG-INTRON, and demonstrated slower clearance in mice than PEG-INTRON with an advantage for a2b-457 over PEGASYS. In an animal lymphoma model, a2b-413 and a2b-457 significantly improved animal survival in comparison to PEG-INTRON but not in animals treated with PEGASYS. These results suggest that the two DNL-PEGylated IFN-a2b molecules have select advantages over both PEG-INTRON and PEGASYS, which warrant further testing in the clinic. Site-specific conjugation of PEG to IFNa2b using DNL was first reported by the Company at the 2007 annual meeting of ASH (www.immunomedics.com/news_pdf/2007_PDF/PR12102007b.pdf).
DNL-modified IFNa2b was also the subject of a second study presented earlier in the week by the Company. 20-2b, which contains 4 IFNa2b groups site-specifically conjugated to veltuzumab, the Company's next generation humanized anti-CD20 antibody that has shown anti-lymphoma activity at low doses in clinical studies, was reported to retain the anti-viral activity of IFNa2b in vitro and have specific activities similar to PEG-INTRON but greater than PEGASYS. Moreover, it was shown to have significantly longer circulating half-life in mice than those of PEG-INTRON and PEGASYS, and found to be stable in human sera and whole blood for at least 10 days. Compared with veltuzumab, 20-2b demonstrated enhanced antibody-dependent cellular cytotoxicity (ADCC) in two human lymphoma cell lines but lacked the complement-dependent cytotoxicity (CDC) of its parental antibody.
Anti-lymphoma efficacy was evaluated in various animal models. In one lymphoma model, a single, low-dose of 20-2b (0.7 pmol) extended medium survival time (MST) by more than 100 days over both untreated animals and the veltuzumab group. Moreover, the 7 long-term survivors in the 20-2b group did not show visible evidence of disease at the end of the study. In an advanced tumor model, the same dosage of 20-2b produced MST that is similar to the group receiving the highest dose of PEGASYS (70 pmol), which is 100-fold higher. Treatment with the same high dose of 70 pmol of 20-2b, in comparison, improved MST to more than 105 days with all 9 animals in the group surviving, while veltuzumab at 70 pmol had only a modest effect on survival with MST of 24 days. Finally, in two models that are resistant to the interferon and less responsive to veltuzumab, 20-2b doubled MST over untreated animals and significantly improved survival over veltuzumab. Based on these results, the veltuzumab-interferon-a2b conjugate could be an attractive candidate for the therapy of CD20-expressing lymphomas and leukemias.
In a separate study, DNL was used to create new protein constructs that contain multiple copies of erythropoietin (EPO) with improved pharmacokinetics and potency. EPO is a hematopoietic growth factor that stimulates the proliferation and differentiation of erythrocytes into mature red blood cells. Several recombinant human EPOs, including Aranesp, are currently used for the treatment of anemia, predominantly associated with chronic kidney failure and cancer chemotherapy. However, the short half-life of these products (4-13 hours) necessitates frequent dosing. Increasing the serum half-life of EPO to allow less frequent dosing is, therefore, highly desirable and has been an important goal for developing next-generation EPO.
The poster presentation described the generation of 3 EPO derivatives: a DNL-PEGylated EPO (PEG-EPO) that contains two copies of EPO, an antibody fragment conjugated to 2 EPOs (Fab-EPO), and an intact antibody linked to 4 copies of the cytokine (IgG-EPO). All 3 derivatives maintain the biological activity of EPO with a similar specific activity to Aranesp. In addition, in vivo activity of IgG-EPO was confirmed in normal mice. A single intravenous administration of IgG-EPO induced a significant increase in hematocrit levels compared to untreated mice.
Like EPO, granulocyte colony-stimulating factor (G-CSF) is also a hematopoietic growth factor and is the subject of the fourth study. G-CSF stimulates the bone marrow to produce more white blood cells. Currently in the U.S., a recombinant methionyl human G-CSF and its longer-acting PEGylated form is largely used for treating chemotherapy-induced neutropenia and for mobilizing transplantable stem cells from bone marrow to the blood for easier collection and processing. In this study, 3 antibody-G-CSF conjugates were generated and characterized. Each conjugate comprising 4 copies of human G-CSF linked site-specifically to one of the Company's three proprietary humanized antibodies: veltuzumab (anti-CD20), labetuzumab (anti-CEACAM5) and h734 (anti-indium-DTPA).
Against a leukemia cell line, h734-G-CSF and veltuzumab-G-CSF were more potent than recombinant human G-CSF. h734-G-CSF also induced a higher number of monocytes and neutrophils in the blood of normal mice, compared to untreated animals. For veltuzumab-G-CSF, enhanced ADCC was observed in CD20-positive lymphoma cells. Because anti-CD20 therapies can cause neutropenia in patients, the potential of veltuzumab-G-CSF to enhance the potency of an anti-CD20 antibody yet prevent neutropenia is very attractive.
In a statement by company President and CEO, Cynthia L. Sullivan: "We believe these findings clearly demonstrated the versatility of DNL in making a wide array of multivalent fusion proteins that are stable for clinical use. To that end, we are pleased to report that TF2, a DNL created bispecific antibody that targets the carcinoembryonic antigen, will be studied for the pretargeted imaging and therapy of colorectal and small cell lung cancers in a number of investigator-sponsored trials," she added.
The generation of DNL-derived antibody-cytokine conjugates has previously been reported by the Company (www.immunomedics.com/news_pdf/2008_PDF/PR04162008.pdf).
About the Dock and Lock Method (DNL)
DNL 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 drugs, chemical polymers, 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 Immunomedics
Immunomedics is a New Jersey-based biopharmaceutical company primarily 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. We also have a majority ownership in IBC Pharmaceuticals, Inc., which is developing a novel Dock-and-Lock (DNL) methodology with us for making fusion proteins and multifunctional antibodies, and a new method of delivering imaging and therapeutic agents selectively to disease, especially different solid cancers (colorectal, lung, pancreas, etc.), by proprietary, antibody-based, pretargeting methods. We believe that our portfolio of intellectual property, which includes approximately 134 patents issued in the United States and more than 300 other patents issued worldwide, protects our product candidates and technologies. For additional information on us, please visit our website at www.immunomedics.com. The information on our website does not, however, form a part of this press release.
This release, in addition to historical information, may contain forward-looking statements made pursuant to the Private Securities Litigation Reform Act of 1995. Such statements, including statements regarding clinical trials, out-licensing arrangements (including the timing and amount of contingent payments), forecasts of future operating results, and capital raising activities, involve significant risks and uncertainties and actual results could differ materially from those expressed or implied herein. Factors that could cause such differences include, but are not limited to, risks associated with new product development (including clinical trials outcome and regulatory requirements/actions), our dependence on our licensing partners for the further development of epratuzumab for autoimmune indications and veltuzumab for non-cancer indications, competitive risks to marketed products and availability of required financing and other sources of funds on acceptable terms, if at all, as well as the risks discussed in the Company's filings with the Securities and Exchange Commission. The Company is not under any obligation, and the Company expressly disclaims any obligation, to update or alter any forward-looking statements, whether as a result of new information, future events or otherwise.