MedImmune, Inc, of Gaithersburg, Maryland, announced that it has completed its acquisition of Cellective Therapeutics, Inc, a privately held early-stage biopharmaceutical company focused on the development of preclinical therapeutic monoclonal antibodies targeting the B-cell surface antigens CD19, CD20, and CD22. The all-cash transaction includes an upfront payment and the potential for future milestone payments, all of which could total approximately $160 million.
Of the three target antigens, the CD19 therapeutic antibody currently appears to have the least risk of competition and perhaps the greatest promise for clinical utility.
Data from transgenic mouse models expressing human CD19 (hCD19) demonstrate that CD19-directed therapies may have clinical benefit for the treatment of autoimmune diseases such as systemic lupus erythematosus, early B-cell malignancies such as leukemias and lymphomas, and transplant rejection.1 The ability of anti-CD19 monoclonal antibodies to deplete B cells prior to antigen receptor selection may result in the effective long-term removal of pathogenic B-cell clones, thus normalizing the immune state.
The potential promise of these monoclonal antibodies, which were developed by Thomas F. Tedder, MD, scientific founder of Cellective Therapeutics and chairman of the department of immunology at Duke University in Durham, North Carolina, has attracted $27.5 million in Series A financing, led by Intersouth Partners, Genentech, Inc, MedImmune Ventures, Inc, and other prominent venture capital partners.
With regard to autoimmunity, the researchers reported that administration of relatively low doses of anti-hCD19 monoclonal antibody rapidly and durably depleted the majority of circulating and peripheral B-cell subsets (without affecting T-cell numbers), markedly reduced primary and secondary antibody responses and, in the mouse model of autoimmune disease, substantially reduced acute and long-term autoantibody responses and eliminated class switching during humoral immune responses.
As is the case for anti-CD20 (rituximab; Rituxan®, Genentech) monoclonal antibody therapy, CD19 monoclonal antibody-induced B-cell depletion depends on FcR-gamma expression, thus implicating macrophage-mediated antibody-dependent cytotoxicity as the major effector mechanism for CD19+ B-cell depletion. However, unlike anti-CD20 immunotherapy, which depletes only mature B cells and which is only moderately effective in depleting peritoneal cavity B cells, CD19-directed therapy is almost twice as durable due to the elimination of B-cell precursors and the effective depletion of peritoneal cavity B cells. Lastly, given the ability of CD19-directed therapy to deplete pathogenic B cells before antigen receptor selection, this approach opens the possibility for reestablishing normal tolerance mechanisms by the effective and durable depletion of pathogenic B cell clones and their autoantibody products.
MedImmune also announced the filing of an investigational new drug application (IND) with the US Food and Drug Administration for MEDI-545, a fully human monoclonal antibody (generated by Medarex, Inc, using its UltiMAb® technology) targeting interferon-alpha, elevated levels of which have been associated with active systemic lupus and other autoimmune disorders. MEDI-545 is believed to target multiple interferon-alpha subtypes.
Preclinical data from a lupus disease animal model indicate that MEDI-545 may suppress the abnormal immune activity associated with lupus, decreasing autoantibody production and disease activity. Under the terms of the agreement with Medarex, prior to the beginning of pivotal studies, Medarex may elect to codevelop the products in return for the opportunity to copromote and receive a share of commercial profits in the US. Currently, MedImmune is fully responsible for all ongoing development activities.
—A. Techman
Reference
- Yazawa N, Hamaguchi Y, Poe JC, Tedder TF. Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease. Proc Natl Acad Sci. 2005;102:15178-15183 [Epub ahead of print. Week of October 10, 2005].