Newsletter - Edition 29
A Major Role for Monoclonal Antibodies in the Successful Translation of Progress in Immunobiology into New Therapeutics
Oxford Innovation Society Lecture - September 1999 Dr Christopher Mirabelli, LeukoSite Inc.
LeukoSite is a biopharmaceutical company located in Cambridge, MA. The company was founded in 1993 with the mission to become a sustainable multi-product pharmaceutical company focused on the discovery, development and commercialization of therapeutics for diseases of the immune system.
A key part of LeukoSite's drug discovery activities has been in identifying receptor molecules and other proteins on white blood cells that play roles in diseases such as inflammation, autoimmunity, hematologic malignancies and infection. By targeting such molecules and blocking their disease promoting actions with drugs, LeukoSite scientists are developing therapies with high degrees of selectivity and improved safety profiles.
In collaboration with Professor Herman Waldmann and Dr. Geoff Hale at the University of Oxford, along with other academic based researchers, LeukoSite recognized the important role that monoclonal antibodies could play in its drug discovery process. As the cellular location of the molecules of interest to LeukoSite are on the surface of white blood cells and in the blood compartment rather than in tissues, monoclonal antibodies have ideal pharmacologic and pharmacokinetic properties by which to aid in the definition of such targets in disease (Figure 1). Upon the generation of monoclonal antibodies that bind to and block the function of the white blood cell molecules of interest, the antibodies are tested in vitro and in vivo models of disease in order to evaluate the potential therapeutic value of such "mechanisms of actions".
In 1994 LeukoSite entered into a collaborative agreement with the Medical Research Council and the University of Oxford to provide research funding for the Therapeutic Antibody Centre (TAC), headed by Professor Waldmann and Dr. Hale. In addition to providing funding for early stage mAb research projects, the collaboration has impacted a number of LeukoSite's therapeutic programs. Areas of collaboration have included the process of humanizing murine antibodies in order to make them less immunogenic, developing processes in cell culture systems to produce antibodies of interest, and the evaluation of certain antibodies in early stage clinical studies to assess their therapeutic value.
The most advanced therapeutic antibody that has been worked on by the collaboration of the TAC and LeukoSite is CAMPATH® (Figure 2). The original form of this antibody was generated by Professor Waldmann and his colleagues at Cambridge University back in the early 1980's. Since that time, it was evaluated in a variety of human diseases based on its ability to deplete lymphocytes in the blood and in tissues while leaving hemeopoetic bone marrow stem cells in tact. LeukoSite in-licensed CAMPATH® from the British Technology Group in 1997 and undertook a project to complete the clinical development of CAMPATH® in chemorefractory chronic lymphocytic leukemia. Based on the recently concluded pivotal study in this group of patients LeukoSite will be filing for regulatory approval of CAMPATH® in the US and Europe. In addition to this indication LeukoSite, Professor Waldmann and the TAC have been exploring other therapeutic uses of CAMPATH® through the clinical research program of the CAMPATH® Users Group consisting of various UK and European clinical investigators. Other antibodies being evaluated in the clinic by LeukoSite have been positively impacted by the collaboration with the TAC and Professor Waldmann. LDP-01, an antibody that binds to a homing receptor of white blood cells, was originally generated and evaluated by Professor Waldmann's group (Figure 3). LeukoSite in-licensed the antibody in 1994 and is currently studying it in Phase I and Phase II trials for use in blocking the rejection of organ transplants and in blocking the inflammation and tissue damage that accompanies ischemic stroke. LeukoSite and the TAC have collaborated on a number of areas of the preclinical and clinical development of LDP-01.
In addition to these mAbs, LeukoSite and the Waldmann Group are collaborating on additional therapeutic antibodies and immuotherapeutics projects (Figure 4). The collaboration has recently expanded into the area of pharmacologically induced immune tolerance. This research may some day lead to the ability to use mAbs in more chronic disease settings and result in long term benefits from brief periods of antibody administration.
The collaboration between LeukoSite, the University of Oxford, Professor Waldmann and the TAC exemplifies a potential value that can be generated when world leading academic based researchers team up with biopharmaceutical companies. In this case the value can be quantified by the advances made in our knowledge of immune system based diseases and the ability to bring new therapies to patients with severe life threatening diseases where few, if any, treatments exist.
Newsletter - Edition 29 Contents
- Monoclonal Antibodies
- Reprogramming the Immune System
- Oxford Gene Technology
- Isis College Fund
- Oxagen Ltd