Immunomedics, Inc (MORRIS Plains, New Jersey), a biopharmaceutical company focused on developing therapeutic monoclonal antibodies, announced that their partner, UCB, SA (BRUSSELS, Belgium) has received notification from the US FDA that the clinical hold on existing trials with epratuzumab (a humanized IgG1 monoclonal antibody targeting the B-cell specific surface antigen CD22) in patients with systemic lupus erythematosus (SLE) has been lifted. Protocol amendments will now be submitted to Institutional Review Boards (IRBs) to seek approval to treat patients who remain on the currently suspended studies, and who are in need of retreatment.
The clinical hold status, since September 2006, resulted from observations by UCB after a routine audit of the end-stage manufacturing processes by Immunomedics, which resulted in UCB's concerns regarding sterility assurance of the final product. These observations, related to the filling processes during final product manufacturing, in UCB's opinion might result in a lack of consistent assurance of sterility in the final dosage form. No products failing sterility standards were administered to patients, and no reports of clinical safety issues that suggest an association with these quality assurance observations were identified.
Immunomedics granted UCB the exclusive worldwide rights to develop, market, and sell epratuzumab for all autoimmune disease indications, the most advanced program of which is for the treatment of SLE.
Epratuzumab's target, CD22, is a B-lymphocyte-restricted member of the immunoglobulin superfamily, and a member of the sialoadhesin family of adhesion molecules that regulate B-cell activation and interaction with T-cells. CD22 is rapidly internalized when cross-linked with its natural ligand, producing a potent co-stimulatory signal in primary B-cells. Epratuzumab binds to domain three of CD22 with high affinity, and once bound, the antibody-antigen complex is rapidly internalized into the cell. Epratuzumab may also block the binding of natural ligands and, similarly to a natural ligand, may signal the down-regulation of the B-cell. This B-cell modulation may also affect T-cell activity and may explain why complete B-cell depletion is not necessary for epratuzumab's activity, but a combination of mild B-cell depletion with B-cell modulation apparently can result in a therapeutic response. Epratuzumab has been shown to mediate ADCC (antibody-dependent cellular cytotoxicity) in vitro.
In a comparative study using lymphoma cells, Immunomedics and collaborators reported that epratuzumab's mode of action is distinct from that of the anti-CD20 monoclonal antibody RITUXAN® (rituximab, another B-cell specific antibody), which is indicated for the treatment of various CD20-positive, B-cell non-Hodgkin's lymphomas and, in combination with methotrexate, is indicated to reduce signs and symptoms in adult patients with moderately-to-severely active rheumatoid arthritis who have had an inadequate response to one or more of the TNF antagonist therapies. Epratuzumab acts as an immunomodulatory agent, while rituximab is an acutely cytotoxic therapeutic antibody. Unlike rituximab, no complement-dependent cytotoxicity (CDC) was detected, and ADCC was modest but significant with epratuzumab. Combining rituximab and epratuzumab did not decrease rituximab's ability to induce apoptosis, CDC, and ADCC, and may in fact be more effective than rituximab alone in inhibiting cell proliferation.
—A. Techman
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