A BiTE (Bispecific T Cell Engager) antibody is a bi-specific antibody (bsAb) which directs T-cells to attack cancer cells, by simultaneously binding the two cells. Upon binding, a physical link is created between the two cells, which in turn triggers the T cell to attack the target cell. Every BiTE antibody has two binding arms, the first binds the CD3 receptor present on T-cells and the second binds a specific element on a cancer cell. The T-cell binding arm provides the activity while the cancer binding arm provides the specificity. By changing the cancer binding arm, the BiTE antibody can be adapted not only from one type of cancer to another, but also from one target to another in the same type of cancer. Therefore, BiTE represents a universal and modular platform for producing bsAbs for an unlimited number of targets.
As previously stated, bi-specific antibodies are aimed at recruiting immune cells against cancer. Therefore, one of the first decisions to be made concerns the type of immune cells to be recruited. The first attempts to develop bi-specific antibodies, mainly included recruiting T-cells, which are considered the most potent cells of the immune system. T cells play a critical role in the body’s efforts to eliminate malfunctioning cells such as cancer or virally infected cells, making them even more obvious candidates.
CD70 is a receptor expressed on many types of blood cancers as well as the majority of renal cancer cases. The expression profile of this target is highly restricted to cancer cells, which, combined with its ability to internalize antibodies, makes it a desirable target for ADCs. Seattle Genetics is evaluating a naked antibody as well as an ADC that target CD70, both candidates are based on the same antibody, which was licensed from CLB-Research and Development. The naked antibody, SGN-70, is evaluated for certain blood cancers and is expected to enter phase I during 2008. Another possible use for SGN-70 is for autoimmune diseases, as it is expressed on white blood cells that are involved in the disease, but not on “resting” cells.
SGN-75 is an ADC based on SGN-70, which is currently evaluated pre-clinically for Renal cell carcinoma. This disease, although not as common as prostate and lung cancers, represents a large market opportunity with over 43,000 new cases and almost 13,000 deaths expected in 2007 in the US alone. Although surgical resection of the kidney has high chances to prevent the disease from spreading, nearly one third of patients are diagnosed at advanced stage, where the cancer has spread to additional organs. In addition, more than 30% of patients who undergo resection will eventually develop metastatic disease, for which very few therapeutic options exist. SGN-75 is expected to enter the clinic only in 2009.
SAR3419, which entered clinical trials just recently, is an ADC comprised of an antibody that targets CD19 and the toxic agent DM4. CD19 is broadly expressed through many types of B-lymphoid malignancies but not on normal B cells. To date, several anti CD19 antibodies were evaluated pre-clinically as well as in clinical trials but did not show a great deal of clinical effect. In addition, CD19 was shown to internalize after an antibody binds it, which makes it a suitable target for Antibody-drug conjugates.
SAR3419 is being developed by Sanofi-Aventis for the treatment B-cell hematological malignancies, including non-Hodgkin’s lymphoma [NHL] and acute lymphoblastic leukemia [ALL]. The huge potential in this market can be demonstrated by the success of Genentech’s Rituxan®, which had worldwide sales of just under 4$ billion in 2006. Since Rituxan’s target (CD20) is different than SAR3419′s, these agents are not necessarily competitors, but even may have a synergistic effect. Even if SAR3419 is found to be clinically active, it might face tough competition from Micromet’s (MITI) promising anti CD19 bispecific antibody, MT103, which has already shown promising results among NHL patients.
Author is long IMGN