The development of T cells which are genetically modified to express a chimeric antigen receptor (CAR) has opened the door for many new potential therapies for cancers and other disorders. Generally, CARs comprise an extracellular antigen recognition domain and an intracellular domain.
Some CARs utilize a non-human extracellular antigen recognition domain, which can introduce an unwanted immune response that can jeopardize the therapeutic benefits of CAR mediated tumor recognition and tumor lysis. For example, patients can react to mouse-derived antibodies and create antibodies that are specific to the foreign mouse-derived antibody. This response, termed the human anti-mouse antibody (HAMA) response, can generate symptoms similar to an allergic reaction that ranges from a mild rash to life-threatening complications. Therefore, CARs that comprise an antigen recognition domain derived from human or humanized antibodies may be beneficial because they would not stimulate such a hazardous immune response.
Bispecific T-cell engagers (BiTEs) are bispecific antibodies that bind to a T cell antigen (e.g. CD3) and a tumor antigen. BiTEs have been shown to induce directed lysis of target tumor cells and thus also provide great potential therapies for cancers and other disorders. However, systemic delivery of BiTEs can result in toxicity, and therefore more directed delivery of BiTEs to a specific tumor environment may be desirable.
Thus, there is an urgent need in the art for compositions and methods for treatment of cancer using human or humanized CARs and for the directed delivery of therapeutic bispecific antibodies. The present invention satisfies this unmet need.