Bispecific monoclonal antibody
A bispecific antibody (abbreviation:. BsMAb ENGL bispecific monoclonal antibody ), also referred to as a hybrid antibody is an immunoconjugate that are composed of components of two different monoclonal antibodies. Bispecific antibodies are a potential therapeutic approach in cancer immunotherapy and the subject of clinical trials.
Structure and mechanism of action
A bispecific antibody of the first generation - also known as Quad Roma - consists of one heavy and one light chain of two different monoclonal antibodies. The two arms of the antibody are directed against each other antigens. The Fc portion (the " toe" of the antibody ) is formed jointly by the two heavy chains of the antibody, and is the third binding site of the bispecific antibody dar. By this construction it is possible for example to the paratope of an anti- tumor antigen antibody and the paratope another directed against a lymphocyte antigen antibody, to be placed on a respective arm of the bispecific antibody. In this example, it is possible that the antibody binds to a tumor cell with the corresponding tumor antigen and a lymphocyte. Can then bind or antigen presenting cells such as B cells, or macrophages, and form a three - cell complex on the Fc portion of the bispecific antibody. Through this three- cell complex arises as a rule, an improved activation of the body's immune cells to the tumor cells.
From this structure, the bispecific antibodies are different from the newer generation. They may be composed of two scFv fragments (fragments of monoclonal antibodies). For example, as an oriented to the antigen CD3 antibodies with the second paratope, with lower affinity, T cells and to bind and activate the tumor cell with the CD3 antigen, the T cell only in the case of the binding. One speaks in this case of bispecific antibodies for the recruitment of effector cells. This concept is " BiTE " (English: bispecific T -cell engager ) called.
Advantages over monoclonal antibodies
If a paratope against T- cells directed, then these cells can be activated. Normal monoclonal antibodies, this is not possible, because T- cells do not have Fc receptors. Bispecific antibodies have in addition to a higher cytotoxic potential. They also bind to antigens that are expressed relatively weak. The necessary dose per patient is in the range of 0.01 mg · m -2 · d -1, and is several orders of magnitude lower than for monoclonal antibodies.
Production
Bispecific antibodies do not occur in normal living beings, which is why they must be produced artificially. The first concepts for bispecific antibodies are derived from the mid-1980s. Subsequently, the first bispecific antibody were prepared in an extremely complicated manner, which greatly limited the development of this concept for many years. One of the methods is the fusion of two Hybdridome with the hybridoma technique ( quadroma technique). Another variant, the chemical coupling of two antibodies or antibody fragments.
With the help of genetic engineering, the synthesis is also of greater amounts of bispecific antibodies for therapeutic applications become possible. In particular the recombinant production of bispecific antibodies from antibody fragments is the presently established production methods. A BiTE antibodies can be made using four genes coding for a single protein of approximately 55 kDa molar mass recombinant.
Development Status
The clinical results with the first generation of bispecific antibodies could not fulfill initial expectations. This was due to the low efficacy - among other things because of a very short plasma half -life of the hybrid antibodies - and their immunogenicity. The quadroma antibodies showed a therapeutic effect in early clinical trials in a subset of patients. The immunogenicity - due to the murine components of the bispecific antibody - led, however, to a humane anti-mouse antibody response, with the release of HABA ( human anti - bispecific antibodies ). This ruled out a longer treatment with bispecific antibodies. In addition, the Fc portion of the antibody quadroma caused a cross-linking with various Fc receptors, thereby making it conditional came to a greatly increased release of cytokines and severe side effects.
Better results - with fewer side effects - could be achieved in chemically linked bispecific Fab fragments. The clinical studies went quite promising. The time consuming and therefore very costly manufacturing process ultimately led to the fact that no extensive clinical trials (Phase III) were carried out. The interest in the concept of bispecific antibodies was in the aftermath of noticeably. However, in 2009 the first production Hybidom technique bispecific antibodies for human use has been authorized, and indeed Catumaxomab for the treatment of malignant ascites.
The development of the BiTE concept, interest in bispecific antibodies in recent years has increased significantly again. Currently ( 2010) are two BiTE antibody in clinical trials. Blinatumomab, an antibody directed against CD3 and CD19 is tested in patients in late stages of non-Hodgkin 's lymphoma and in patients with acute lymphoblastic leukemia of B- cell lineage (B- ALL). The second BiTE antibody in clinical trials is MT110. It is against the antigens CD3 and EpCAM (English: epithelial cell adhesion molecule ) and directed to be effective against the lung and gastrointestinal cancers.