Bispecific antibodies usually do not occur in nature but are constructed by recombinant DNA or cell-fusion technologies. Most are designed to recruit cytotoxic effector cells of the immune system effectively against pathogenic target cells. This complex task explains why, after more than 15 years of extensive research, many different formats of bispecific antibodies have been developed but only a few have advanced to clinical trials. Here, we give a brief history of bispecific antibodies and review very recent progress towards formats that are beginning to solve the major issues of earlier formats. These improved bispecific antibodies are expected to show clinical efficacy in patients with cancer and other diseases, in a way that monoclonal antibodies have shown in recent years.
Until now, the hybridoma technology invented by Ko¨hler and Milstein to generate monoclonal antibodies has nourished the hope for therapeutic breakthroughs in diseases with high medical needs not served sufficiently by conventional therapies. The hallmark of monoclonal antibodies is their specific binding to a particular antigen, which enables them to find their target precisely in vivo while ignoring antigen-negative sites. Bound to a target, therapeutic antibodies can deliver a toxic payload, act as agonists or antagonists of receptors, or as neutralizers of ligands. Antibodies might even bind many targets that are not recognizable by small-molecule drugs.
Monoclonal antibodies of the IgG type contain two identical antigen-binding arms and a constant fragment, (Fc)g. The Fc part enables the antibody to function as an adaptor protein, linking antibody-bound cells to immune cells bearing Fcg receptors. Because there are different Fcg receptors and other proteins binding to Fc portions of antibodies, such as complement, monoclonal antibodies can mediate multiple effects ranging from the recruitment of immune effector functions to mere increase of serum half-life by retention of IgG on non-signaling Fc receptors. It was observed recently that human antibodies of the IgG4 type can exchange their halves with each other, potentially creating antibodies with dual specificity [2]. However, the biological relevance of this observation remains obscure.
For treatment of malignant diseases, monoclonal antibodies typically need to be modified to enhance efficacy and to use them in humans. One important modification is the reduction of immunogenicity of rodent monoclonal antibodies by chimerization, humanization throughgrafting of complementarity determining regions (CDRs) or using various technologies for recovery of fully human antibodies, such as phage display libraries or transgenic mice expressing human antibody repertoires. Reduced immunogenicity of antibodies can prolong their half life and, in the absence of a neutralizing immune response, enable prolonged treatment. Another important modifi-cation is arming the humanized antibody with additional cytotoxic mechanisms, be it radioisotopes, bacterial toxins,
inflammatory cytokines, chemotherapeutics or prodrugs. There is a growing number of approved cancer therapeutics that are efficacious either as chimerized antibody or humanized IgG1,or as conjugate with chemotherapeutics or a radioisotope. In spite of this progress, the efficacy of monoclonal antibodies for cancer treatment is still limited, leaving great potential for further improvements. One class of antibody derivatives with the promise of enhanced potency for cancer treatment are bispecific antibodies.
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