Bispecific antibodies for cancer therapy: the light at the end of the tunnel?

Abstract

With 23 approvals in the US and other countries and four approvals outside US, antibodies are now widely recognized as therapeutic molecules. The therapeutic and commercial successes met by rituximab, trastuzumab, cetuximab and other mAbs have inspired antibody engineers to improve the efficacy of these molecules. Consequently, a new wave of antibodies with engineered Fc leading to much higher effector functions such as antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity is being evaluated in the clinic, and several approvals are expected soon. In addition, research on a different class of antibody therapeutics, bispecific antibodies, has recently led to outstanding clinical results, and the first approval of the bispecific antibody catumaxomab, a T cell retargeting agent that was approved in the European Union in April 2009. This review describes the most recent advances and clinical study results in the field of bispecific antibodies, a new class of molecules that might outshine conventional mAbs as cancer immunotherapeutics in a near future.

Figure 1

A conventional antibody is depicted in green (light for light chain, dark for heavy chain, blue triangle indicate the glycosylation site) and the derived fragments (shaded areas represent the binding sites). The orange color symbolizes a different specificity. The blue and red shapes represent the DDD2 and AD2 peptides of the dock and lock (DNL) method. All flexible linkers are in grey. bsAb, bispecific antibody; bsFab, bispecific Fab fragment; scFv, single chain Fv fragment; dAb, domain antibody.