The concept of using monoclonal antibodies (mAbs) for therapeutic purposes was devised a long time ago, mainly taking advantage of the high specificity of antigen-antibody interactions for drug delivery by means of targeted cytotoxicity. Indeed, Orthoclone OKT3, the first therapeutic monoclonal antibody for the prevention of kidney transplant rejection, entered the market as early as 1986. Such concepts of utilizing the high specificity of monoclonal antibodies gradually evolved and, recently, resulted in the research and development of bispecific antibodies (bsAbs). The bsAbs, as their names imply, combine specificities of two different antibodies and are able to simultaneously address different antigens or epitopes. With the first approval of bsAbs by the FDA in 2009, there has been a surge in the R&D of bsAbs and several breakthroughs in 2015. Here, we will briefly introduce the concept of bsAbs, the breakthroughs, and the perspectives for future development.
The first successful attempt of making recombinant bsAbs was achieved by Sherie Morrison et al. in 1997, from which they fused flexible linker peptides to the C termini of the heavy chains of IgG of different binding specificities. Currently, whilst more than ten different approaches in conjugating the antigen-specific Fab fragments from different mAbs have been developed and patented, the core concept of physical/chemical conjugation remains less changed. In brief, by simultaneously possessing the Fab fragments from two different antibodies, the bsAbs are able to mediate the interaction of different types of cells (such as the recruitment of T cells onto tumor cells presenting specific antigens), as well as concurrently interfere with more than one type of membrane-tethered ligands (such as Receptor Tyrosine Kinases, RTKs) for therapeutic purposes.
As noted, one of the main therapeutic functions of bsAbs is to mediate physical interactions between tumor cells and immune (killer) cells. Catumaxomab (Removab®) from Trion Pharma is the first bsAb that has received market approval. The anti-epithelial cell adhesion molecule (EpCAM)/anti-CD3) bsAb recruits T effector cells to the surface of tumor cells of ovarian carcinoma which present EpCAM surface antigens. It also has the ability to activate monocytes, macrophages, dendritic cells, as well as natural killer cells by the binding of Fcγ-receptor to further enhance the specific elimination of EpCAM-presenting tumour cells. On the other hand, bsAbs are also able to interfere with receptor signalling ligands and therefore inactivate the transduction of specific growth signals through such ligands. For example, whilst several mAbs such as cetuximab (Erbitux™) and trastuzumab (Herceptin™) have been developed to perform targeted interference of HER1 and HER2 signalling pathways to inhibit the growth of tumor cells by inactivating the corresponding RTK ligands, the tumor cells may be able to escape growth inhibition by switching from one pathway to another and hence complicate the treatment. Therefore, it will be desired for one single antibody to possess the ability of interfering more than one signalling pathway simultaneously. The bsAb MM111 from Merrimack provides a good case in this point, by binding to and therefore blocking HER2 and HER3 receptors simultaneously using two antagonistic scFv fragments. The MM111 is currently in phase 2 trial stage for patients with advanced gastric and/or esophageal cancer.
The year 2015 is deemed special in terms of both the new numbers of bsAbs R&D projects as well as the new therapeutic approaches that have been developed for bsABs. For numbers, there are more than 10 new bsAb projects reported to enter at least phase I clinical trials in this year alone. In addition, nearly all major pharmaceutical companies, including, but not limited to, Trion, Amgen, Bayer, several subsidiaries from Roche, Abbvie, Abbott, Boehinger Ingelheim, and Eli Lilly, possess at least one bsAb project under their development, which reflects the intense competition as well as the forecasted revenue scale within the field. For therapeutic approaches, two new techniques have been reported that have entered phase I trials. One new technique uses bsAbs for targeted/pre-targeted drug delivery, such as delivering nano-scale radioactive particles onto the surface of tumor cells that presents specific antigens (in this case, the CEA-expressing cells) for precision cytotoxicity effects (TF2, immunomedics, phase I trial). The other new technique uses the characteristic bi-specificity of bsAbs to bring together two different coagulation factors (in this case factor IXa and factor X) to compensate a missing coagulation factor in patients (in this case, factor VIIIa that is missing in patients with haemophilia A). Therefore, it ensures that proper coagulation takes place and eliminates the immune responses and accompanied complications when using a supplementation of foreign proteins (which is sometimes found in as many as 30% of the patients), along with a much longer serum half-life (RG6013, Chugai, subsidiary of Roche, phase II trial).
As a concluding remark, the rapid surge of bsAb technology would undoubtedly endorse it as one of the most important events in 2015. Current clinical development of bsAbs mainly focus on the areas of cancer therapy and treatment of inflammatory diseases, with certain attempts to explore emerging, novel strategies. Still, there are obstacles that need to be overcome, such as addressing the appropriate candidate pairs during pathophysiological processes and, in doing so, increasing the therapeutic efficacy, as well as the potential of using bsAbs to not only neutralize but also modulate the activities of RTKs, therefore inhibiting the growth and metastasis of tumor cells. With more than 25 bsAbs (as of Nov. 2015) currently in phase I/II trials as well as two mature products in the market, it is with high likeness that such intense interest within the pharmaceutical industry will continue, which indisputably encourages the discoveries of further therapeutic potentials of these molecules.
References:
http://www.sciencedirect.com/science/article/pii/S135964461500077X
http://www.omicsonline.org/open-access/advances-in-bispecific-antibodies-engineering-novel-concepts-for-immunotherapies-2155-9864.1000243.php?aid=39103
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