Post written by Maarten Janmaat & Janine Schuurman

The antibody product landscape is continuously changing : more potent formats including antibody-drug conjugates and bispecific antibodies are on the rise (1). Although the concept of bispecifics has been known for more than 30 years, many technical challenges have only been resolved in recent years, resulting in bispecifics in different flavors entering the clinic. Numerous platforms, each with their own specific functional characteristics and manufacturing requirements, have led to two approved bispecific antibody products, catumaxomab and blinatumomab, and >50 bispecific antibody products in clinical evaluations (Figure 1). Roughly, the landscape of bispecific antibody platforms can be divided over 3 major classes: fragments, symmetric and asymmetric antibodies. Products representative of all 3 classes have reached the stage of clinical evaluation (Figure 2).

Multi-targeting approaches, including bispecifics, are generally being recognized to address disease heterogeneity and therapy escape. We believe, however, that the real excitement in the field of bispecific antibodies comes from the ability to couple two (or more) specificities, thereby introducing novel functionalities that were not present in the parent molecules. This class is also termed “obligatory bispecifics” by Spiess et al (2) and Labrijn et al (3).

Well-known examples of obligatory bispecifics, and the most validated use, are CD3 bispecifics, which activate T cells solely when bound in close proximity to a target-expressing cell, resulting in specific and effective tumor-cell killing. The two clinical approved therapeutics, catumaxomab and blinatumomab, belong to this class.

Another example of an innovative bispecific application is emicizumab (Chugai), which crosslinks Factor IXa and Factor X and mimics the natural function of Factor VIIIa. This Factor VIII replacement therapy is currently in a Phase 3 clinical trial in hemophilia patients (NCT02622321).

Bispecifics can also be used to guide translocation to immune-privileged sites, such as the human brain.  Yu et al have described a molecule that binds with one arm to the transferrin receptor, which guides crossing over the endothelium (4). Upon accessing the brain, the molecule binds to its therapeutic target β-secretase (BACE1), resulting in reduction of brain amyloid-β.

Recently, Wec et al. presented a very elegant ’Trojan horse’ bispecific approach to target Ebola infections (5). By combining knowledge of the molecular mechanisms of filovirus infection and the availability of mAbs against relevant epitopes, a molecule was generated that binds to a conserved surface-exposed Ebola epitope with one domain, while the second binding domains attacks the receptor  binding site within the endosomal compartment upon internalization, thereby preventing viral entry.

Some other interesting uses of obligatory bispecifics include enhanced lysosomal delivery of antibody-drug conjugates by targeting lysosomal membrane protein CD63 in combination with a tumor-specific target (6), fixing HER2 receptors in a conformational state (7) and induction of tumor cell DR5 clustering by using simultaneously binding to fibroblasts (8).

Taken together, technical progresses in the past years has advanced the development of therapeutic bispecific into the clinic.  In particular, obligatory bispecifics offer exciting and innovative treatment opportunities by revealing completely new functionalities.

What ideas do you have?

References
1.            J. Schuurman, P. W. Parren, Curr Opin Immunol 40, vii (Jun, 2016).
2.            C. Spiess, Q. Zhai, P. J. Carter, Mol Immunol 67, 95 (Oct, 2015).
3.            A. Labrijn, P. W. Parren, Science in press,  (2016).
4.            Y. J. Yu et al., Sci Transl Med 3, 84ra44 (May 25, 2011).
5.            A. Z. Wec et al., Science,  (Sep 8, 2016).
6.            B. E. de Goeij et al., Mol Cancer Ther,  (Aug 24, 2016).
7.            C. Jost et al., Structure 21, 1979 (Nov 5, 2013).
8.            P. Brunker et al., Mol Cancer Ther 15, 946 (May, 2016).

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