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The History Development and Future Challenges of Bispecific Antibodies

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Bispecific antibodies (bsAbs) combine specificities of two antibodies and simultaneously address different antigens or epitopes. BsAbs with “two-target” functionality can interfere with multiple surface receptors or ligands associated.

1. Development history of three generations of bispecific antibodies

The advent of hybridoma technology in the 1970s reminded people whether the same antibody could be used to target two different targets, namely Bispecific Antibody (bsAb).

Most of the earliest bispecific antibodies are developed by chemical coupling methods. Although the method is much simple, the resulting products are complex and heterogeneous and difficult to use in industrial production. Until the 1980s, scFv-based recombinant bispecific antibodies appeared and gradually became the focus of research with the popularization of recombinant DNA technology.

Amgen/Micromet’s BiTE (Bispecific T cell Engager) is the archetype of the first generation of bispecific antibodies, characterized by a simple structure and two scFvs connection. But it also has obvious disadvantages such as short half-life and low expression. A pump for continuous administration is clinically necessary due to the short half-life with only two hours. Fortunately, the clinical dose of BiTE is less than one tenth of the amount of common antibodies, which virtually solves the problem of mass production. The first recombinant bispecific antibody Blinatumomab (CD3-CD19 BiTE) was finally approved by the FDA in December 2014 for marketing in the United States after various difficulties.

Genentech’s Paul Carter team invented the knob-into-holes bispecific antibody in the 1990s as the second-generation bispecific antibodies, with a structure and stability similar to that of natural IgG. Roche/Chugai’s Emicizumab (factor IX and factor X bsAb) using the knob-into-hole technology was approved by the FDA in November 2017 as the second bispecific antibody marketed in the United States.

There are currently about 120 bispecific antibodies in different clinical development stages around the world, including third generation bispecific antibodies. If taking T cell-targeted therapy as an example, Roche’s CEA-TCB (CD3-CEA bispecific antibody) is a typical representative of third-generation bispecific antibodies, which utilizes the knob-into-hole technology of second-generation bispecific antibodies, and Roche engineers invented CrossMab technology shortly after the acquisition of Genentech and successfully solved the bottleneck of knob-into-hole in common light chain. In addition, CEA-TCB achieves bivalent binding of tumor antigens and monovalent binding of CD3, enabling the bispecific antibody to produce avidity effects when combined with tumor antigens while reducing CD3 antibody binding toxicity. At present, CEA-TCB has completed Phase 1 clinical trials and achieved satisfactory results.

2. The challenges for bispecific antibodies development

Since 1986, the first antibody drug, Muromonab (OKT3), has been approved for marketing, the FDA has approved the listing of 73 antibody drugs by the end of 2017, and there are only two bispecific antibodies listed above. The development of bispecific antibodies lags significantly behind therapeutic monoclonal antibodies, which mainly results from the following reasons: Early bispecific antibody has a difficult expression and poor stability, as well as a complicated production process; The early development cost of bispecific antibodies is significantly higher than that of monoclonal antibodies; Bispecific antibody project involves target biology, structural biology, antibody engineering, and screening strategies.

In 2017, the market capacity of antibody drugs broke through the $100 billion mark for the first time. Antibody drugs have become one of the fastest growing areas in the pharmaceutical industry. Bispecific antibodies at the forefront of antibody drug development have long been the development direction of major pharmaceutical companies around the world. It is believed that bispecific antibody will have a considerable market share in the field of solid tumor treatment. Compared with CAR-T, bispecific antibody drugs have the advantages of dose controllable and flexible drug administration period. At the same time, bispecific antibody drugs can also target other immune cells, such as NK, Macrophage, etc.

Author Bio

Creative Biolabs was established in 2004 by scientists who are dedicated to conquering of cancer. Over the past 10 years, Creative Biolabs has grown into a recognized world leader in antibody (rAb) discovery, engineering, production, and analysis. Standing on the shoulder of a giant, the bispecific antibody (BsAb) team has a collective of experienced scientists committed to providing high-quality services to customers all over the world. Now, with the cutting-edge platforms and methods (quadroma development, chemical conjugation, and genetic engineering), a comprehensive list of bispecific antibody products is available to customers in academia and industry fields.


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