Bispecific Antibody: hidden worry behind

Posted by beauty33 on January 17th, 2019

Recently, the progress in the field of cancer has been intensively released. Tumor immunotherapy remains the most eye-catching. Among them, a number of companies also announced the latest clinical progress. Roche also recently released the company's unique bispecific antibody phase I clinical study data. Bispecific antibody CEA-TCB monotherapy based on crossmab or combined with tecentriq has excellent anti-tumor activity. This solid tumor colorectal cancer treatment of antibody drugs has attracted much attention whose triple body is worthy of reference. Bispecific antibody research and development enthusiasm, domestic companies, regardless of size are interested in the layout of bispecific antibodies.

Bispecific antibody: technical threshold is relatively low

Bispecific antibodies are different from monoclonal antibodies and can bind to two antigenic epitopes at the same time. In general, triple body can be divided into two types, T cell recruitment type, including tumor cell target-T cell recruitment site. The T cell recruitment site refers to CD3 (T cell) and CD16 target, and the target is usually located in tumor cell. In addition, triple body may bind to double target sites (such as VEGF-PDGF,VEGF-Ang2) and inhibit two signaling pathways, thus reducing the possibility of drug resistance.

The molecular design of bispecific antibody is a very important key point. At present, there are several relatively mature technology platforms of bispecific antibody:

BiTE platform of Amgen Company

At present, the Blincyto based on the platform has been approved for listing. The technique of non-IgG subtype bispecific T cell connector (Bispeific T cell Engager, BiTE) is relatively mature. The double antibody based on this technique can bind to T cell and tumor cell by CD3 and CD19, Hybrid hybridoma T cell by CD3 to kill the tumor cells.

Roche's crossmab technique

On the basis of Knobs-into-holes (KiH) scheme, crossmab technology of Roche Company solves the problem of light chain wrong connection further. In brief, Knobs-into-holes heterodimer connection is designed in Fc region. At the same time, the CH1 and CL of the Fab region are interchanged to reduce the light chain mismatch, as shown in the figure below.

Other anti-technology platforms such as DART, tandAB, Bi-nanobody and so on (see below) are similar in principle to the above two technologies. We will not repeat them here. We need to refer to the relevant information, and the research is already quite clear. As can be seen, antibody technical threshold is not high. And the antibody design is a key, which is a small and medium-sized bispecific antibody layout of a factor.

Specific antibodies: industrialization challenges, the market performance of listed products does not give strength!

At present, the market performance of the two drugs does not help. Removab was successfully approved by the European Union for application in malignant ascites, whose annual sales peak of only .54 million; In 2012, FDA approved the sale of Amgen's Blincyto which is used for acute lymphoblastic leukemia (ALL) who brought Amgen million in revenue, with a peak expected to reach 0m. However, with high prices and short half-lives, Amgen's .1 billion bite has underperformed expectations.

In fact, the progress of the clinical phase is very slow, and there are many examples of terminating development. Roche's vanucizumab, Alberto ABT-122 has stopped development and Amgen's AMG110 is in trouble because of serious adverse events.