Abstract: Bispecific antibody research and development has received industry attention in recent years. These antibodies can bind to two antigens at the same time, thus being able to explore therapeutic opportunities that monospecific antibodies cannot reach.

Cancer immunotherapy has made significant progress in multiple directions, such as immune checkpoint inhibitors and CAR-T cell therapy. Nobel Prize winner Dr. James P Allison’s research on CTLA-4 eventually led to the FDA-approved immune checkpoint inhibitor, ipilimumab (Yervoy), and Dr. Tasuku Honjo’s discovery of PD-1 brought anti-PD-1 drugs such as pembrolizumab, which, together with other immune checkpoint inhibitors, have a major impact on cancer treatment.
CAR-T cell therapy is another major research direction of cancer immunotherapy. This therapy works by engineering T cells to turn them into cellular weapons that attack tumors.
Although immune checkpoint inhibitors and CAR-T cell therapies based on monospecific antibody are still progressing and improving, bispecific antibody (BsAb) as a cancer immunotherapy may provide significant advantages.
· Monospecific Antibody vs. Bispecific Antibody
Monospecific antibodies are antibodies whose specificity to antigens is singular in any of several ways: antibodies that all have affinity for the same antigen; antibodies that are specific to one antigen or one epitope; or antibodies specific to one type of cell or tissue. Monoclonal antibodies are monospecific, but monospecific antibodies may also be produced by other methods than producing them from a common germ cell.
BsAb is an artificially engineered antibody that can simultaneously bind to two specific epitopes or target proteins. With the ability to simultaneously bind to two different epitopes, it can perform some special biological functions.
· Advantages of Bispecific Antibody
BsAb can bind to two targets at the same time, block two signaling pathways, exert unique or overlapping functions, and effectively prevent drug resistance. BsAb also has stronger specificity and targeting, as well as reduced off-target toxicity.
In addition, BsAb can also effectively reduce the cost of treatment. Compared with monospecific antibody, BsAb has stronger tissue penetration, tumor-killing efficiency and clinical indications, and thus the dose can be reduced to 1/2000 of the original, leading to the significant reduction of the medication cost.
· The Development of Bispecific Antibody
BsAb mediates the killing of tumors by immune cells. Two antigen binding arms, one binds to the target antigen, and the other binds to the labeled antigen on the effector cell. The latter activates effector cells to target and kill tumor cells. For example, the three BsAbs currently approved for marketing all have this feature:
(1) Catumaxomab, approved by the European Commission in 2009, is used to treat malignant ascites caused by EpCAM-positive tumors;
(2) Blinatumomab is approved by the FDA in 2014 for the treatment of acute lymphoblastic leukemia;
(3) Emicizumab, approved by the FDA in 2017, is used to treat hemophilia A.
In addition, the research and development of BsAb also has many new breakthroughs in 2020. For example, the newly developed CD28 BsAb-TSAxCD28, which can bind tumor antigen on one side and T cell co-stimulatory receptor on the other side, which can provide T cell the second signal, co-stimulation. Studies have found that this CD28 BsAb has little activity when used alone, but when it is combined with CD3 BsAb (TSAxCD3), it significantly promotes T cell activation in heterogeneous and homologous tumor models, and exerts strong and safe anti-tumor activity without toxicity to mice or primates.
According to statistics, nearly 40 companies and organizations at home and abroad have deployed research on bispecific antibody design and manufacture, with popular research targets of CTLA4, PD-1, PD-L1, OX40, 4-1BB, CD40. The development of BsAb is undergoing rapid development and has strong research and development potential in the field of immunotherapy. However, most BsAbs are still in the stage of pre-clinical research, and there are still many challenges before the commercialization. It is expected that more effective antibody therapeutics can be obtained in the near future to treat a variety of cancers and autoimmune indications.