Different formats of Bispecific Antibodies Redirect T Cells to Target Tumors

Posted by Candy Swift on March 12th, 2020

Therapeutic antibodies have become the main force for the treatment of various diseases, such as cancers, autoimmune diseases, inflammations. However, the single target of monoclonal antibodies fails to effectively destroy cancer cells due to multiple signal pathways involved in cancer. Compared to monoclonal antibodies, bispecific antibodies (bsAbs) are hailed as one of the most promising immunotherapy drugs owing to its unique ability to bind two different types of antigens simultaneously.

Cytotoxic T lymphocytes play an important role in the immune response against cancer cells. However, during the immune response, tumor-specific T cell responses are often limited by the immune escape mechanisms utilized by tumor cells. To solve this problem, different formats of bsAbs can be designed to redirect T cells to tumor cells, with the formation of temporary cytolytic synapses between T cells and tumor cells. Then, T cells are activated and proliferate to lyse tumor cells.

As a bsAb that can redirect T cells to target tumors, Triomab produced by mouse hybridoma cells usually has high yields and purity. It can not only bind antigens related to tumors and CD3 on t cells, but also can preferentially identify helper cells such as macrophages, dendritic cells, and NK cells through FC region. Catumaxomab is the first Triomab bsAb approved to treat patients with EpCAM-positive cancer who have failed standard therapies, produced by co-expressing mouse IgG2b and mouse IgG2a in a host cell. Compared to bi-specific T cell engager (BiTE), IgG-like bsAb has a longer serum half-life. After patients received 4 to 5 intraperitoneal injections, most patients showed an acceptable humoral immune response to Catatumxomab, which is beneficial for clinical results. This protection relies on the immunogenic response caused by the catumaxomab chimeric Fc region. Possible adverse reactions include transient fever, nausea, and vomiting, which may result from cytokine release-related symptoms.

The bispecific T cell engager is used to develop tandem single-chain bsAbs, for instance, Blinatumomab. It can be associated with both CD3 on T cells and CD19-expressing B cell malignancies, which is the first bsAb approved by FDA for the treatment of acute B lymphocytic leukemia cells. Blinatumomab is able to transport T cells to tumor cells and shows strong tumor-killing capabilities. The large collection of various proteases lay foundation for the formation of cytolytic synapses between T cells and target cells. At the same time, T cells begin to proliferate and release cytokines. Due to its small size, blinatumomab can be easily cleared by the kidneys.

DART is another technology that can redirect T cells. It uses small linker peptides to increase the stability of bsAbs and reduce immunogenicity. Unlike BiTE, the covalent connection between the two chains of dual-affinity re-targeting proteins (DARTs) limits the antigen binding site. Therefore, DARTs can form stable contacts between target and sensory cells. It has been demonstrated that CD19 and CD3 DART is more effective than BiTE molecules in redirecting and killing B-cell lymphomas due to the higher affinity of DART-type antibodies for CD3 and the low off-rate constant for CD19.

There is no doubt that bispecific antibody is the bridge between therapeutic drugs and tumors, which can block two different pathogens. It is expected that bispecific antibodies bring more positive effects.

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Candy Swift

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Candy Swift
Joined: December 11th, 2015
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