The Tumor Therapeutic Mechanism of Bispecific Antibodies

Posted by beauty33 on September 17th, 2021

The incidence and case fatality rate of cancer is increasing with the deterioration of the global environment and the changes in people\'s living habits, which urges the development of anti-tumor drugs and related studies. Bispecific antibodies (BsAbs) are one of the novel concepts that are regarded as the second-generation antibodies for tumor therapies with broad prospects.

Bispecific antibodies are featured with a structure of binding to two different epitopes on the same or different antigens, which make them more efficient in the process of killing tumor cells. BsAbs can facilitate the recruitment and activation of immune cells and the blocking of tumor signaling pathways, as well as bind to Fc receptors and drugs.

T cells present in the blood circulation of the whole body are one of the most important and powerful immune cells to attack tumor cells. However, it\'s difficult for T cells to focus on a specific cancerous part of the body. On the one hand, tumor cells will inhibit the activation of T cells; and on the other hand, few Fc receptors are available on the surface of T cells for ordinary antibodies to bind to the antigens on the surface of tumor cells. Bispecific antibodies are capable of tightly and simultaneously binding to antigens on both tumor cells and T cells, and consequently, recruiting more T cells to the target tissues and eliminate tumor cells.

Though BsAbs can enhance the recruitment and activation of T cells, factors like deficiency or modulation of antigens, abnormal costimulatory signals, and expression of immunosuppressive molecules can help tumor cells evade immune attack. In the case that tumor cells overexpress PD-L1 or PD-L2 to bind to the highly expressed PD-1 on T cells and inhibit the activation and anti-tumor effects of T cells, bispecific antibodies can prevent the binding of PD-L1 and PD-1 and block the signal pathway of inhibition. BsAbs can also block signaling pathways that are abnormally activated in the tumor to restrain the oncogene expression and the tumor cell proliferation, invasion, and metastasis. In some cases, bispecific antibodies are used to bind to different antigens on the same tumor cells to increase the affinity, meanwhile blocking two pathways to enhance the anti-tumor effects.

Besides, some bispecific molecules with Fc segments can bind to the Fc receptors on the surface of B cells, macrophages, neutrophils, etc. that are able to kill tumor cells.

BsAbs induce anti-tumor effects not only through the body\'s immune system but also by carrying drugs. These drug molecules are known as immunotoxins, including chemotherapeutic drugs, enzymes, cytokines, and some other biological toxins. Immunotoxins that can inhibit protein synthesis are usually collected from plants, bacteria, and fungi. Common plant toxins include ricin, gelonin, and pokeweed antiviral protein, and bacterial toxins include Pseudomonas exotoxin (PE) and diphtheria toxin (DT).

Bispecific immunotoxins are a class of hybrid molecules consisting of the targeting bispecific antibody with two different targeting ligands and the toxic moieties, in which bispecific antibody is responsible for the specificity of the immunotoxin. The targeting ligands on the BsAbs will bind to molecular markers that are highly overexpressed in tumor cells but absent in normal cells, so that toxins can be delivered to the cancerous tissue by the specific antibodies and eliminate tumor cells.

Bispecific antibodies can also be used for other BsAb-drug conjugates development. Some drugs are directly connected to the bispecific antibodies for tumor therapy, while some use bispecific antibodies as carriers to support the redirection of molecular effectors, for instance, injection of peptides containing immunotoxins into the body after BsAbs bind to tumor cells.

Scientists are endeavoring to modify the structure, relative molecular mass, and chemical valency of bispecific antibodies to improve drug efficiency and stability. Therefore, bispecific antibodies have a greater potential than monospecific antibodies in anti-tumor activities.