Opportunities and Obstacles of Bispecific Antibody in Cancer Immunotherapy
With more than three dozen companies developing bispecific antibodies, the next frontier of cancer therapy may well involve these genetically engineered, recombinant antibodies.
With the rapid development of antibody drug technology, a new type of antibody drug, bispecific antibody (BsAb), has ushered in a wave of antibody research and development. Up to now, more than 30 different technology platforms in the world can be used to design and develop BsAb. There are more than 60 kinds of designed molecular structures for BsAb, and 3 have been approved for marketing. The Marketwatch report shows that by 2023, the bispecific antibody market will reach $ 4.4 billion. BsAb has been the “gold mining” that pharmaceutical companies are striving for.
Bispecific antibody is an artificial antibody containing two specific antigen binding sites. It is a product of genetic engineering, allowing one antibody molecule to bind multiple different antigens at a time. Through interacting with target cells and functional cells, it is able to enhance the tumor cells-killing efficiency. Therefore, it has broad application in tumor immunotherapy as following:
Cytotoxic T lymphocytes (CTL) play a key role in the immune response to cancer treatment. Tumor cells can create an immunosuppressive environment through related cytokines secreted by themselves or the interaction with the tumor microenvironment, which makes CTL cells in the tumor microenvironment dysfunctional. One strategy for regulating immune cells is to use BsAbs to activate T cells and to approach tumor cells, in which subsequent T cell proliferation and activation lead to tumor cell lysis. In addition to T cells, other immune cells such as macrophages, monocytes, granulocytes, and natural killer cells also play a role in killing tumor cells.
Signaling pathway refers to a series of enzymatic reaction pathways that transmit outside molecular signals to the cell through the membrane. These extracellular molecular signals (called ligands) include hormones, growth factors, neurotransmitters, and other small molecule compounds. When the ligand specifically binds to the cell membrane or the receptor in the cell, the signal will be transmitted in the cell, which takes part in the biological process of cell growth, proliferation, apoptosis, angiogenesis, autophagy, etc. The occurrence, growth and metastasis of tumors will involve multiple signaling pathways, and bispecific antibodies can simultaneously target signaling proteins of two signaling pathways and thus block the path.
Some cytokines are considered to be the key factors causing inflammation and autoimmune diseases. Therefore, blocking these factors has therapeutic potential. For example, IL17 or TNFα BsAb has a notable therapeutic effect on psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, juvenile arthritis, etc.
BsAbs can specifically recognize protein. Therefore, anti-tumor drugs or immunomodulatory drugs can be bound together through a certain coupling technology, thereby increasing the drug concentration at the tumor site.
BsAb has shown significant advantages in clinical application such as low cost and good therapeutic effect. Compared with traditional antibodies, it has strong competitiveness in indicators such as tissue penetration rate, tumor cell killing efficiency, off-target rate and clinical indications. Especially in terms of dosage, since its therapeutic effect can reach 100-1000 times that of ordinary antibodies, the minimum dosage can be reduced to 1/2000 of the original, which significantly reduces the cost of drug treatment and increases the market space.
As a forward-looking technology, it still faces many challenges in industrialization, such as mismatches and purification, the instability of downstream processes, the stability and the expression of two antibodies, etc. With the advancement of technology, it’s believed that in the future, more and better strategies can be used to optimize various BsAbs, so that they could be more powerful with lower side effects, and bring relief to cancer patients.
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