How Bispecific Antibody Treat Cancer?

Cancer immunotherapy has made significant progress in several directions,

most notably immune checkpoint inhibitors and CAR-T cell therapy. However,
in recent years, bispecific antibody (bsAb) has also attracted increasing
attention, which is known for its unique ability to bind to two or more antigens
simultaneously, thus exploring therapeutic opportunities that are not
accessible to monoclonal antibodies (mAbs).

What’s the difference between bsAbs and mAbs? Traditional antibodies are
immunoglobulins that bind specifically to antigens, composed of four
polypeptide chains, called the heavy chain (H chain) and the light chain (L
chain). The monoclonal antibody has identical amino acid compositions of two
H chains and two L chains, whereas bispecific antibody is developed by
coexpressing two different H chains and two different L chains.

Bispecific antibodies can bind two targeting sites, a tumor antigen on the
surface of tumor cells and an antigen on the surface of immune cells, such as
T cells, NK cells, etc. The recruitment of T cells plays a significant role. As is
known, T cells are featured by a potent anti-tumor effect and are widely
present in the systemic blood circulation. When the body encounters
carcinogenesis at a certain site, it’s tough for T cells to be specifically
assembled resulting from the inhibition from tumor cells on T cell activation
and the few numbers of Fc receptors on the surface of T cells. BsAbs tightly
bind both antigens on the surface of T cells and tumor , allowing the rapid
recruitment of T cells to tumor tissue and the effective elimination. In
addition, they can also recruit NK cells by targeting CD16, which are anti-
CD16 bispecific antibodies, or kill tumor tissue by activating immune cells
such as monocytes, macrophages, and dendritic cells.

Absence or modulation of antigens, abnormal costimulatory signals, and

expression of immunosuppressive molecules can all allow tumor cells to
evade killing by the immune system. When some tissues become cancerous,
T cells will be stimulated to highly express PD-1, but tumor cells will also over-
express PD-L1 or PD-L2 to inhibit the activation of T cells, resulting in the
failure of T cells to play an anti-tumor effect. BsAbs can avoid the binding of
PD-L1 and PD-L2 to its receptor PD-1 on the surface of tumor cells, thereby
blocking the signaling pathway of tumor cells that inhibits T cell activation.
Tumor antigens targeted by BsAbs can also block certain aberrantly activated
signaling pathways in tumors, thereby inhibiting oncogene expression and
tumor cell proliferation, invasion and metastasis. In addition, BsAbs can also
bind to two different antigens of the same tumor cell to improve the affinity of
the antibody and the anti-tumor therapeutic efficacy by simultaneously
blocking two signaling pathways.
Some bispecific antibodies with drug sites can not only mediate the body's
immune system, but also exert effects by binding and carrying drug molecules
that includes chemoradiotherapy drugs, enzymes, cytokines or other
biological toxins, collectively called immunotoxins. If drug molecules can be
directly attached to BsAbs for treatment, or if BsAbs are attached to cancer
cells and then peptides containing immunotoxins are injected into the body,
these drugs can specifically bind to the tumor site to work, thereby reducing
the time spent in normal tissue cells to reduce their side effects.

Despite the increased complexity of the dual-targeting concept compared to

monoclonal antibodies, which pose additional challenges at different stages of
discovery and development, bispecific antibodies still bring thrilling
opportunities for the design and development of novel drugs. The contining
development of bispecific antibodies will have a lasting impact on the
treatment of diseases such as cancer.