In 1986, Staerz and Bevan used bispecific antibody(bsAb
) for the first time to apply cytotoxic T lymphocytes (CTL) to cancer cell lysis experiments. In December 2014, the US Food and Drug Administration (FDA) approved the bispecific antibody immunotherapeutic drug Blinatumomab developed by Amgen for relapsed or refractory Philadelphia chromosome-negative ( Ph-) pre-B cell acute lymphoid. The structure of this constant region-containing bispecific antibodies is very similar to that of a general antibody structure, and is also called a bispecific antibody of an IgG-like structure. It differs from the general IgG antibody and non-IgG-like structure of bispecific antibodies in which it has both bispecificity and the corresponding function of the constant region, and its relatively large molecular weight, so it has higher stability and longer half-life. And also it is beneficial for the purification of antibody products, but its tissue permeability is also relatively low. Different types can be formed depending on the different domains of the fusion, such as scFv-Fc antibody, Minibody
, Bi-nanobody and the like.
is also a bispecific antibody that does not contain the C region of the antibody. It cross-pairs the light and heavy chains of the variable regions of two different antibodies, which are connected by a short peptide so that they cannot be spatially paired. The light and heavy chains of the same antibody variable region in the two different pairs are joined by a longer peptide chain, and finally the Diabody will fold back in the middle to spatially pair the light and heavy chains of the same antibody to form a dimeric structure. It has been reported in the literature that the antibody affinity at both ends of bispecific antibodies changes. The affinity of the variable region light and heavy chains bound in the form of dimer can be increased by nearly 10-fold, and can play a role in the induction of tumor cells to induce a large number of cytokines and eliminate tumor cells such as IL-2, IL-7, IL-10, IL-15, IL-18, TNF-α, and the like. The two Diabodys are linked to form a tetravalent dimeric derivative called tandem diabody (TandAb
), which has two identical binding sites for different antigens, and its relative molecular mass is relatively high with a higher binding efficiency. In addition, a new type of bispecific antibodies is very similar to the structure of Diabody, but it also contains a chain of disulfide bonds to stabilize it, called Dual-affinity Retargeting molecules.
Two different scFv fragments can be linked by a short peptide to form a bispecific antibody that does not contain the C region, called Bispecific T cell Engager
which can connect T cells and tumor cells. Two single-chain antibody fragments consisting of VLA-VHA and VLB-VHB form two different conformations in space, respectively, and then bind to two different antigens, respectively. In in vitro
cell culture experiments, a low concentration (10 pg / mL) of Bispecific T cell Engagers can trigger a powerful tumor elimination and ultimately lead to specific tumor cell lysis. Studies have shown that tandem scFv
fragments have the ability to recruit effector lymphocytes, such as anti-CD3 and anti-CD19. Bispecific T cell Engagers have produced good results in the clinical treatment of several different B-cell lymphomas.
Bispecific T cell Engager
can recognize and bind two different antigens separately, so it can connect immune cells, viral molecules, etc
. to tumor cells, thereby enhancing the killing effect on target cells, and it can also combine different antigens on the same tumor cell to enhance its binding specificity, thereby reducing side effects such as off-target toxicity. The ScFv-Fc antibody (100-105 k) is a class of bispecific antibodies containing both scFv and Fc segments. The scFv segment
can be fused to CH2 and CH3 of human IgG and can also be fused to the hinge region.