Anti-GD2 mAb for Neuroblastoma

GD2

• Structure of GD2

GD2, a bis-sialic acid ganglioside, consists of a ceramide and two sialic acid residues connected to three monosaccharide units (galactose, glucose, and n-acetylaminogalactose).

Fig.1 Molecular structure of GD2. (Wikipedia)

• Function of GD2

GD2 has the effects of inducing apoptosis of T cells, inhibiting proliferation of T cells, and inhibiting the differentiation of human CD34+ cells into mature dendritic cells. In addition, GD2 promotes the adhesion of platelets to collagen-coated wells by increasing focal adhesion kinase phosphorylation, suggesting that it may be involved in tumor metastasis.

Fig.2 Physiological role of GD2 on tumor surface

• Expression site of GD2

As a carcinoembryonic antigen, GD2 is detectable in mesenchymal cells and neural stem cells during embryonic development. After birth, GD2 is normally mainly present in the brain, peripheral pain fibers, and cutaneous melanocytes, and the expression level is weak. In addition, GD2 is abundantly expressed in various neuroectodermomas, such as neuroblastoma, melanoma, glioma, small-cell lung cancer, and sarcoma. Regardless of tumor stage, primary or metastasis, GD2 is expressed at high density on the surface of NB cells, promoting the bonding of tumor cells to the extracellular matrix.

ADCC Effect of GD2 mAb

The main effects of GD2 mAb are divided into antibody-dependent and complement-dependent. The former includes NK cells, neutrophil-mediated cytolysis mechanism ADCC and macrophage-mediated phagocytosis ADCP. The latter is a CDC mediated by the complement cascade, CDCC mediated by complement breakdown products, and CDCP in which complement breakdown products work together with macrophages. In vitro experiments, researchers usually measure the magnitude of tumor lethality through the above effects. In addition, studies have shown that GD2 monoclonal antibodies can also directly induce apoptosis in tumor cells.

Fig.3 Mechanism of GD2 monoclonal antibody

ADCC is considered to be the most important tumor-killing mechanism of monoclonal antibodies. GD2 antibody specifically recognizes GD2 and forms antigen-antibody complexes (IC), recruits and activates effector cells such as NK cells, and secretes granzyme, perforin, and lyase to dissolve and kill tumor cells. This process mainly relies on the binding of FcγRIIIα expressed on the surface of effector cells to the Fc segment of GD2 monoclonal antibody, and the functional polymorphisms of FcγRIIIα have been shown to have a significant correlation with the clinical outcomes of multiple therapeutic antibodies, which is a structure of interest in GD2 monoclonal antibody research.

Corresponding functions of different structures of GD2 mAb

Through the antibody structure diagram below, we can find that the binding point of monoclonal antibody and target cells is located at the Fab end, while the structure related to immune effector cells and factors (FcγRIII., C1q) is the Fc segment, in which the CH2 part is connected to the oligosaccharide structure of the Asn297 site, which is the binding site of FcγRIII., which is of great significance for the enhancement of ADCC.

Fig.4 The general structure of lgG corresponds to the key regions corresponding to each functional enhancement.

In summary, the binding of GD2 mAb to GD2 allows the body's immune system to regain the ability to specifically recognize and fight NB cells. Therefore, the significance of such drugs in the treatment of NB is obvious. Only by further understanding the position of GD2 mAb between tumor cells and immune effector cells, analyzing the physiological effects and influencing factors of each immune mechanism, and comparing and analyzing key binding sites, can the tumor-killing effect of GD2 mAb be further improved.

References

1. Yu, J.; et al. Targeting glycosphingolipids for cancer immunotherapy. FEBS letters. 2020, 594(22): 3602-3618.
2. Park, J.A.; et al. Targets and antibody formats for immunotherapy of neuroblastoma. Journal of Clinical Oncology. 2020, 38(16): 1836-1848.
3. Kubota, T.; et al. Engineered therapeutic antibodies with improved effector functions. Cancer science. 2009, 100(9): 1566-1572.