Antibody-Dependent Cellular Phagocytosis (ADCP)

IgG and ADCP

IgG, IgM, IgA, IgE, and IgD are the five most common types of antibodies in the body's immune system, and they protect us from foreign antigens through their different abilities. As one of the most common, IgG is the main component of serum immunoglobulin, accounting for about 75% of its total. At the same time, IgG is also the most durable and important antibody in the primary immune response. IgG antibody is composed of two parts: Fab fragment binds to the target effector cell epitope, and Fc fragment binds to FcR on the surface of killer cells (NK cells and macrophages, etc.), so as to mediate antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell phagocytosis cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) effects.

Fig.1 Schematic diagram of IgG and the three effects. ¹

In the ADCP effect, the IgG antibody molecule binds to the antigen on the cell surface and recruits aggregated macrophages through its Fc fragment. Then the macrophages engulf and digest the tumor cells or germ cells. This process can attack and destroy tumor cells, which is an important mechanism that makes ADCP an important mechanism for antibody drug development.

Fig.2 Simplified schematic diagram of the mechanism of mAb-induced ADCP. ²

ADCP is mediated by multiple effector cells, including macrophages, monocytes, dendritic cells, and neutrophils, through FcγR. When the Fab region of the antibody binds to a specific antigen on the surface of the target cell, the Fc region of the antibody binds to and activates various Fcγ receptors on the effector cells. Activation of specific Fcγ receptors (e.g., FcγRIIa, FcγRI, and FcγRIIIa) leads to the activation of various complex pathways, resulting in phagocytosis and destruction of target cells in the lysosomes of effector cells.

Fig.3 Binding affinity of Fc receptors associated with ADCP. ³

FcγRIIa and ADCP

FcγRIIa is the main Fcγ receptor involved in the ADCP process, which is mainly expressed in myeloid effector cells, including neutrophils and macrophages, and plays an important activation role in the ADCP effect.

FcγRIIa exhibits polymorphisms, with higher affinities for the R131H variant and IgG1. On the one hand, the ADCP effect can induce effector cells to directly engulf target cells, and on the other hand, when the ADCP effect is initiated, macrophages and others will present the processed tumor antigen to T cells, thereby initiating long-term tumor-specific immunity. At present, the phagocytic effect of macrophages on tumor cells mediated by the enhancement of Fc-terminal amino acid substitution of antibodies has already been applied to therapeutic antibodies.

Factors Influencing ADCP

• The abundance of the target protein in the target cells
• The binding activity of the antibody to the target
• Antibody subtypes
• Whether the target cells also overexpress other immunosuppressive molecules
• Maintenance of phagocytic activity of effector cells

Prospective and Feature

There is substantial evidence that ADCP can help prevent or reduce the severity of different types of viral infections. Further research into the role of ADCP in different responses and the specific epitopes targeted by ADCP antibodies may provide insight into rational vaccine design strategies to elicit these types of antibody responses while avoiding deleterious antibody-dependent enhancement activity.

References

1. Chen, Yu.; et al. "Looking for the optimal PD-1/PD-L1 inhibitor in cancer treatment: A comparison in basic structure, function, and clinical practice." Frontiers in Immunology. (2020) 11 1088.
2. Gül, Nuray, and Marjolein van Egmond. "Antibody-dependent phagocytosis of tumor cells by macrophages: A potent effector mechanism of monoclonal antibody therapy of cancer." Cancer research. 75,23 (2015): 5008-13.
3. Tay, M.Z. et al. "Antibody-dependent cellular phagocytosis in antiviral immune responses." Frontiers in Immunology. (2019) 10 332. 28.