Antibody recruiting molecules (ARMs): synthetic immunotherapeutics to fight cancer

Abstract

Antibody-recruiting molecules (ARMs) are one of the most promising tools to redirect the immune response towards cancer cells.

The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities

“…These synthetic agents consist of covalently linked bifunctional constructs comprising a tumor binding module (TBM), interacting with overexpressed cancer-specific biomarkers, and an antibody binding module (ABM), a hapten able to bind endogenous antibodies. By virtue of this design, ARMs have the ability to prime and direct downstream antibody-dependent effector mechanisms, including antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), and complement-mediated cytotoxicity (CDP), toward the target-expressing cancer cells that are not efficiently recognized by the immune system on its own [ 255 ] ( Figure 11 b,c).…”

“…In the complement-mediated cytotoxicity, the C1q complement protein binds to the Fc part of the antibodies and activates the complement cascade, which culminates in the formation of the membrane attack complex (MAC) on the cancer cell surface and its lysis. Alternatively, the antibody’s Fc can also interact with the Fc-receptors expressed on the surface of various immune cells, such as macrophages or natural killer cells, followed by target cell phagocytosis (ADCP) or tumor-cell lysis via NK releasing potent oxidizing agents and protein toxins, such as granzyme and perforin (ADCC) [ 255 ]. Created with BioRender.com.…”

Metabolic labelling of cancer cells with glycodendrimers stimulate immune-mediated cytotoxicity

“…[1][2][3] To this aim, synthetic antibody recruiting molecules (ARMs) combining two binding modules, one for tumor cell (TBM) and the other for the antibody recruitment (ABM, typically dinitrophenol, αGal or Rha) have been demonstrated to successfully trigger immune cytotoxicity against cancer cells by CDC or ADCC mechanisms. [4][5][6][7] From the first generation of ARMs to the more sophisticated Antibody Recruiting Polymers (ARPs) 8 or Glycodendrimers (ARGs) 8 , significant advances have been made in the understanding of functional and structural requirements to improve immunological effects. If the multivalent presentation of ABM was clearly demonstrated as a key element to recruit endogenous antibodies, 10,11 the major shortcoming of this approach concerns the TBM which has to ensure the binding of the cell surface without promoting internalisation to maintain the ABM exposure and accessibility at the cell surface.…”

Antibody Recognition of Cancer Cells via Glycan Surface Engineering

“…We reasoned that the functionalization of the cell surface with an antibody recruiting small molecule by metabolic glycoengineering would represent an attractive alternative to ARMs [41] . The metabolic glycoengineering approach could combine both the versatility and the selectivity needed for further potential therapeutic application.…”

“…Selective glycoengineering was also achieved by galactosidase‐mediated activation of suitable precursors [47] . All these approaches offer several advantages and limitations, which have been recently reviewed [41,48] …”