Site-Selective Tyrosine Reaction for Antibody-Cell Conjugation and Targeted Immunotherapy

Area of Science:

• Biochemistry
• Immunology
• Chemical Biology

Background:

• Targeted immunotherapies leverage antibody binding for tumor destruction.
• Antibody-dependent cellular cytotoxicity (ADCC) involves antibody conjugation to immune cells for cancer cell killing.

Purpose of the Study:

• To develop a chemoenzymatic reaction for site-selective functionalization of therapeutic antibodies.
• To enable precise modification of tyrosine residues in immunoglobulin G (IgG) Fc domains.

Main Methods:

• A one-pot chemoenzymatic reaction was employed, combining tyrosinase-catalyzed tyrosine oxidation with [3+2] photoaddition.
• This method specifically targets the Y296 residue in therapeutic IgGs.
• Fluorescent molecules or bioorthogonal groups were installed at the targeted tyrosine residue.

Main Results:

• The developed reaction successfully functionalized the Y296 residue in therapeutic IgGs.
• Monofunctionalized antibody-drug conjugates (ADCs) were constructed.
• Antibody/nanobody-conjugated effector cells (e.g., natural killer cells, macrophages) were created.

Conclusions:

• Site-selective antibody functionalization holds significant potential for advancing targeted cancer immunotherapy.
• The developed chemoenzymatic method offers precise control for creating novel antibody-based therapeutics.