A highly potential cleavable linker for tumor targeting antibody-chemokines

Area of Science:

• Biochemistry and Molecular Biology
• Immunology
• Cancer Therapeutics

Background:

• Chemokines are crucial for leukocyte migration, playing a key role in immune responses.
• Current antibody-chemokine fusion proteins aim to attract leukocytes to tumor sites, but effective gradient creation is challenging.
• Precise release of chemokines from antibodies is vital for maximizing leukocyte recruitment to the tumor microenvironment.

Purpose of the Study:

• To design and evaluate a novel linker for antibody-chemokine fusion proteins.
• To enable enzyme-mediated cleavage of the linker by tumor-specific proteases.
• To enhance leukocyte recruitment to tumors and inhibit tumor progression.

Main Methods:

• Design of a novel linker susceptible to cleavage by tumor microenvironment enzymes.
• Inclusion of cleavage sites for cathepsin B, urokinase-type plasminogen activator (uPA), and matrix metalloproteinases (MMPs).
• Bioinformatic analysis to assess linker stability, detectability, and enzymatic cleavage.

Main Results:

• The designed linker demonstrated structural stability through in silico evaluation.
• The linker is predicted to be detectable and cleavable by target tumor proteases (cathepsin B, uPA, MMPs).
• The linker's design allows it to compete with native substrates, potentially inhibiting key proteases.

Conclusions:

• The novel enzyme-cleavable linker is a promising tool for enhancing chemokine-based cancer immunotherapies.
• This linker facilitates targeted chemokine release, improving leukocyte recruitment to tumors.
• The approach offers a strategy to inhibit tumor progression by modulating the tumor microenvironment.