A novel fully human anti-NCL immunoRNase for triple-negative breast cancer therapy

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Breast cancer is a leading global cancer in women.
• Targeted therapies using monoclonal antibodies against tumor-associated antigens (TAAs) are a promising anti-cancer strategy.
• Nucleolin (NCL) is a TAA overexpressed on Triple Negative Breast Cancer (TNBC) cells, regulating microRNAs involved in tumor progression and drug resistance.

Purpose of the Study:

• To construct and characterize a novel immuno-RNase, 4LB5-HP-RNase, for targeted TNBC therapy.
• To evaluate the anti-tumor efficacy of 4LB5-HP-RNase in vitro and in vivo.
• To assess the impact of 4LB5-HP-RNase on tumorigenic microRNA levels.

Main Methods:

• Construction of an immuno-RNase by conjugating an anti-NCL single-chain variable fragment (4LB5) with human pancreatic RNase (HP-RNase).
• Assessment of the immuno-RNase's binding specificity to NCL-positive breast cancer cells.
• Evaluation of cell viability, proliferation, and apoptosis induction in vitro and in vivo.
• Quantification of specific microRNA levels (miR-21, -221, -222).

Main Results:

• The 4LB5-HP-RNase retained both enzymatic activity and specific binding to NCL-positive cancer cells.
• The immuno-RNase significantly reduced viability and proliferation of NCL-positive breast cancer cells in vitro and in vivo.
• Treatment with 4LB5-HP-RNase induced apoptosis and decreased levels of oncogenic miRNAs miR-21, -221, and -222.

Conclusions:

• The novel 4LB5-HP-RNase demonstrates potent and selective anti-tumor activity against TNBC.
• This immuno-agent represents a potential therapeutic strategy for TNBC patients unresponsive to current treatments.
• Targeting NCL with immuno-RNases offers a promising avenue for advanced breast cancer therapy.