Targeting transmembrane TNF-α suppresses breast cancer growth

Area of Science:

• Oncology
• Immunology
• Cancer Therapeutics

Background:

• Tumor necrosis factor-alpha (TNF-α) antagonists show therapeutic potential in solid tumors.
• High serum TNF-α levels correlate with non-response to infliximab, suggesting antibody consumption and ectodomain shedding of transmembrane TNF-α (tmTNF-α).
• tmTNF-α is identified as a potential therapeutic target in breast cancer.

Purpose of the Study:

• To develop a monoclonal antibody (mAb) targeting transmembrane TNF-α (tmTNF-α) for cancer therapy.
• To evaluate the efficacy of tmTNF-α mAb in preclinical models of solid tumors.
• To investigate the mechanisms underlying the antitumor activity of tmTNF-α mAb.

Main Methods:

• Development of a novel monoclonal antibody (mAb) specific for tmTNF-α, distinguishing it from soluble TNF-α.
• Quantification of tmTNF-α expression in breast cancer tissues.
• In vitro and in vivo assessments of tmTNF-α mAb's cytotoxic and anti-tumor effects, including antibody-dependent cell-mediated cytotoxicity (ADCC), tumor growth inhibition, and metastasis suppression.

Main Results:

• High tmTNF-α expression was observed in primary breast cancers, with lower levels in hyperplastic tissues and undetectable levels in normal tissue.
• tmTNF-α mAb demonstrated potent antibody-dependent cell-mediated cytotoxicity (ADCC) against tmTNF-α-expressing cells.
• In vivo studies showed tmTNF-α mAb delayed tumor growth, induced complete regressions in some mice, inhibited metastasis, and reduced expression of prometastatic CD44v6.
• The antibody inhibited NF-κB activation and Bcl-2 expression by reducing tmTNF-α-positive cells, without activating pro-survival reverse signaling.

Conclusions:

• The developed tmTNF-α mAb exhibits significant antitumor activities.
• This tmTNF-α mAb is a promising therapeutic candidate for tmTNF-α-positive tumors.
• It offers a potential treatment strategy for patients nonresponsive to current TNF antagonists.