Activated vitronectin as a target for anticancer therapy with human antibodies

Area of Science:

• Biochemistry
• Oncology
• Immunology

Background:

• Tumor growth and angiogenesis involve the formation of a provisional extracellular matrix.
• Activated matrix proteins undergo conformational changes, exposing unique cryptic sites and epitopes.
• These activated epitopes may be suitable targets for therapeutic monoclonal antibodies due to restricted tissue distribution.

Purpose of the Study:

• To generate human monoclonal antibodies (huMabs) that can differentiate between activated and native conformations of the extracellular matrix protein vitronectin.
• To evaluate the potential of activated vitronectin as a therapeutic target for human cancer.

Main Methods:

• Phage antibody display technology and subtractive phage selection were employed to generate antibody fragments.
• A human monoclonal antibody fragment, scFv VN18, was selected and engineered into a full human IgG/kappa monoclonal antibody.
• Immunohistochemical analysis and radio-labeling studies were performed using the developed antibody.

Main Results:

• The generated antibody fragments, including scFv VN18, specifically recognized the activated conformation of vitronectin.
• The fully human monoclonal antibody VN18 demonstrated high affinity (9.3 nM) for activated vitronectin.
• Immunohistochemistry confirmed that huMab VN18 targets activated vitronectin in tumor tissues with minimal detection in normal tissues.
• Radio-labeled huMab VN18 successfully targeted tumors in a chicken model, validating its tumor-targeting capability.

Conclusions:

• Activated vitronectin presents unique epitopes that can be targeted by specific therapeutic antibodies.
• The human monoclonal antibody VN18 effectively targets activated vitronectin in tumor tissues.
• Activated vitronectin is established as a promising target for developing novel human cancer therapies.