Small antibody mimetics comprising two complementarity-determining regions and a framework region for tumor targeting

Area of Science:

• Biotechnology
• Immunology
• Oncology

Background:

• Antibodies are crucial for targeted therapies but face challenges in tumor penetration.
• Antibody fragments can improve penetration but may compromise antigen-binding affinity.

Purpose of the Study:

• To develop novel antibody mimetics with enhanced tumor penetration and retained antigen recognition.
• To create fusion proteins (pheromonicins) for targeted tumor growth inhibition.

Main Methods:

• Fusion of VHCDR1 and VLCDR3 with a cognate framework region (VHFR2) to create ~3 kDa mimetics.
• Linking antibody mimetics to the bacterial toxin colicin Ia to form pheromonicins.
• In vivo evaluation of pheromonicins in mice bearing human malignant tumors.

Main Results:

• The engineered mimetics retained antigen recognition and demonstrated superior tumor penetration compared to fragments lacking framework regions.
• Pheromonicins exhibited enhanced tumor targeting and penetration in mice compared to parent antibodies.
• In vivo activity suggested CDRs in mimetics approximate the conformation found in antibody-antigen complexes.

Conclusions:

• Rational recombination of binding sites and framework regions can yield effective targeting moieties for cancer therapy.
• Antibody mimetics offer a promising strategy for improving the efficacy of targeted cancer treatments.