In vitro-engineered non-antibody protein therapeutics

Area of Science:

• Biotechnology
• Protein Engineering
• Therapeutic Development

Background:

• Antibodies are effective therapeutics but are limited by high manufacturing costs.
• Non-antibody binding proteins are being developed as alternative therapies.
• New protein scaffolds are continuously being discovered and designed.

Purpose of the Study:

• To review protein scaffolds currently in human use or clinical trials as therapeutic alternatives to antibodies.
• To categorize these scaffolds based on their ligand-binding residue location.
• To discuss the advantages and limitations of these protein scaffolds compared to antibodies.

Main Methods:

• Categorization of protein scaffolds based on the location of ligand-binding residues (flexible loops vs. secondary structures).
• Identification of specific protein scaffolds within each category (e.g., adnectins, anticalins, avimers, Fynomers, Kunitz domains, knottins, affibodies, β-hairpin mimetics, DARPins).
• Review of existing clinical trial data and FDA approvals for these scaffolds.

Main Results:

• Protein scaffolds are classified into two main categories: those with binding residues in flexible loops and those with binding residues in secondary structures like α-helices.
• Examples of scaffolds in the flexible loop category include adnectins, anticalins, avimers, Fynomers, Kunitz domains, and knottins.
• Examples of scaffolds in the secondary structure category include affibodies, β-hairpin mimetics, and designed ankyrin repeat proteins (DARPins).

Conclusions:

• Protein scaffolds offer significant benefits as therapeutic alternatives to antibodies, including high stability and low immunogenic potential.
• Many scaffolds can be produced cost-effectively in microorganisms or via chemical synthesis.
• Continued investigation and development of these protein scaffolds are expected due to their therapeutic potential.