Antibody mutations favoring pH-dependent binding in solid tumor microenvironments: Insights from large-scale...

Area of Science:

• Biotechnology
• Immunology
• Oncology

Background:

• Antibody-based therapeutics are increasingly used for cancer treatment.
• Off-tumor effects and cytotoxicity remain significant safety concerns.
• Targeted delivery of antitumor drugs is crucial for improving efficacy and safety.

Purpose of the Study:

• To expand a previously developed pH-switch approach for antibody engineering.
• To identify specific mutations and positions for enhanced pH-dependent binding.
• To create a sequence-based method for engineering pH-selective anticancer antibodies.

Main Methods:

• Computational analysis of over 400 antibody structures complexed with over 100 oncoproteins.
• Identification of key amino acid residues (His, Trp, Arg, Tyr) for pH-switch incorporation.
• Prediction of successful mutation sites within antibody complementarity-determining regions.

Main Results:

• Calculations suggest specific mutations (His to Trp, Arg, Tyr) can enhance pH-dependent binding.
• Ten specific positions in the complementarity-determining region were identified as promising for engineering pH-selectivity.
• The study provides two accessible metrics for sequence-based engineering of pH-selective binding.

Conclusions:

• A sequence-based engineering approach for pH-selective antibody binding is feasible.
• This method can be applied to a broad range of anticancer antibodies, including those lacking detailed structural data.
• The engineered antibodies offer improved safety profiles by targeting acidic tumor microenvironments.