PH-Dependent Antibodies (AI-Assisted Design)

Background:

The strategy of using phage display technology to construct a reverse mutation library can also be used for screening pH-dependent antibodies. Compared to conventional antibodies, pH-dependent antibodies have different affinities for binding to antigens in different pH environments, making them uniquely advantageous in various applications. Satralizumab, developed by Roche, is a humanized IgG monoclonal antibody against the IL-6 receptor, currently in clinical development for the treatment of neuromyelitis optica spectrum disorder. The antibody has high affinity at pH 7.4 and rapid antigen dissociation at pH 6.0, allowing multiple antigen binding and prolonging its half-life while reducing the required dosage per administration. H15L54, a pH-dependent antibody developed by the Sui Jianhua team at the Beijing Institute of Life Sciences, targets CD98 antigen highly expressed in tumor cells, but also present in various normal tissues. To enhance the antibody's targeting specificity, the team reduced its binding affinity in neutral environments by activating it in tumor’s low-PH environment.

Process and Case

Case Study 1:

Development of Sweeping Antibodies: Designing a multi-binding antibody that separates from the antigen under acidic conditions in lysosomes and only decomposes the antigen.

Case Study 2:

Fc Engineering: The neonatal Fc receptor (FcRn) is expressed during pregnancy and lactation to transport IgG across the placental barrier and intestine. The Fc fragment of IgG has pH-dependent binding with FcRn, with FcRn binding IgG at pH 5.8 and dissociating at neutral and weakly alkaline conditions (pH 7.0-7.5).