Innovative pH-selective antibody engineering for cancer therapy

Background

Antibody-based cancer therapies have demonstrated impressive specificity but can lead to adverse effects by targeting antigens present on healthy cells. The acidic tumor microenvironment presents an opportunity for the development of anti­bodies with heightened tumor specificity through pH-dependent binding interactions.

Technology and key findings

Dr. Maynard’s lab engineered the human IgG1 Fc domain to enhance pH-selective binding to CD16, crucial for antibody-dependent cellular cytotoxicity (ADCC). Through modifications in Fc residues to interact with positively charged histidine residues, a site-directed library was created. Mammalian cell display facilitated the isolation of Fc variants with reduced CD16 affinities at neutral pH but physiological affinities at the tumor-typical pH of 6.5.

The lead variant, acid-Fc, demonstrated a twofold pH-selectivity for CD16 binding, maintaining efficacy at the acidic tumor microenvironment's pH. In vitro assays confirmed nearly 20-fold weaker ADCC activity at pH 7.4 compared to pH 6.5, indicating enhanced tumor selectivity.

Benefits

• Enhanced tumor specificity: pH-selective antibodies target tumor cells specifically, minimizing off-target effects on healthy tissues.
• Improved safety profile: By sparing healthy cells, these antibodies reduce the risk of adverse reactions associated with traditional therapies.
• Precision targeting: Leveraging the acidic tumor microenvironment allows for precise delivery of therapeutic effects to malignant cells.

Commercial applications

• Cancer therapy: pH-selective antibodies offer potential applications in developing more effective and safer cancer treatments.
• Personalized medicine: These antibodies could contribute to personalized treatment approaches by targeting specific tumor characteristics.
• Biopharmaceutical industry: Pharmaceutical companies can utilize this technology to enhance the efficacy of antibody-based therapies and develop novel treatments for various cancers.

Opportunity

This technology opens doors for the development of next-generation cancer therapies with improved efficacy and safety profiles. Further research and development efforts could explore the potential of pH-selective antibodies in other disease areas and advance personalized medicine approaches in oncology. Additionally, collaborations between academia and industry could accelerate the translation of this technology into clinical applications.

The University of Texas at Austin is looking for innovative collaborators to further develop and commercialize pH-selective antibody technology for improved cancer treatment.