Improved therapeutic index of an acidic pH-selective antibody

MAbs. 2022 Jan-Dec;14(1):2024642. doi: 10.1080/19420862.2021.2024642.


Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that prevents maximal efficacious clinical outcomes and can lead to discontinuation of treatment. We hypothesized that an acidic pH-selective ipilimumab (pH Ipi), which preferentially and reversibly targets the acidic tumor microenvironment over the neutral periphery, may have a more favorable therapeutic index. While ipilimumab has pH-independent CTLA-4 affinity, pH Ipi variants have been engineered to have up to 50-fold enhanced affinity to CTLA-4 at pH 6.0 compared to pH 7.4. In hCTLA-4 knock-in mice, these variants have maintained anti-tumor activity and reduced peripheral activation, a surrogate marker for toxicity. pH-sensitive therapeutic antibodies may be a differentiating paradigm and a novel modality for enhanced tumor targeting and improved safety profiles.

Keywords: Antibody; conditional activation; immunology; oncology; pH; selectivity.

MeSH terms

  • Animals
  • Hydrogen-Ion Concentration
  • Ipilimumab / therapeutic use
  • Mice
  • Neoplasms*
  • Therapeutic Index
  • Tumor Microenvironment*


  • Ipilimumab

Grants and funding

The author(s) reported there is no funding associated with the work featured in this article.