Improved therapeutic index of an acidic pH-selective antibody

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 acidi...

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Published inmAbs Vol. 14; no. 1
Main Authors Lee, Peter S., MacDonald, Katherine G., Massi, Evan, Chew, Pamela V., Bee, Christine, Perkins, Padma, Chau, Bryant, Thudium, Kent, Lohre, Jack, Nandi, Pradyot, Deyanova, Ekaterina G., Barman, Ishita, Gudmundsson, Olafur, Dollinger, Gavin, Sproul, Tim, Engelhardt, John J., Strop, Pavel, Rajpal, Arvind
Format Report
LanguageEnglish
Published Taylor & Francis 31.12.2022
Subjects
Antibody
conditional activation
immunology
oncology
selectivity
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Summary: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.
ISSN:1942-0862
1942-0870
DOI:10.1080/19420862.2021.2024642