Improved therapeutic index of an acidic pH-selective antibody
| Autor: | Peter S. Lee, Katherine G. MacDonald, Evan Massi, Pamela V. Chew, Christine Bee, Padma Perkins, Bryant Chau, Kent Thudium, Jack Lohre, Pradyot Nandi, Ekaterina G. Deyanova, Ishita Barman, Olafur Gudmundsson, Gavin Dollinger, Tim Sproul, John J. Engelhardt, Pavel Strop, Arvind Rajpal |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | mAbs, Vol 14, Iss 1 (2022) |
| Druh dokumentu: | article |
| ISSN: | 1942-0862 1942-0870 19420862 |
| DOI: | 10.1080/19420862.2021.2024642 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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