Details

Autor(en) / Beteiligte

• 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

Titel

Improved therapeutic index of an acidic pH-selective antibody

Ist Teil von

• mAbs, 2022, Vol.14 (1), p.2024642-2024642

Ort / Verlag

United States: Taylor & Francis

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.