7SU0

Crystal structure of an acidic pH-selective Ipilimumab variant Ipi.105 in complex with CTLA-4

Summary for 7SU0

• Entry DOI: 10.2210/pdb7su0/pdb
• Descriptor: Cytotoxic T-lymphocyte protein 4, Fab heavy chain, Fab light chain, ... (7 entities in total)
• Functional Keywords: immunoglobulin, checkpoint, antibody, complex, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 124623.12

Authors

Lee, P.S.,Chau, B.,Strop, P. (deposition date: 2021-11-15, release date: 2022-03-02, Last modification date: 2024-10-16)

Primary citation

Lee, P.S.,MacDonald, K.G.,Massi, E.,Chew, P.V.,Bee, C.,Perkins, P.,Chau, B.,Thudium, K.,Lohre, J.,Nandi, P.,Deyanova, E.G.,Barman, I.,Gudmundsson, O.,Dollinger, G.,Sproul, T.,Engelhardt, J.J.,Strop, P.,Rajpal, A.
Improved therapeutic index of an acidic pH-selective antibody.
Mabs, 14:2024642-2024642, 2022

PubMed Abstract: 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.

PubMed: 35192429
DOI: 10.1080/19420862.2021.2024642

Experimental method

X-RAY DIFFRACTION (2.41 Å)