Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2019 Aug;29(8):601-602.
doi: 10.1038/s41422-019-0198-8.

pH-sensitive anti-CTLA4 antibodies: yes to efficacy, no to toxicity

Amnon Altman  1 , Kok-Fai Kong  2
Affiliations
Comment

pH-sensitive anti-CTLA4 antibodies: yes to efficacy, no to toxicity

Amnon Altman et al. Cell Res. 2019 Aug.
No abstract available

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Mechanisms of action of anti-CTLA-4 antibodies possessing or lacking irAE. When Ipilimumab and Tremelimumab, the prototypic irAE-prone antibodies, bind to Treg surface-expressed CTLA-4, the complex is internalized into recycling endosomes that mature into early endosomes. These antibodies are insensitive to the early endosomal pH, remaining in a complex with the internalized CTLA-4. This prevents CTLA-4 from binding to the chaperone LRBA, a requirement for CTLA-4 surface recycling. Instead, the CTLA-4-antibody complex is targeted for degradation in the lysosome (left side of broken line in the figure). The loss of surface CTLA-4 promotes potent irAE, as exemplified in some cancer patients treated with Ipilimumab. Similarly, pH-sensitive antibodies such as HL12 and HL32 also bind to CTLA-4 expressed on the surface of Tregs and the CTLA-4-antibody complex is internalized into recycling endosomes, which mature into early endosomes having a pH of of 6.0–6.5. Unlike the pH-resistant Ipilimumab and Tremelimumab, however, at this pH HL12 and HL32 dissociate from the endocytosed CTLA-4, enabling CTLA-4 to bind to LRBA, which recycles CTLA-4 to the cell surface. This results in continuous CTLA-4 surface expression on Tregs (right side of broken line in the figure), which is required for protection against irAE. The continuous recycling and surface expression of CTLA-4 also allows for more stable antibody binding and Fc-dependent, ADCC-mediated depletion of Tregs,, leading to enhanced CITE
See this image and copyright information in PMC

Comment on

References

    1. Tivol EA, et al. Immunity. 1995;3:541–547. doi: 10.1016/1074-7613(95)90125-6. - DOI - PubMed
    1. Waterhouse P, et al. Science. 1995;270:985–988. doi: 10.1126/science.270.5238.985. - DOI - PubMed
    1. Lo B, et al. Science. 2015;349:436–440. doi: 10.1126/science.aaa1663. - DOI - PubMed
    1. Walker LS, Sansom DM. Trends Immunol. 2015;36:63–70. doi: 10.1016/j.it.2014.12.001. - DOI - PMC - PubMed
    1. Wing K, et al. Science. 2008;322:271–275. doi: 10.1126/science.1160062. - DOI - PubMed