An anti-CTLA-4 heavy chain-only antibody with enhanced Treg depletion shows excellent preclinical efficacy and safety profile

Xin Gan, Qianqian Shan, He Li, Rick Janssens, Yuqiang Shen, Yun He, Fei Chen, Rien Van Haperen, Dubravka Drabek, Jin Li, Yang Zhang, Jiuqiao Zhao, Beibei Qin, Ming Jin Jheng, Victor Chen, Jingsong Wang, Yiping Rong, Frank Grosveld*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Scopus)
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Abstract

The value of anti-CTLA-4 antibodies in cancer therapy is well established. However, the broad application of currently available anti-CTLA-4 therapeutic antibodies is hampered by their narrow therapeutic index. It is therefore challenging and attractive to develop the next generation of anti-CTLA-4 therapeutics with improved safety and efficacy. To this end, we generated fully human heavy chain-only antibodies (HCAbs) against CTLA-4. The hIgG1 Fc domain of the top candidate, HCAb 4003-1, was further engineered to enhance its regulatory T (Treg) cell depletion effect and to decrease its half-life, resulting in HCAb 4003-2. We tested these HCAbs in in vitro and in vivo experiments in comparison with ipilimumab and other anti-CTLA4 antibodies. The results show that human HCAb 4003-2 binds human CTLA-4 with high affinity and potently blocks the binding of B7-1 (CD80) and B7-2 (CD86) to CTLA-4. The results also show efficient tumor penetration. HCAb 4003-2 exhibits enhanced antibodydependent cellular cytotoxicity function, lower serum exposure, and more potent antitumor activity than ipilimumab in murine tumor models, which is partly driven by a substantial depletion of intratumoral Tregs. Importantly, the enhanced efficacy combined with the shorter serum half-life and less systemic drug exposure in vivo potentially provides an improved therapeutic window in cynomolgus monkeys and preliminary clinical applications. With its augmented efficacy via Treg depletion and improved safety profile, HCAb 4003-2 is a promising candidate for the development of next generation anti-CTLA-4 therapy.

Original languageEnglish
Article numbere2200879119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number32
DOIs
Publication statusPublished - 4 Aug 2022

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We are grateful to Jia Lu and Dr. Xiaolu Tao in the Harbour BioMed pharmacokinetics team for supporting the PK experiment design and parameter calculation. This study is supported by Harbour BioMed.

Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.

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