7DV4

Crystal structure of anti-CTLA-4 VH domain in complex with human CTLA-4

Summary for 7DV4

• Entry DOI: 10.2210/pdb7dv4/pdb
• Descriptor: Cytotoxic T-lymphocyte protein 4, 4003-1(VH), 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: anti-tumor, vh domain, complex, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 102367.85

Authors

Li, H.,Gan, X.,He, Y. (deposition date: 2021-01-12, release date: 2022-01-12, Last modification date: 2024-10-16)

Primary citation

Gan, X.,Shan, Q.,Li, H.,Janssens, R.,Shen, Y.,He, Y.,Chen, F.,van Haperen, R.,Drabek, D.,Li, J.,Zhang, Y.,Zhao, J.,Qin, B.,Jheng, M.J.,Chen, V.,Wang, J.,Rong, Y.,Grosveld, F.
An anti-CTLA-4 heavy chain-only antibody with enhanced T reg depletion shows excellent preclinical efficacy and safety profile.
Proc.Natl.Acad.Sci.USA, 119:e2200879119-e2200879119, 2022

PubMed 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 (T) 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 antibody-dependent cellular cytotoxicity function, lower serum exposure, and more potent anti-tumor activity than ipilimumab in murine tumor models, which is partly driven by a substantial depletion of intratumoral Ts. 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 T depletion and improved safety profile, HCAb 4003-2 is a promising candidate for the development of next generation anti-CTLA-4 therapy.

PubMed: 35925889
DOI: 10.1073/pnas.2200879119

Experimental method

X-RAY DIFFRACTION (2.38 Å)