7DF1

Crystal structure of human CD98 heavy chain extracellular domain in complex with S1-F4 scFv

Summary for 7DF1

• Entry DOI: 10.2210/pdb7df1/pdb
• Descriptor: 4F2 cell-surface antigen heavy chain, S1-F4 VH, IGL c2062_light_IGKV4-1_IGKJ5 (3 entities in total)
• Functional Keywords: complex, tumor growth, antibody, antitumor protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 298265.29

Authors

Liu, X.,Ding, J.,Sui, J.,Tian, X. (deposition date: 2020-11-06, release date: 2022-12-07, Last modification date: 2024-10-23)

Primary citation

Tian, X.,Liu, X.,Ding, J.,Wang, F.,Wang, K.,Liu, J.,Wei, Z.,Hao, X.,Li, Y.,Wei, X.,Zhang, H.,Sui, J.
An anti-CD98 antibody displaying pH-dependent Fc-mediated tumour-specific activity against multiple cancers in CD98-humanized mice.
Nat Biomed Eng, 2022

PubMed Abstract: The cell-surface glycoprotein CD98-a subunit of the LAT1/CD98 amino acid transporter-is an attractive target for cancer immunotherapies, but its widespread expression has hampered the development of CD98-targeting antibody therapeutics. Here we report that an anti-CD98 antibody, identified via the screening of phage-display libraries of CD98 single-chain variable fragments with mutated complementarity-determining regions, preserves the physiological function of CD98 and elicits broad-spectrum crystallizable-fragment (Fc)-mediated anti-tumour activity (requiring Fcγ receptors for immunoglobulins, macrophages, dendritic cells and CD8 T cells, as well as other components of the innate and adaptive immune systems) in multiple xenograft and syngeneic tumour models established in CD98-humanized mice. We also show that a variant of the anti-CD98 antibody with pH-dependent binding, generated by solving the structure of the antibody-CD98 complex, displayed enhanced tumour-specific activity and pharmacokinetics. pH-dependent antibody variants targeting widely expressed antigens may lead to superior therapeutic outcomes.

PubMed: 36424464
DOI: 10.1038/s41551-022-00956-5

Experimental method

X-RAY DIFFRACTION (2.806 Å)