4.6 Article

An anti-CD98 antibody displaying pH-dependent Fc-mediated tumour-specific activity against multiple cancers in CD98-humanized mice

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NATURE BIOMEDICAL ENGINEERING
卷 7, 期 1, 页码 8-23

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NATURE PORTFOLIO
DOI: 10.1038/s41551-022-00956-5

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An anti-CD98 antibody with pH-dependent binding has been found to elicit broad-spectrum anti-tumour activity in CD98-humanized mice. This discovery suggests that pH-dependent antibody variants targeting CD98 may have superior therapeutic outcomes.
An anti-CD98 antibody with pH-dependent binding elicits tumour-specific Fc-mediated anti-tumour activity in multiple xenograft and syngeneic tumour models established in CD98-humanized mice. 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 Fc gamma 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.

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