Structure-guided disulfide engineering restricts antibody conformation to elicit TNFR agonism

Isabel G. Elliott, Hayden Fisher, H. T. Claude Chan, Tatyana Inzhelevskaya, C. Ian Mockridge, Christine A. Penfold, Patrick J. Duriez, Christian M. Orr, Julie Herniman, Kri T. J. Müller, Jonathan W. Essex, Mark S. Cragg and Ivo Tews ()
Additional contact information
Isabel G. Elliott: University of Southampton
Hayden Fisher: University of Southampton
H. T. Claude Chan: University of Southampton
Tatyana Inzhelevskaya: University of Southampton
C. Ian Mockridge: University of Southampton
Christine A. Penfold: University of Southampton
Patrick J. Duriez: University of Southampton
Christian M. Orr: Diamond Light Source
Julie Herniman: University of Southampton
Kri T. J. Müller: University of Southampton
Jonathan W. Essex: University of Southampton
Mark S. Cragg: University of Southampton
Ivo Tews: University of Southampton

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract A promising strategy in cancer immunotherapy is activation of immune signalling pathways through antibodies that target co-stimulatory receptors. hIgG2, one of four human antibody isotypes, is known to deliver strong agonistic activity, and modification of hIgG2 hinge disulfides can influence immune-stimulating activity. This was shown for antibodies directed against the hCD40 receptor, where cysteine-to-serine exchange mutations caused changes in antibody conformational flexibility. Here we demonstrate that the principles of increasing agonism by restricting antibody conformation through disulfide modification can be translated to the co-stimulatory receptor h4-1BB, another member of the tumour necrosis factor receptor superfamily. Furthermore, we explore structure-guided design of the anti-hCD40 antibody ChiLob7/4 and show that engineering additional disulfides between opposing F(ab’) arms can elicit conformational restriction, concomitant with enhanced agonism. These results support a mode where subtle increases in rigidity can deliver significant improvements in immunostimulatory activity, thus providing a strategy for the rational design of more powerful antibody therapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-58773-8

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