8PUK

ChiLob 7/4 H2 HC-T219C/C224S Kappa LC-E123C/C214S F(ab')2

Summary for 8PUK

• Entry DOI: 10.2210/pdb8puk/pdb
• Related: 6FAX 6TKB 6TKC 6TKD 6TKE 6TKF
• Descriptor: Chilob 7/4 H2 heavy chain T219C/C224S, Chilob 7/4 H2 kappa chain E123C/C214S, SULFATE ION, ... (4 entities in total)
• Functional Keywords: antibody, igg2, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 48619.03

Authors

Elliott, I.G.,Fisher, H.,Tews, I. (deposition date: 2023-07-17, release date: 2025-03-05, Last modification date: 2025-07-16)

Primary citation

Elliott, I.G.,Fisher, H.,Chan, H.T.C.,Inzhelevskaya, T.,Mockridge, C.I.,Penfold, C.A.,Duriez, P.J.,Orr, C.M.,Herniman, J.,Muller, K.T.J.,Essex, J.W.,Cragg, M.S.,Tews, I.
Structure-guided disulfide engineering restricts antibody conformation to elicit TNFR agonism.
Nat Commun, 16:3495-3495, 2025

PubMed 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.

PubMed: 40221417
DOI: 10.1038/s41467-025-58773-8

Experimental method

X-RAY DIFFRACTION (2.671 Å)