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Cryo-EM structure of the TNF-alpha-Ozoralizumab (OZR)-HSA complex
Structural highlights
DiseaseTNFA_HUMAN Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). FunctionTNFA_HUMAN Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.[1] The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.[2] Publication Abstract from PubMedOzoralizumab (OZR) is a next-generation TNF inhibitor composed of two identical humanized anti-TNFalpha NANOBODY(R) molecules (TNF30s) recombinantly linked via one humanized anti-human serum albumin (HSA) NANOBODY(R) molecule (ALB8) and two peptide linkers. OZR is designed as a unique format to exert potent inhibitory effects against TNFalpha with long plasma half-life. However, the three-dimensional structure of OZR-TNFalpha-HSA complex has not yet been elucidated, and a complete understanding of its interaction mechanism with TNFalpha is yet to be gained. In this study, we successfully observed the formation of the OZR-TNFalpha-HSA ternary complex by single-particle cryo-electron microscopy. The single-particle analysis revealed that the two TNF30 molecules of OZR simultaneously bind bivalently to TNFalpha in a 1:1-bivalent binding mode, while the ALB8 molecule binds to HSA, forming a ternary complex. Thus, OZR exhibits a binding mode significantly different from that of other IgG-type TNFalpha inhibitors. Furthermore, surface plasmon resonance (SPR) analysis demonstrated that the 1:1-bivalent binding mode confers an exceptionally slow dissociation rate, thereby contributing to the potent TNFalpha-neutralizing activity of OZR. These findings not only lend support to the favorable clinical efficacy of OZR from a structural standpoint but also lay the foundation for the rational design and development of next-generation TNFalpha inhibitors with enhanced and sustained efficacy. Cryo-EM elucidates the interaction mechanism of ozoralizumab, a humanized anti-TNFalpha NANOBODY(R) compound.,Mima M, Sato K, Yokoyama T, Mishima-Tsumagari C, Ohnuki T, Tanaka Y, Iwamoto K Biochem Biophys Res Commun. 2026 Jun 4;816:153572. doi: , 10.1016/j.bbrc.2026.153572. Epub 2026 Mar 6. PMID:41935434[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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