8FSL

Human Mesothelin bound to a neutralizing VH domain antibody

Summary for 8FSL

• Entry DOI: 10.2210/pdb8fsl/pdb
• Descriptor: VH domain, Mesothelin (2 entities in total)
• Functional Keywords: mesothelin vh, antitumor protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 6
• Total formula weight: 115563.07

Authors

Calero, G. (deposition date: 2023-01-10, release date: 2024-05-29, Last modification date: 2024-11-06)

Primary citation

Sun, Z.,Chu, X.,Adams, C.,Ilina, T.V.,Guerrero, M.,Lin, G.,Chen, C.,Jelev, D.,Ishima, R.,Li, W.,Mellors, J.W.,Calero, G.,Dimitrov, D.S.
Preclinical assessment of a novel human antibody VH domain targeting mesothelin as an antibody-drug conjugate.
Mol Ther Oncolytics, 31:100726-100726, 2023

PubMed Abstract: Mesothelin (MSLN) has been a validated tumor-associated antigen target for several solid tumors for over a decade, making it an attractive option for therapeutic interventions. Novel antibodies with high affinity and better therapeutic properties are needed. In the current study, we have isolated and characterized a novel heavy chain variable (VH) domain 3C9 from a large-size human immunoglobulin VH domain library. 3C9 exhibited high affinity (KD [dissociation constant] <3 nM) and binding specificity in a membrane proteome array (MPA). In a mouse xenograft model, 3C9 fused to human IgG1 Fc was detected at tumor sites as early as 8 h post-infusion and remained at the site for over 10 days. Furthermore, 3C9 fused to a human Fc domain drug conjugate effectively inhibited MSLN-positive tumor growth in a mouse xenograft model. The X-ray crystal structure of full-length MSLN in complex with 3C9 reveals interaction of the 3C9 domains with two distinctive residue patches on the MSLN surface. This newly discovered VH antibody domain has a high potential as a therapeutic candidate for MSLN-expressing cancers.

PubMed: 37771390
DOI: 10.1016/j.omto.2023.09.002

Experimental method

X-RAY DIFFRACTION (2.9 Å)