Preclinical assessment of a novel human antibody VH domain targeting mesothelin as an antibody-drug conjugate

Zehua Sun; Xiaojie Chu; Cynthia Adams; Tatiana V Ilina; Michel Guerrero; Guowu Lin; Chuan Chen; Dontcho Jelev; Rieko Ishima; Wei Li; John W Mellors; Guillermo Calero; Dimiter S Dimitrov

doi:10.1016/j.omto.2023.09.002

Preclinical assessment of a novel human antibody VH domain targeting mesothelin as an antibody-drug conjugate

Mol Ther Oncolytics. 2023 Sep 13:31:100726. doi: 10.1016/j.omto.2023.09.002. eCollection 2023 Dec 19.

Authors

Zehua Sun¹, Xiaojie Chu¹, Cynthia Adams², Tatiana V Ilina³, Michel Guerrero³, Guowu Lin³, Chuan Chen¹, Dontcho Jelev¹, Rieko Ishima³, Wei Li¹, John W Mellors^{1

2}, Guillermo Calero³, Dimiter S Dimitrov^{1

2}

Affiliations

¹ Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
² Abound Bio, 1401 Forbes Avenue, Pittsburgh, PA 15219, USA.
³ Department of Structural Biology, University of Pittsburgh School of Medicine, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA.

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.

Keywords: ADC; MSLN; VH domain; in vivo distribution; library; structure.