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A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer.
- Source :
-
Journal of nanobiotechnology [J Nanobiotechnology] 2024 May 16; Vol. 22 (1), pp. 256. Date of Electronic Publication: 2024 May 16. - Publication Year :
- 2024
-
Abstract
- Background: Gastric cancer represents a highly lethal malignancy with an elevated mortality rate among cancer patients, coupled with a suboptimal postoperative survival prognosis. Nectin-4, an overexpressed oncological target for various cancers, has been exploited to create antibody-drug conjugates (ADCs) to treat solid tumors. However, there is limited research on Nectin-4 ADCs specifically for gastric cancer, and conventional immunoglobulin G (IgG)-based ADCs frequently encounter binding site barriers. Based on the excellent tumor penetration capabilities inherent in nanobodies (Nbs), we developed Nectin-4-targeting Nb drug conjugates (NDCs) for the treatment of gastric cancer.<br />Results: An immunized phage display library was established and employed for the selection of Nectin-4-specific Nbs using phage display technology. Subsequently, these Nbs were engineered into homodimers to enhance Nb affinity. To prolong in vivo half-life and reduce immunogenicity, we fused an Nb targeting human serum albumin (HSA), resulting in the development of trivalent humanized Nbs. Further, we site-specifically conjugated a monomethyl auristatin E (MMAE) at the C-terminus of the trivalent Nbs, creating Nectin-4 NDC (huNb26/Nb26-Nbh-MMAE) with a drug-to-antibody ratio (DAR) of 1. Nectin-4 NDC demonstrated excellent in vitro cell-binding activities and cytotoxic efficacy against cells with high Nectin-4 expression. Subsequent administration of Nectin-4 NDC to mice bearing NCI-N87 human gastric cancer xenografts demonstrated rapid tissue penetration and high tumor uptake through in vivo imaging. Moreover, Nectin-4 NDC exhibited noteworthy dose-dependent anti-tumor efficacy in in vivo studies.<br />Conclusion: We have engineered a Nectin-4 NDC with elevated affinity and effective tumor uptake, further establishing its potential as a therapeutic agent for gastric cancer.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Animals
Cell Line, Tumor
Mice
Mice, Inbred BALB C
Female
Xenograft Model Antitumor Assays
Oligopeptides chemistry
Oligopeptides pharmacology
Nectins
Stomach Neoplasms drug therapy
Single-Domain Antibodies chemistry
Single-Domain Antibodies pharmacology
Cell Adhesion Molecules metabolism
Immunoconjugates chemistry
Immunoconjugates pharmacology
Immunoconjugates pharmacokinetics
Mice, Nude
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1477-3155
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of nanobiotechnology
- Publication Type :
- Academic Journal
- Accession number :
- 38755613
- Full Text :
- https://doi.org/10.1186/s12951-024-02521-5