The small molecule antibody mimic SH7139 targets a family of HLA-DRs expressed by B-cell lymphomas and other solid cancers. (25th November 2020)

• Record Type: Journal Article
• Authors: Balhorn, Rod; Balhorn, Monique Cosman; Balakrishnan, Karuppiah; Rebhun, Robert B.
• Is Part Of: Journal of drug targeting. Volume 28:Number 10(2020)
• Page Start: 1124
• Page End: 1136
• Publication Date: 2020-11-25
• Subjects: SH7139 -- SH7129 -- selective high-affinity ligand (SHAL) -- small molecule ADC mimic -- HLA-DR -- HLA-DR10 -- Lym-1 -- computational docking -- targeted prodrug; Drug delivery systems -- Periodicals; Drug Delivery Systems; Vehicles; Drug Administration Routes; Drug Evaluation; 615.7
• DOI: 10.1080/1061186X.2020.1787418
• Languages: English
• ISSNs: 1061-186X

Abstract

Abstract: Selective high-affinity ligands (SHALs) belong to a novel class of small-molecule cancer therapeutics that function as targeted prodrugs. SH7139, the most advanced of the SHAL drugs designed to bind to a unique β-subunit structural epitope located on HLA-DR10, has exhibited exceptional preclinical efficacy and safety profiles. A comparison of SH7139 and SH7129, a biotin derivative of the drug developed for use as a diagnostic, showed the incorporation of a biotin tag did not alter the SHALs ability to target or kill HLA-DR10 expressing Raji cells. The use of SH7129 in an immuno-histochemical type assay to stain peripheral blood mononuclear cells (PBMCs) obtained from individuals expressing specific HLA-DRB1 alleles has also revealed that in addition to HLA-DR10, seven other more commonly expressed HLA-DRs are targeted by the drug. Computational dockings of the SHAL's recognition ligands to a number of HLA-DR structures explain, in part, why the targeting domains of SH7129 and SH7139 bind to some HLA-DRs but not others. The results also substantiate the selectivity of SH7129 and suggest it may prove useful as a companion diagnostic for pre-screening biopsy samples to identify those patients whose tumours should respond to SH7139 therapy.