The small molecule antibody mimic SH7139 targets a family of HLA-DRs expressed by B-cell lymphomas and other solid cancers

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.

Keywords:

• SH7139
• SH7129
• selective high-affinity ligand (SHAL)
• small molecule ADC mimic
• HLA-DR
• HLA-DR10
• Lym-1
• computational docking
• targeted prodrug

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Disclosure statement

R. Balhorn and M. Cosman Balhorn are co-founders and employees of SHAL Technologies Inc. K. Balakrishnan and R. Rebhun report no conflict of interest.

Notes

1 SwissDock is a free access internet docking program supported by the FNS project grant #310030_130857 and the Swiss Institute of Bioinformatics.

Additional information

Funding

This research was supported by the National Cancer Institute Phase II SBIR Award [R44CA159844].