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