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

Rod Balhorn, Monique Cosman Balhorn, Karuppiah Balakrishnan, Robert B. Rebhun

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalJournal of Drug Targeting
DOIs
StatePublished - 2020

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science

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