Nanomolecular HLA-DR10 Antibody Mimics: A Potent System for Molecular Targeted Therapy and Imaging

Abstract

To mimic the molecular specificity and cell selectivity of monoclonal antibody (mAb) (1,4,7,10- tetraazacyclododecane-N,NЈ,NЉ,Nٞ-tetraacetic acid), using a solid-phase lysine-polyethyleneglycol backbone to link sets of ligands shown previously to bind to HLA-DR10. Using cell-binding and death assays and confocal microscopy, SHAL uptake, residualization, and cytocidal activity were evaluated in HLA-DR10 expressing and nonexpressing live, human lymphoma cell lines. All of the SHALs tested were selective for, and accumulated in, expressing cells. Reflecting binding to HLA-DR10 inside the cells, SHALs having the Ct ligand (3-(2-([3-chloro-5-trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid) residualized in expressing cells

Therapeutic applications of the selective high affinity ligand drug SH7139 extend beyond non-Hodgkin’s lymphoma to many other types of solid cancers

“…SH7129 staining of biopsy tissues containing cells expressing HLA-DR show binding to HLA-DR proteins located on the surface of the tumor cells, in the cytoplasm, and near the nucleus where the endoplasmic reticulum is located in agreement with previously reported results in cultured Burkitt lymphoma (Raji) cells [51,175]. Connective tissue is not stained.…”

“…In an effort to create small molecule targeting agents for use in cancer therapy that exhibit the same avidity and selectivity of antibodies but lack human antibody-mouse antibody (HAMA) responses and other antibody induced adverse effects [41][42][43][44][45][46][47][48][49][50], a series of selective high affinity ligands (SHALs) were developed to target the HLA-DR10 epitope recognized by Lym-1. This work led to the development of the family of tridentate SHALs, which include SH7139 and SH7129, that are the first of a new class of NHL small molecule drug and diagnostic candidates that target tumor cells expressing HLA-DR [51,52].…”

“…During the course of this testing a biotinylated analog of SH7139, SH7129, was developed for use as a potential companion diagnostic to identify NHL patients whose tumors express the HLA-DRs targeted by the drug. Previous analyses of SH7129 binding to a small number of B-cell derived lymphoma cell lines [ 51 ] and human [ 53 ] and canine [ 54 ] tumor biopsy samples have shown the diagnostic selectively binds to lymphoma cells expressing certain HLA-DRs or their canine DLA-DR orthologs. The specific HLA-DRs SH7129 target include HLA-DR7, HLA-DR9, HLA-DR10, HLA-DR11, HLA-DR12, HLA-DR13, HLA-DR15, and HLA-DR16 [ 53 ].…”

Update:Systemic Radiotherapy Can Cure Lymphoma: A Paradigm for Other Malignancies?

“…7). 81 Although the SHALs differed with respect to the number and nature of ligands, polyethylene glycol monomers, and lysines, all SHALs were neutral, readily diffused into cells, and bound selectively to HLA-DR10 protein and expressing cells. Histochemical analyses of NHL tissues showed that the SHALs bind to lymphoma from patients.…”

“…9 and 10). 81 Readily conjugated to a radionuclide, SHALs also serve as carriers for selective cell level radiation.…”