Direct antilymphoma activity of novel, first-generation "antibody mimics" that bind HLA-DR10-positive non-Hodgkin's lymphoma cells.
A first-generation series of novel small molecules, collectively known as selective high-affinity ligands (SHALs), were designed and synthesized to mimic the binding of Lym-1, a monoclonal antibody (mAb) shown to be an effective cytotoxic and radionuclide carrier molecule for targeting non-Hodgkin's lymphoma (NHL). Created as radionuclide targeting molecules, these SHALs were intended to have the human leukocyte antigen-DR (HLA-DR) selectivity of Lym-1 mAb and the pharmacokinetics of a small molecule. Because of the remarkable bioactivity of Lym-1 in vitro, the direct antilymphoma activity of three of these SHALs was tested. Two of these SHALs were bidentate and consisted of two ligands connected to the carboxyl and amino groups of lysine and polyethylene glycol (PEG); the third SHAL was a dimeric version of one of the former two SHALs linked with PEG. The three SHALs tested were: LeLPLDB, that contained one deoxycholate and one 5-leu-enkephalin as ligands; (LeacPLD)2LPB, a bis version of LeLPLDB intended to improve "functional affinity"; and ItPLDB, that contained the ligands, deoxycholate and triiodothyronine. Micromolar concentrations of all three SHALs showed binding to Raji, an HLA-DR10-positive human malignant B-cell line but no binding to CEM or Jurkat's, HLA-DR10-negative malignant T-cell lines. Additionally, the Raji cell membrane distributions of all three SHALs and of Lym-1 were remarkably similar. Unlike Lym-1, which causes substantial growth inhibition and cell death in NHL cell lines, these SHALs had no direct antilymphoma activity. In summary, three first-generation SHALs lacked direct antilymphoma activity, although they had selective NHL B-cell binding like Lym-1 mAb. Because of their small size, these SHALs have potential as radionuclide carrier substitutes for Lym-1 mAb to target the HLA-DR10 NHL-related cell-surface protein.
West
Jeremy
J
Department of Internal Medicine and Radiology, University of California, Davis, Sacramento, CA 95816, USA.
Perkins
Julie
J
Hok
Saphon
S
Balhorn
Rodney
R
Lightstone
Felice C
FC
Cosman
Monique
M
DeNardo
Sally J
SJ
DeNardo
Gerald L
GL
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006684:HLA-DR Antigens / Q000378:metabolism*; D059810:HLA-DR Serological Subtypes; D006801:Humans; D008024:Ligands; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism* / Q000473:pathology; D019809:Streptavidin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C421823:HLA-DR10 antigen; D008024:Ligands; C410509:Lym-1 monoclonal antibody; D019809:Streptavidin