title: Selective high-affinity ligand antibody mimics for cancer diagnosis and therapy: initial application to lymphoma/leukemia.
abstract: OBJECTIVE
  More than two decades of research and clinical trials have shown radioimmunotherapy to be a promising approach for treating various forms of cancer. Lym-1 antibody, which binds selectively to HLA-DR10 on malignant B-cell lymphocytes, has proved to be effective in delivering radionuclides to non-Hodgkin's lymphoma and leukemia. Using a new approach to create small synthetic molecules that mimic the targeting properties of the Lym-1 antibody, a prototype, selective high-affinity ligand (SHAL), has been developed to bind to a unique region located within the Lym-1 epitope on HLA-DR10.
  
  
  METHODS
  Computer docking methods were used to predict two sets of small molecules that bind to neighboring cavities on the beta subunit of HLA-DR10 surrounding a critical amino acid in the epitope, and the ligands were confirmed to bind to the protein by nuclear magnetic resonance spectroscopy. Pairs of these molecules were then chemically linked together to produce a series of bidentate and bisbidentate SHALs.
  
  
  RESULTS
  These SHALs bind with nanomolar to picomolar K(d)'s only to cell lines expressing HLA-DR10. Analyses of biopsy sections obtained from patients also confirmed that SHAL bound to both small and large cell non-Hodgkin's lymphomas mimicking the selectivity of Lym-1.
  
  
  CONCLUSIONS
  These results show that synthetic molecules less than 1/50th the mass of an antibody can be designed to exhibit strong binding to subtle structural features on cell surface proteins similar to those recognized by antibodies. This approach offers great potential for developing small molecule therapeutics that target other types of cancer and disease.
authors: Chemistry, Materials and Life Sciences and Computations, Lawrence Livermore National Laboratory, Livermore, California, 94550, USA. balhorn2@llnl.gov
authors: Rod
authors: R
authors: Balhorn
authors: Saphon
authors: S
authors: Hok
authors: Patricia A
authors: PA
authors: Burke
authors: Felice C
authors: FC
authors: Lightstone
authors: Monique
authors: M
authors: Cosman
authors: Adam
authors: A
authors: Zemla
authors: Gary
authors: G
authors: Mirick
authors: Julie
authors: J
authors: Perkins
authors: Arutselvan
authors: A
authors: Natarajan
authors: Michele
authors: M
authors: Corzett
authors: Sally J
authors: SJ
authors: DeNardo
authors: Huguette
authors: H
authors: Albrecht
authors: Jeff P
authors: JP
authors: Gregg
authors: Gerry L
authors: GL
authors: DeNardo
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006684:HLA-DR Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D059810:HLA-DR Serological Subtypes; D006801:Humans; D008024:Ligands; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008958:Models, Molecular; D019809:Streptavidin / Q000378:metabolism
chemical_list: 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