Selective high-affinity ligand antibody mimics for cancer diagnosis and therapy: initial application to lymphoma/leukemia.
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.
Balhorn
Rod
R
Chemistry, Materials and Life Sciences and Computations, Lawrence Livermore National Laboratory, Livermore, California, 94550, USA. balhorn2@llnl.gov
Hok
Saphon
S
Burke
Patricia A
PA
Lightstone
Felice C
FC
Cosman
Monique
M
Zemla
Adam
A
Mirick
Gary
G
Perkins
Julie
J
Natarajan
Arutselvan
A
Corzett
Michele
M
DeNardo
Sally J
SJ
Albrecht
Huguette
H
Gregg
Jeff P
JP
DeNardo
Gerry L
GL
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
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