Synthesis and radiolabeling of selective high-affinity ligands designed to target non-Hodgkin's lymphoma and leukemia.
Selective high-affinity ligands (SHALs) were synthesized as molecular targeting agents for HLA-DR10, a cell surface receptor upregulated on malignant B-cell lymphocytes in non-Hodgkin's lymphoma and leukemia. SHALs are designed to mimic the affinity and selectivity of Lym-1, an antibody that binds to the beta-subunit of HLA-DR10. To bind selectively to HLA-DR10, SHALs were constructed to bind to two adjacent pockets on the surface of the beta-subunit of HLA-DR10 located within an epitope recognized by the Lym-1 antibody. A series of multivalent SHALs with molecular masses of 1500-3000 Da were synthesized using solid/polymer-supported synthesis on chlorotrityl chloride resin in 50-80% yield. To enable their use as radionuclide carriers in mouse studies, SHALs were conjugated to DOTA in a solution-phase reaction with 70-100% yield. 57Co/CoCl2 titrations revealed that 50-60% of the DOTA in the DOTA-conjugated SHALs was available for radiometal chelation. These DOTA-SHALs were labeled with 111In and used to carry out pharmacokinetic studies in mice. Radiolabeling reactions of DOTA-SHALs, with exactly one DOTA entity per targeting SHAL molecule, yielded products with greater than 90% radiochemical purity and specific activities ranging from 97 to 150 muCi/mug.
Hok
Saphon
S
Chemistry, Materials and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, California 94551, USA.
Natarajan
Arutselvan
A
Balhorn
Rod
R
DeNardo
Sally J
SJ
DeNardo
Gerald L
GL
Perkins
Julie
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D058846:Antibodies, Monoclonal, Murine-Derived; D001402:B-Lymphocytes / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D059810:HLA-DR Serological Subtypes; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry*; D007938:Leukemia / Q000276:immunology*; D008024:Ligands; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology*; D051379:Mice
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C421823:HLA-DR10 antigen; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D008024:Ligands; C410509:Lym-1 monoclonal antibody; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid