Radiolocalization of human small cell lung cancer and antigen-positive normal tissues using monoclonal antibody LS2D617.
The murine monoclonal antibody LS2D617, which reacts with an antigen associated with human small cell lung carcinoma (SCLC), was tested in preclinical models to assess its potential for specific targeting of tumors in human SCLC cancer patients. LS2D617 detects a cell antigen on the surface of cultured SCLC and neuroblastoma cell lines. Scatchard analysis of the binding of LS2D617 to NCIH69 SCLC cells indicates an affinity constant of about 1 x 10(8) M-1 and an epitope expression level of approximately 2 x 10(6) antigenic sites/cell. Molecular weight analysis of the target antigen and antibody competition experiments showed that LS2D617 should be classified as a SCLC Cluster 1 antibody (i.e., reacts with the neural cell adhesion molecule). LS2D617 was labeled with 111In and tested for biodistribution (4, 24, 48, 72, and 96 h postinjection) in nude mice bearing the human SCLC NCIH69 tumor. Tumor values peaked at about 35% injected dose/g (Day 3) compared with about 8% injected dose/g for an irrelevant IgG1 antibody while normal tissue accumulation for both antibodies was about 2-8% injected dose/g. Immunohistochemical studies demonstrated that LS2D617 reacts with the central nervous system, peripheral nerves, endocrine tissues, and heart tissue of rabbits as it does in human tissues. The ability of LS2D617 to accumulate in vivo in normal tissues that express the specific target antigen was tested in rabbits. Rabbits given i.v. injections of 111In-LS2D617 or control labeled antibody were sacrificed at 48 h and tissues were examined by gamma well counting, autoradiography, and immunohistochemical staining for murine immunoglobulin. Specific uptake was seen in all sites defined as antigen positive by immunohistology (i.e., heart, liver bile duct, peripheral nerves, pituitary, adrenal), excepting the central nervous system (brain and spinal cord) which was inaccessible to antibody because of the blood brain barrier. The use of preclinical in vivo targeting models to assess tumor as well as antigen-positive normal tissue targeting should aid in the strategy of antibody-based therapeutic intervention of human cancer by providing insight into the potential for tumor targeting and normal tissue toxicity that may be encountered in the clinic.
Wilson
B S
BS
Division of Therapeutics, Hybritech Inc., San Diego, California 92126.
Petrella
E
E
Lowe
S R
SR
Lien
K
K
Mackensen
D G
DG
Gridley
D S
DS
Stickney
D R
DR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000912:Antibodies, Neoplasm / Q000276:immunology; D000915:Antibody Affinity; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology*; D018288:Carcinoma, Small Cell / Q000000981:diagnostic imaging / Q000276:immunology*; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology; D006801:Humans; D007124:Immunoenzyme Techniques; D007205:Indium Radioisotopes; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D011817:Rabbits; D011877:Radionuclide Imaging
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D015816:Cell Adhesion Molecules, Neuronal; D007205:Indium Radioisotopes