Redirecting circulating antibodies via ligand-hapten conjugates eliminates target cells in vivo.
The elimination of cell populations in vivo often relies on reagents that are self-limiting, are difficult to design and produce or contain highly toxic components. Here we describe a novel immunotherapy using molecules that combine a cell-specific ligand and a hapten binding to preexisting antibodies in serum. The F(ab')2 fragment of a polyclonal anti-thymocyte globulin (ATG) preparation was used as a T-cell-specific ligand, and fluorescein isothiocyanate (FITC), as the hapten. Clearance of ligand-hapten conjugates from the circulation through formation of immune complexes was prevented through controlled synthesis of conjugates so that they contained one F(ab')2 fragment and one FITC molecule. Administration of a single dose of F(ab')2 or F(ab')2ATG-FITC into naive mice had no effect on the number of circulating T cells. In contrast, injection of F(ab')2ATG-FITC into mice with circulating anti-FITC antibodies resulted in the elimination of peripheral T cells. The reduction in cell numbers was equivalent to that obtained with a corresponding dose of intact ATG. Experiments in thymectomized mice demonstrated that the reduction of circulating T cells was due to target-cell elimination and not to immunomodulation or cellular sequestration. The adaptability of the model to other sources of effector antibodies and more useful ligands is discussed.
Lussow
A R
AR
SangStat Medical Corporation, Menlo Park, CA 94025, USA.
Buelow
R
R
Fanget
L
L
Peretto
S
S
Gao
L
L
Pouletty
P
P
D000818:Animals; D000906:Antibodies / Q000097:blood*; D000918:Antibody Specificity / Q000187:drug effects* / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D003165:Complement System Proteins / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000276:immunology; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology*; D006241:Haptens / Q000378:metabolism* / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D008024:Ligands; D012515:Mast-Cell Sarcoma; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000936:Antigen-Antibody Complex; D000961:Antilymphocyte Serum; D006241:Haptens; D008024:Ligands; D003165:Complement System Proteins; D016650:Fluorescein-5-isothiocyanate