Targeting of antihapten antibodies to activated T cells via an IL-2-hapten conjugate prolongs cardiac graft survival.
Antihapten antibodies binding to ligand-hapten conjugates are able to mediate complement mediated lysis in vitro. Based on this observation we propose a new in vivo immunotherapy using molecules that combine a low molecular weight hapten binding to antibodies preexisting in serum and a cell specific ligand. The ligand-hapten conjugates are potential cytotoxic drugs which may (1) be specific for a given target cell, (2) be nonimmunogenic, (3) be of low molecular weight, (4) form soluble complexes with preexisting antibodies resulting in prolonged half life of the drug, and (5) induce a potent antibody mediated rejection of target cells. These novel compounds could be useful for the elimination of certain cell subsets involved in allograft rejection, cancers, infectious diseases, etc., without some of the pitfalls of conventional immunotherapies. The feasibility of this approach was demonstrated in an animal model using a compound consisting of one interleukin 2 and one fluorescein molecule (IL-2-FITC). BALB/c mice (H2d) previously immunized and expressing anti-FITC antibodies were transplanted with a fully mismatched C57BL/6 (H2b) heterotopic heart allograft. Untreated controls rejected their graft by day 9 (MSD = 9 +/- 0.7). Mice with preexisting anti-FITC antibodies treated with IL-2-FITC maintained their grafts for 38.7 +/- 7.1 days (P < 0.02). No prolongation of graft survival was observed in immunized animals that were treated with IL-2 alone (MSD = 10 +/- 1.4). Nonimmunized animals treated with IL-2-FITC rejected their grafts on day 9.4 +/- 1.1. This demonstrates that IL-2-FITC therapy specifically prolonged graft survival in animals with circulating anti-FITC antibodies. The data suggest that a ligand/hapten pair can redirect preexisting antihapten antibodies toward target cells in vivo. Such compounds may be developed for human use as alternatives to polyclonal or monoclonal antibody therapy.
Lussow
A R
AR
SangStat Medical Corporation, Menlo Park, California 94025, USA.
Fanget
L
L
Gao
L
L
Block
M
M
Buelow
R
R
Pouletty
P
P
D000818:Animals; D000906:Antibodies; D000911:Antibodies, Monoclonal / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006085:Graft Survival / Q000276:immunology; D006241:Haptens / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D000906:Antibodies; D000911:Antibodies, Monoclonal; D005456:Fluorescent Dyes; D006241:Haptens; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D016650:Fluorescein-5-isothiocyanate