Bispecific-antibody-mediated targeting of radiolabeled bivalent haptens: theoretical, experimental and clinical results.
Chemically conjugated bispecific (anti-cell surface antigen, anti-hapten) Fab'-Fab antibodies (Bs-MAbs) have been used to target 125I-, 111In- and 99mTc-labeled haptens to cell sub-sets. In vitro, bivalent haptens were found to bind more strongly than their monovalent analogs to the Bs-MAbs bound to ("ordered" on) the cell surface, or than to free ("disordered") Bs-MAbs: they are selective for cell-bound Bs-MAbs. In tumor-grafted nude mice models, the sequential injections of microgram amounts of Bs-MAb, and 1 day later, of microC amounts of bivalent haptens permits to sharply delineate small tumors (using a gamma camera), hours after injection. Further, the isotope biodistribution was found to be at least 3 times more selective for the tumor than that obtained with directly labeled anti-CEA F(ab)'2 or with monovalent haptens. This better in vivo selectivity of the 2-step targeting of bivalent haptens was also demonstrated in a pharmacokinetic study using therapeutic amounts of reagents. In primary-colon-carcinoma patients, a similar comparative immunoscintigraphy study confirmed the better selectivity of bivalent hapten targeting over direct targeting, on the basis of image quality and ex vivo tissue counting. In patients with medullary carcinoma of the thyroid, bivalent hapten targeting allowed us to confirm tumor extension and to find occult lesions. Interestingly, radio-immunoguided surgery was necessary to resect these small lesions. These experimental results, together with technological and theoretical considerations, suggest that Bs-MAb-mediated targeting of isotopes (or other agents) is one of the major ways to increase the clinical performance of MAb-based targeting diagnostic and therapeutic tools.
Le Doussal
J M
JM
Immunotech SA., Luminy, Marseille, France.
Barbet
J
J
Delaage
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D000915:Antibody Affinity; D000918:Antibody Specificity; D002460:Cell Line; D006241:Haptens; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use; D008545:Melanoma / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy / Q000379:methods; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D006241:Haptens; D007205:Indium Radioisotopes