Optimizing therapeutic strategies to inhibit circulating soluble   target molecules with monoclonal antibodies: example of the   soluble IL-6 receptors.
Therapeutic targeting of soluble molecules such as cytokines can be achieved with monoclonal antibodies (mAb). Anti-IL-6 mAb have been shown to form circulating complexes, resulting in the increase of the half-life of the cytokine in vivo. In IL-6-related diseases, the soluble human IL-6 receptors (shIL-6R), which have been shown to possess strong agonist activity, circulate in the plasma at a high concentration and must be neutralized. Their clearance was studied in mice that had been made to express circulating shIL-6R after i.p. grafting of mouse thymoma cells transfected with a gene coding for shIL-6R, treated with various anti-shIL-6R mAb recognizing different epitopes of the molecule. Injection of one anti-hIL-6R mAb stabilized the short-lived hIL-6R and led to their accumulation. The same result was observed when two mAb directed against two different epitopes of the hIL-6R were used. Clearance of the receptors was only achieved when three mAb specific for three different epitopes were injected. A permanent clearing of the hIL-6R could be obtained by repeated injections of the clearing mixture. No correlation was found between the ability of the mAb to clear the sIL-6R and to immunoprecipitate them in agarose gel. The F(ab')2 fragments lost the clearing ability of the intact mAb. These results clearly show that therapeutic clearance of sIL-6R by mAb need at least three mAb directed against three different epitopes of the molecule, a conclusion which is likely to apply for clearing any soluble target molecule.
Brochier
J
J
INSERM U475, F-34197 MontpellierCedex 05, France. brochier@montp.inserm.fr
Liautard
J
J
Jacquet
C
C
Gaillard
J P
JP
Klein
B
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000097:blood; D013945:Thymoma / Q000097:blood / Q000628:therapy*
D000911:Antibodies, Monoclonal; D019947:Receptors, Interleukin-6