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Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting "high-zone" tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.

Original publication




Journal article


J Immunol

Publication Date





763 - 768


Adolescent, Adult, Alemtuzumab, Amino Acid Substitution, Antibodies, Anti-Idiotypic, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibodies, Neoplasm, Dose-Response Relationship, Immunologic, Drug Administration Schedule, Female, Humans, Immune Tolerance, Magnetic Resonance Imaging, Male, Multiple Sclerosis, Relapsing-Remitting, Pilot Projects, Point Mutation, Randomized Controlled Trials as Topic, Treatment Outcome, Young Adult