A novel strategy to reduce the immunogenicity of biological therapies.
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.
Department of Medicine, University of Auckland, Auckland, New Zealand.
Jennifer
J
Somerfield
Grant A
GA
Hill-Cawthorne
Andrew
A
Lin
Michael S
MS
Zandi
Claire
C
McCarthy
Joanne L
JL
Jones
Michael
M
Willcox
David
D
Shaw
Sara A J
SA
Thompson
Alastair S
AS
Compston
Geoff
G
Hale
Herman
H
Waldmann
Alasdair J
AJ
Coles
D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis / Q000097:blood; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D008279:Magnetic Resonance Imaging; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy*; D010865:Pilot Projects; D017354:Point Mutation / Q000235:genetics / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D055815:Young Adult
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000074323:Alemtuzumab