Reduction of established antibody responses against botulinum neurotoxin A by synthetic monomethoxypolyethylene glycol peptide conjugates.
In cervical dystonia, injection of botulinum neurotoxin (BoNT) A or B into affected neck muscle reduces symptoms but may elicit anti-toxin antibodies (Abs) that block responsiveness to treatment. Previously, we localized the BoNT/A and BoNT/B sites that bind mouse or human blocking Abs. We also reported that site-specific auto-Abs can be suppressed by a monomethoxypolyethylene glycol (mPEG)-epitope conjugate. So we elicited here anti-toxin Abs in outbred mice by immunization with sublethal-suboptimal doses of active BoNT/A and determined the efficacy of selected mPEG-epitopes in reducing established anti-BoNT/A Abs. We tested in outbred mice four synthetic mPEG-N(α)-epitopes [N8 (residues 547-565), N25 (785-803), C15 (1051-1069), C31 (1275-1296)] of BoNT/A in tolerance against ongoing anti-toxin Abs. After short immunizations, tolerization with an mPEG-peptide reduced Abs to correlate peptide and caused varying Ab reductions to the other 3 peptides. Anti-N8 Abs were unaffected by mPEG-N25 tolerization, but mPEG-N8 and mPEG-N25 caused drop in anti-BoNT/A Abs. After long immunization with BoNT/A, tolerization with mPEG-N8 lessened anti-N8 Abs. Anti-C15 Abs decreased by tolerization with mPEG-C15 or any other mPEG-peptide. Anti-N25 Abs were not altered by mPEG-N25, but decreased after tolerization with mPEG-C15. Anti-C31 Abs disappeared on day 474 by tolerization with mPEG-C31 or mPEG-N8, mPEG-N25 or mPEG-C15. When an Ab response returns, a decrease can be re-established by re-administering the correlate mPEG-peptide. The method may be beneficial for extending BoNT treatment in immunoresistant patients.
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, United States; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, United States. Electronic address: matassi@bcm.edu.
M Zouhair
MZ
Atassi
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, United States.
Masooma
M
Naqvi
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, United States.
Behzod Z
BZ
Dolimbek
The Neurotoxin Research Program, Department of Biological Sciences, Allergan, Inc., Irvine, CA 92612, United States.
K Roger
KR
Aoki
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000917:Antibody Formation; D019274:Botulinum Toxins, Type A / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011863:Radioimmunoassay; D013574:Synaptosomes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
D000906:Antibodies; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D019274:Botulinum Toxins, Type A
Antibodies; Botulinum neurotoxin A; Monomethoxypolyethylene glycol; Mouse protection assay; Synaptosome binding; Synthetic peptides; Tolerization