CD206-Targeted Liposomal Myelin Basic Protein Peptides in Patients with Multiple Sclerosis Resistant to First-Line Disease-Modifying Therapies: A First-in-Human, Proof-of-Concept Dose-Escalation Study.
Previously, we showed that CD206-targeted liposomal delivery of co-encapsulated immunodominant myelin basic protein (MBP) sequences MBP46-62, MBP124-139and MBP147-170(Xemys) suppressed experimental autoimmune encephalomyelitis in dark Agouti rats. The objective of this study was to assess the safety of Xemys in the treatment of patients with relapsing-remitting multiple sclerosis (MS) and secondary progressive MS, who failed to achieve a sustained response to first-line disease-modifying therapies. In this phase I, open-label, dose-escalating, proof-of-concept study, 20 patients with relapsing-remitting or secondary progressive MS received weekly subcutaneously injections with ascending doses of Xemys up to a total dose of 2.675 mg. Clinical examinations, including Expanded Disability Status Scale score, magnetic resonance imaging results, and serum cytokine concentrations, were assessed before the first injection and for up to 17 weeks after the final injection. Xemys was safe and well tolerated when administered for 6 weeks to a maximum single dose of 900 μg. Expanded Disability Status Scale scores and numbers of T2-weighted and new gadolinium-enhancing lesions on magnetic resonance imaging were statistically unchanged at study exit compared with baseline; nonetheless, the increase of number of active gadolinium-enhancing lesions on weeks 7 and 10 in comparison with baseline was statistically significant. During treatment, the serum concentrations of the cytokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and interleukin-7 decreased, whereas the level of tumor necrosis factor-α increased. These results provide evidence for the further development of Xemys as an antigen-specific, disease-modifying therapy for patients with MS.
M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.|Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan, Russia.|Institute of Gene Biology RAS, Moscow, Russia.
Alexey
A
Belogurov
OJSC Pharmsynthez, St. Petersburg, Russia.
Konstantin
K
Zakharov
M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.|Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan, Russia.
Yakov
Y
Lomakin
OJSC Pharmsynthez, St. Petersburg, Russia.
Kirill
K
Surkov
OJSC Pharmsynthez, St. Petersburg, Russia.
Sergey
S
Avtushenko
OJSC Pharmsynthez, St. Petersburg, Russia.
Peter
P
Kruglyakov
M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.|Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan, Russia.
Ivan
I
Smirnov
Center of multiple sclerosis and AID of St. Petersburg City Clinical Hospital #31, St. Petersburg, Russia.|Pavlov First Saint-Petersburg State Medical University, St. Petersburg, Russia.
Gleb
G
Makshakov
Xenetic Biosciences Inc., Lexington, MA, USA.
Curtis
C
Lockshin
Xenetic Biosciences Inc., Lexington, MA, USA.
Gregory
G
Gregoriadis
OJSC Pharmsynthez, St. Petersburg, Russia.
Dmitry
D
Genkin
M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. gabibov@mx.ibch.ru.|Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan, Russia. gabibov@mx.ibch.ru.|Chemistry Department of Moscow State University, Moscow, Russia. gabibov@mx.ibch.ru.
Alexander
A
Gabibov
Center of multiple sclerosis and AID of St. Petersburg City Clinical Hospital #31, St. Petersburg, Russia.|Pavlov First Saint-Petersburg State Medical University, St. Petersburg, Russia.|SBI "Center of Clinical Trials Management and Performance of Moscow Department of Healthcare", Moscow, Russia.
Evgeniy
E
Evdoshenko
D000328:Adult; D015703:Antigens, CD / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use*; D010743:Phospholipids / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D055815:Young Adult
D015703:Antigens, CD; C121916:CD207 protein, human; D016207:Cytokines; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010743:Phospholipids; C050797:liposom
Clinical trial; Liposomes; MRI; Mannose; Myelin basic protein; Xemys