A phase I trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis.
OBJECTIVE
To assess the safety, tolerability, and biologic and clinical activity of a solubilized complex comprised of human leukocyte antigen-DR2 with myelin basic protein84-102 (AG284)in patients with secondary progressive MS.


BACKGROUND
Soluble species-specific major histocompatibility complex myelin basic protein91-103 complexes ameliorate disease in a dose-dependent manner when administered to SJL/J mice with chronic relapsing experimental allergic encephalomyelitis. Preincubation with AG284 reduces the proliferative response of a DR2-restricted, myelin basic protein84-102-reactive T cell clone, derived from a MS patient, to myelin basic protein84-102 in the presence of autologous antigen-presenting cells.


METHODS
Thirty-three patients with secondary progressive MS were randomly assigned to receive three alternate day IV doses of AG284 or placebo in a double-masked dose escalation study. The primary outcome was safety and tolerability. Secondary outcomes included a comparison of pre- and post-treatment gadolinium-enhanced brain MRI activity, Kurtzke Expanded Disability Status Scale, and Nine Hole Peg Test scores.


RESULTS
The frequency of adverse events was similar in the AG284 and placebo recipients. No significant treatment effect was detected by Expanded Disability Status Scale, Nine Hole Peg Test, or number of new gadolinium-enhancing MRI lesions.


CONCLUSIONS
AG284 as administered during this study was safe and well tolerated. Further studies are warranted to determine the biologic activity and clinical efficacy of this potential treatment for MS.
Goodkin
D E
DE
University of California at San Francisco/Mt. Zion Multiple Sclerosis Center, CA 94115-1610, USA.
Shulman
M
M
Winkelhake
J
J
Waubant
E
E
Andersson
P
P
Stewart
T
T
Nelson
S
S
Fischbein
N
N
Coyle
P K
PK
Frohman
E
E
Jacobs
L
L
Holcenberg
J
J
Lee
M
M
Mocci
S
S
D000328:Adult; D001323:Autoantibodies / Q000097:blood; D001921:Brain / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D015802:HLA-DR2 Antigen / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D004676:Myelin Basic Protein / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D018074:Vaccines, Conjugate / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*
D001323:Autoantibodies; D006680:HLA Antigens; D015802:HLA-DR2 Antigen; C571326:MOG protein, human; C571327:Mog protein, mouse; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D018074:Vaccines, Conjugate; C407155:myelin basic protein 84-102; D007371:Interferon-gamma