Multivalent poly(ethylene glycol)-containing conjugates for in vivo antibody suppression.
Poly(ethylene glycol) (PEG) was incorporated into multivalent conjugates of the N-terminal domain of beta(2)GPI (domain 1). PEG was incorporated to reduce the rate of elimination of the conjugates from plasma and to putatively improve their efficacy as toleragens for the suppression of anti-beta(2)GPI antibodies and the treatment of antiphospholipid syndrome (APS). Three structurally distinct types of multivalent platforms were constructed by incorporating PEG into the platform structures in different ways. The amount of PEG incorporated ranged from about 5000 g per mole to about 30000 g per mole. The platforms were functionalized with either four or eight aminooxy groups. The conjugates were prepared by forming oxime linkages between the aminooxy groups and N-terminally glyoxylated domain 1 polypeptide. The plasma half-life of each conjugate, labeled with (125)I, was measured in both mice and rats. The half-lives of the conjugates ranged from less than 10 min to about 1 h in mice, and from less than 3 h to about 19 h in rats. The ability of five tetravalent conjugates to suppress anti-domain 1 antibodies in immunized rats was also measured. Incorporation of PEG in the conjugates significantly reduced the doses required for suppression, and the amount of reduction correlated with the amount of PEG incorporated.
Jones
David S
DS
La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, California 92121, USA. dave.jones@ljpc.com
Branks
Michael J
MJ
Campbell
Mary-Ann
MA
Cockerill
Keith A
KA
Hammaker
Jeffrey R
JR
Kessler
Christina A
CA
Smith
Eric M
EM
Tao
Anping
A
Ton-Nu
Huong-Thu
HT
Xu
Tong
T
D000818:Animals; D000917:Antibody Formation; D001323:Autoantibodies / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D007108:Immune Tolerance; D018796:Immunoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007205:Indium Radioisotopes; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053482:beta 2-Glycoprotein I
D001323:Autoantibodies; D006023:Glycoproteins; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D053482:beta 2-Glycoprotein I; D011092:Polyethylene Glycols