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Company Abstracts :: 2003 :: Selected
Company Abstract
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MULTIVALENT
POLY(ETHYLENE GLYCOL)-CONTAINING CONJUGATES FOR IN VIVO ANTIBODY
SUPPRESSION
Jones DS, Branks MJ, Campbell MA, Cockerill KA, Hammaker JR, Kessler
CA, Smith EM, Tao A, Ton-Nu HT, Xu T
La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego,
California 92121, USA.
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.
Published in
Bioconjugate Chemistry, 2003
Volume 14, Issue 6: 1067-1076
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