Polymer Conjugates with Decreased Antigenicity, Methods of Preparation and Uses Thereof
First Claim
1. A conjugate comprising one or more bioactive components covalently attached to at least one linear or branched polyalkylene glycol, wherein said polyalkylene glycol does not comprise an alkoxyl group at any terminus and said polyalkylene glycol is attached to a single bioactive component at a single site on the polyalkylene glycol.
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Abstract
Methods are provided for the preparation of conjugates of a variety of bioactive components, especially proteins, with water-soluble polymers (e.g., poly(ethylene glycol) and derivatives thereof), which conjugates have reduced antigenicity and immunogenicity compared to similar conjugates prepared using poly(ethylene glycol) containing a methoxyl or another alkoxyl group. The invention also provides conjugates prepared by such methods, compositions comprising such conjugates, kits containing such conjugates or compositions and methods of use of the conjugates and compositions in diagnostic and therapeutic protocols.
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Citations
100 Claims
- 1. A conjugate comprising one or more bioactive components covalently attached to at least one linear or branched polyalkylene glycol, wherein said polyalkylene glycol does not comprise an alkoxyl group at any terminus and said polyalkylene glycol is attached to a single bioactive component at a single site on the polyalkylene glycol.
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54. A method of producing a conjugate between a bioactive compound and a polyalkylene glycol activated at only one terminus (“
- a monoactivated polyalkylene glycol”
), comprising;(a) obtaining a polyalkylene glycol that does not contain any end group that is a stably linked alkoxyl group; (b) optionally, prior to the conversion of the polyalkylene glycol of step (a) to a monofunctionally activated polyalkylene glycol, protecting all except one of the end groups by the addition of one or more removable blocking groups, such as t-butoxyl group(s), aryloxyl group(s) or triphenylmethyl group(s) (“
trityl group(s)”
);(c) producing a monofunctionally activated derivative of said polyalkylene glycol by reacting said polyalkylene glycol with a derivatizing compound or compounds under conditions such that said polyalkylene glycol is derivatized with a single derivatizing group at an end that does not contain said removable blocking group or groups; (d) if a blocking group was added to protect the end group(s), as described in step (b) above, removing said blocking group, in one or more steps, without removing the activating group attached as described in step (c) above, to produce a monofunctionally activated polyalkylene glycol wherein the distal terminus or distal termini are hydroxyl groups; and (e) contacting said monofunctionally activated polyalkylene glycol with at least one bioactive component, under conditions that favor the covalent binding of said monofunctionally activated polyalkylene glycol to said bioactive component, or (f) Alternatively, performing step (e) prior to performing step (d). - View Dependent Claims (55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 96)
- a monoactivated polyalkylene glycol”
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57. A method for separating a linear monohydroxyPEG-monoaldehyde from the corresponding PEG-dialdehyde comprising:
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(a) converting all hydroxyl groups on the PEG-aldehyde to trityl derivatives; (b) separating monotritylPEG-monoaldehyde from the PEG-dialdehyde and any ditritylPEG by reversed-phase chromatography, and (c) converting the monotritylPEG-monoaldehyde to monohydroxyPEG-monoaldehyde by hydrolytic removal of the trityl group in an acidic medium. - View Dependent Claims (58)
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- 97. A PEG-liposome composition, wherein the PEG component does not comprise an alkoxyl group at any terminus and each molecule of PEG is attached to a single lipid molecule at a single site on the lipid molecule and on said molecule of PEG.
Specification