Branched Discreet PEG Constructs

Abstract

Disclosed are general and “substantially pure” branched discrete polyethylene glycol constructs useful in attaching to a variety of biologically active groups, for example, preferential locators, as well as biologics like enzymes, for use in diagnostics, e.g. imaging, therapeutics, theranostics, and moieties specific for other applications. In its simplest intermediate state, a branched discrete polyethylene glycol construct is terminated at one end by a chemically reactive moiety, “A”, a group that is reactive with a biologic material that creates “A”, which is a biologically reactive group, connected through to a branched core (BC) which has attached at least two dPEG-containing chains, indicated by the solid line, , having terminal groups, which can be charged, non-reactive or reactable moieties and containing between about 2 and 64 dPEG residues.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit of application Ser. No. 61 / 528,915 filed on Aug. 30, 2011, the disclosure of which is expressly incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH[0002]Not applicable.FIELD OF DISCLOSURE[0003]The present disclosure sets forth substantially pure branched discrete polyethylene glycol construct compositions (dPEG® reagents, a registered trademark of Quanta BioDesign, Ltd., Powell, Ohio) that can be attached to a large range of useful compounds, primarily of therapeutic or diagnostic significance, in order to significantly effect and control the biodistribution and pharmacokinetics of the useful compounds. Such branched dPEG reagents can be used alone or in combination with linear discrete polyethylene glycols (dPEGs). These compositions can also be made to attach “A” (biologically active groups) in multiples or in combinations in order to control the total avidity of “A.” These c...

AI Technical Summary

Benefits of technology

[0029]By designing the chemical connections through A (chemically reactable moiety) and within and their attachment within the various branched cores versatile multifunctional constructs one can control the architecture and functional multiplicity of the general branched dPEG construct, thereby allowing a variety of in vivo parameters to be designed into the final conjugate, along with the ability to detect or probe with it, and deliver a therapeutic.

Problems solved by technology

These are generally compounds that due to their small “size” and MW have to be dosed at a high frequency that is too high to be tolerated toxicologically or immunologically by the patient.

Potential customers often will not even consider purchasing PEGylation reagents that do not offer a linear 20 kD or branched 40 kD PEG construct.

However, with the benefit of the increased blood half-life, there are serious drawbacks with these polymers.

Additionally, there is no clear (or generally accepted) model as to the structure of the polymeric PEGs in solution, much less the conformational options that exist in solution.

The high molecular weight polymeric PEGs are, first of all, extraordinarily complex mixtures, containing up to hundreds of individual and inseparable components, making characterization of the products virtually impossible and as is known in the art of polymer chemistry, the key challenge is in the reproducibility of the polymer's mixture by careful process control.

Also, these large sizes most often significantly block the site of action on the compound it is modifying and the activity is commonly decreased significantly, often by as much as 10 to 100-fold.

In addition these tools could be applied to other broad sets of unexplored applications, currently inaccessible due to a lack of proper tools for modification with control.

Regardless, of the many other drawbacks of conventional polymeric PEGs being used to modify biologics, their sheer size overwhelms the precision that should be apparent from the constructs set forth herein.

Some additional drawbacks of the current art which are directly and intentionally impacted by the current invention include the following:The formation of intractable mixtures is further exacerbated when the conventional polymeric PEGs are formed into branched constructs, making their reproducible preparation impractical and exacerbates the issues already stated for a single polymer chain.The very large minimum size of the polymers currently in use, i.e., 40 kDa, to effect serum half-life also most often has seriously deleterious effects on the activity of the biologicalWith the “one size fits all” solution of the conventional PEGylation, there are few options for a fine-tuning the pharmacokinetics of biologics, as there will be with using a range of branched dPEG constructs in the context of the growing art of engineered protein and other biological scaffolds.

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