Chemistry: analytical and immunological testing – Biospecific ligand binding assay
Reexamination Certificate
2000-11-06
2003-08-26
Wang, Andrew (Department: 1639)
Chemistry: analytical and immunological testing
Biospecific ligand binding assay
C435S007100, C435S091500, C435S091500, C435S091500, C424S009100, C424S009200, C424S009300, C424S009400, C424S009520
Reexamination Certificate
active
06610547
ABSTRACT:
This is invention relates to a method of identifying candidate contrast agents (“contrast agent drug candidates”) using combinatorial libraries of compounds or molecular aggregates.
Traditionally, drug discovery has involved the manufacture and testing of individual compounds, often as a result of an initial fortuitous finding of efficacy for a naturally occurring compound and the subsequent synthesis of structurally similar compounds. Recently however an alternative approach to drug discovery has developed in which a large range of compounds of random or directed random structure are synthesised and tested for efficacy. In such “combinatorial” libraries, the library members may either be separate or be present in admixture. The present invention is concerned with the latter case.
Such admixture libraries may readily be tested for efficacy in vitro—however if the desired drug effect is found, drug candidate identification requires deconvolution, the identification of which member or members of the library have the desired effect. Several deconvolution techniques have been developed and particular mention here may be made of biological tagging and orthogonal scanning. In biological tagging, the individual library members carry a unique biological tag that can be amplified, e.g. an oligonucleotide sequence or a virus, so enabling the “successful” library member, once isolated from the unsuccessful members, to be identified. In orthogonal scanning, numbers of sub-libraries are screened in order to identify the “successful” library members.
Screening of combinatorial libraries containing the library members in admixture is generally done on an in vitro basis with in vivo testing being left until potential drug candidates have been identified and then being performed using individual drug candidates, much as in conventional drug discovery.
In vitro screening however is of limited applicability since it requires a sample of the target tissue or a culture of target cells to be used and thus it does not allow one to determine whether or not the “successful” library members associate specifically with the target and it does not allow one to determine targeting ability for unknown targets.
It is possible to screen mixed combinatorial libraries in vivo where the library members carry a biological, amplifiable tag. The “successful” library members may then be identified by excision of tissue from the desired target site, amplification and identification. Again however this has drawbacks since the removal of tissue from the animal, and often the sacrifice of the animal, is required and thus this technique is generally suitable only for small laboratory animals such as mice, guinea pigs and rats. Accordingly, it does not generally allow one to determine targeting ability and specificity for unknown targets in larger, e.g. more human-like, animals.
These drawbacks however can be overcome by in vivo screening of a mixed combinatorial library in which the library members incorporate reporters which are detectable and interdistinguishable in vivo.
Thus viewed from one aspect the invention provides a method of contrast agent drug candidate selection which involves:
(i) obtaining a combinatorial library comprising an admixture of potential contrast agent drug candidates each incorporating a reporter moiety which is detectable in the animate human or non-human animal body (e.g. mammalian, avian or reptilian body), said library comprising a plurality of said reporter moieties which are interdistinguishably detectable in said body,
(ii) administering said library to an animate human or non-human animal body,
(iii) identifying in vivo one or more of said reporter moieties having a desired distribution and/or elimination pattern (e.g. which distributes to a particular site in said body) and thereby identifying a member of said library which has said pattern (e.g. which distributes to said site) or a sub-set of said library which contains a member of said library which has said pattern (e.g. which distributes to said site).
For the candidate contrast agents to be deemed “successful”, ie. to progress to a further stage of development, they must possess a desired pattern of biodistribution and bioelimination following administration. This may be referred to by the acronym “ADME” standing for administration, distribution, (metabolism) and excretion. The method of the present invention serves to identify members of the combinatorial library or subsets within the combinatorial library that have an ADME pattern which meets the selection criteria set down for contrast agent candidate identification.
The library members in the combinatorial library used according to the invention incorporate a reporter moiety which is detectable in an animate body. By this it is meant that the reporter should be such as to allow its detection without requiring removal (ie. separation) from the body of a sample of a body site of interest and so also without requiring the animal to be sacrificed. Examples of reporter moieties detectable directly in this fashion include chromophores, heavy atoms, radiolabels and magnetic particles, ie. moieties such as are commonly used for image contrast enhancement in diagnostic imaging modalities such as light imaging, X-ray imaging, magnetic resonance imaging, ultrasound imaging and nuclear imaging.
However it is central to the invention that the library should contain a plurality of interdistinguishable reporters, ie. reporters which can not only be detected in the animate body but which can be distinguished from each other in such detection. Particularly desirably, each different library member has a different reporter so that detection of a reporter identifies the library member it forms part of. In this case the number of different reporters is equal to the number of different library members. However in practice it will often be preferable to have a smaller number of different reporters than different library members so that detection of a reporter identifies a sub-set of the library members that include that particular reporter. In this case, with the sub-set identified, orthogonal scanning techniques can be used to identify the “successful” members of the initial library. Conventional deconvolution techniques may be used in this regard. Thus for example a series of libraries may be scanned in which the reporters used to tag the library members are varied with the successful members being identified by a unique combination of reporters detected in the series of scans. Alternatively a sub-library may be prepared using the members of the initially identified library sub-set but labelling these with a plurality of different reporters. A second scan can then be used to identify either the successful library member or a smaller sub-set containing it (in which latter case the procedure is repeated to identify the successful library member).
The interdistinguishability of the reporters may be achieved in a variety of ways. Thus for example reporters may be used which are detectable by different imaging techniques (in which case screening will involve imaging the body or a site of interest therein using two or more imaging techniques) or alternatively or additionally reporters may be used which are interdistinguishable in one imaging technique. In this regard, particular mention may be made of radiolabels which emit detectable radiation of different types or energies detectable by multichannel gamma counters, of chromophores with different characteristic absorption or emission maxima, of tags with different detectable radiofrequencies (see for example Nicolaou et al. Angew. Chem. Int. Ed. Engl. 34: 2289-2291 (1995)), of tags with different magnetic moments (preferably using different monosized crystals, optionally differentiating with SQUID magnetometers, or Mössbauer or other spectroscopie techniques), of tags with different paramagnetic centres (e.g. differentiating using epr), or tags with differently sized or membraned gas containing microballoons. In a further embodiment of the invention
Cockbain Julian
Dugstad Harald
Klaveness Jo
Amersham Health AS
Bacon & Thomas
Friend Tomas
Wang Andrew
LandOfFree
Selection of contrast agent drug from a combinatorial library does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Selection of contrast agent drug from a combinatorial library, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Selection of contrast agent drug from a combinatorial library will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3124388