1. A polyvalent or polyspecific protein complex, comprising three or more polypeptides which associate to form three or more functional target-binding regions (TBRs), and in which each individual polypeptide comprises two or more immunoglobulin-like domains which are covalently joined together, such that two Ig-like domains in a single peptide do not associate with each other to form a TBR.
2. A polyvalent or polyspecific protein complex according to claim 1 in which the immunoglobulin-like domains are linked by a peptide of fewer than 3 amino acid residues.
3. A polyvalent or polyspecific protein complex according to claim 2 in which the immunoglobulin-like domains are covalently joined without a linker peptide.
4. A polyvalent or polyspecific protein complex according to any one of claims 1 to 3, comprising polypeptides in which each polypeptide comprises two or more immunoglobulin-like domains, and in which the domains are covalently joined without requiring a foreign linker polypeptide.
5. A polyvalent or polyspecific protein complex according to any one of claims 1 to 4, in which the polypeptides comprise the immunoglobulin-like domains of any member of the immunoglobulin superfamily.
6. A polyvalent or polyspecific protein complex according to any one of claims 1 to 5, in which the immunoglobulin-like domain is derived from an antibody, a T-cell receptor fragment, CD4, CD8, CD80, CD86, CD28, or CTLA4.
7. A polyvalent or polyspecific protein complex according to any one of claims 1 to 6, comprising different polypeptides, each of which comprises antibody VH and VL domains or other immunoglobulin domains, which are covalently joined preferably without a polypeptide linker, and in which the polypeptides associate to form active TBRs directed against different target molecules.
8. A polyvalent or polyspecific protein complex according to claim 7, which comprises one TBR directed to a cancer cell-surface molecule and one or more TBRs directed to T-cell surface molecules.
9. A polyvalent or polyspecific protein complex according to claim 7, which comprises one TBR directed against a cancer cell surface molecule, and a second TBR directed against a different cell surface molecule on the same cancer cell.
10. A polyvalent or polyspecific protein complex according to any one of claims 1 to 6, comprising two polypeptides which may be the same or different, each polypeptide comprising two or more immunoglobulin-like domains, in which the polypeptides associate to form a trimer with three or more active TBRs directed against different molecules.
11. A polyvalent or polyspecific protein complex according to claim 8, which comprises one TBR directed to a costimulatory T-cell surface moleculeselected from the group consisting of CTLA4, CD28, CD80 and CD86.
12. A polyvalent or polyspecific protein complex according to any one of claims 1 to 11, in which one of the polypeptides is a non-antibody immunoglobulin-like molecule.
13. A polyvalent or polyspecific protein complex according to claim 12, in which the immunoglobulin-like molecule is the immunoglobulin-like molecule extracellular domain of CTLA4 or CD28, or a derivative thereof, or the immunoglobulin-like extracellular domain of B7-1 or of B7-2.
14. A polyvalent or polyspecific protein complex according to either claim 12 or claim 13, in which the immunoglobulin-like domain is an affinity-matured analogue of the natural mammalian sequence of said domain which has been selected to possess higher binding affinity to the cognate receptor than that of the natural sequence.
15. A polyvalent or polyspecific protein complex according to claim 1, comprising a non-immunoglobulin-like domain.
16. A polyvalent or polyspecific protein complex according to any one of claims 1 to 15, in which the TBRs of each of the monomer polypeptides are respectively directed to three separate targets, whereby the complex possesses a plurality of separate specifities.
17. A polyvalent or polyspecific protein complex according to any one of claims 1 to 6, comprising identical polypeptides, each of which comprises immunoglobulin VH and VL domains which are covalently joined preferably without a polypeptide linker, in which the polypeptides associate to form active TBRs specific for the same target molecule.
18. A polyvalent or polyspecific protein complex according to claim 17, comprising identical scFv molecules which are inactive as monomers, but which form active and identical antigen combining sites in the complex.
19. A polyvalent or polyspecific protein complex a cording to claim 16, comprising different scFv molecules which are inactive as monomers, but which form active and different antigen combining sites in the complex.
20. A polyvalent or polyspecific protein complex according to any one of claims 1 to 19, which is a trimer.
21. A polyvalent or polyspecific protein complex according to any one of claims 1 to 19, which is a tetramer.
22. A polyvalent or polyspecific protein complex according to any one of claims 1 to 21, in which one or more of the polypeptides is linked to a biologically-active substance, a chemical agent, a peptide, a protein or a drug.
23. A polyvalent or polyspecific protein complex according to claim 22, in which any of the polypeptides are linked using chemical methods.
24. A polyvalent or polyspecific protein complex according to claim 22, in which any of the polypeptides are linked using recombinant methods.
25. A pharmaceutical composition comprising a polyvalent or polyspecific protein complex according to any one of claims 1 to 24, together with a pharmaceutically-acceptable carrier.
26. A method of treatment of a pathological condition, comprising the step of administering an effective amount of a polyvalent or polyspecific protein according to any one of claims 1 to 24 to a subject in need of such treatment, wherein one or more TBRs of the protein is directed to a marker which is:
a) characteristic of an organism which causes the pathological condition, or
b) characteristic of a cell of the subject which manifests the pathological condition,
and another TBR of the protein binds specifically to a therapeutic agent suitable for treatment of the pathological condition.
27. A method according to claim 26, in which two different TBRs of the protein are directed against markers of the pathological condition, and a third is directed to the therapeutic agent.
28. A method according to claim 26, in which one TBR of the protein is directed to a marker for the pathological condition or its causative organism, and the remaining TBRs of the trimer are directed to different therapeutic agents.
29. A method according to any one of claims 26 to 28 for treatment of tumours, in which the therapeutic agent is a cytotoxic agent, a toxin, or a radioisotope.
30. A method of diagnosis of a pathological condition, comprising the steps of administering a polyvalent or polyspecific protein according to any one of claims 1 to 24 to a subject suspected of suffering from said pathological condition, and identifying a site of localisation of the polyvalent or polyspecific protein using a suitable detection method.
31. A method according to claim 30 for detection andor localisation of cancers or blood clots.
32. An imaging reagent comprising a polyvalent or polyspecific protein according to any one of claims 1 to 24.
33. An imaging reagent according to claim 32, in which all the TBRs of the polyvalent or polyspecific protein are directed to a molecular marker specific for a pathological condition, and in which the protein is either labelled with radioisotopes or is conjugated to a suitable imaging reagent.
34. An imaging reagent according to claim 32, in which two TBRs of the polyvalent or polyspecific protein are directed to two different markers specific for a pathological condition or site, and a third is directed to a suitable imaging reagent.
35. An imaging reagent according to claim 32, in which one TBR of the polyvalent or polyspecific protein is directed to a marker characteristic of a pathological condition, a second TBR is directed to a marker specific for a tissue site where the pathological condition is suspected to exist, and a third TBR is directed to a suitable imaging agent.
36. An imaging reagent according to claim 32, in which one TBR of the protein is directed to a marker characteristic of the pathological condition and the remaining TBRs are directed to different imaging agents.
37. An imaging reagent according to any one of claims 32 to 36, in which the polyvalent or polyspecific protein is a trimer or a tetramer.
38. An imaging reagent according to any one of claims 32 to 37, in which the molecular marker is specific for a tumour.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An access control method in a wireless communication network, wherein when a User Equipment (UE) is denied access to the network through a first access point, the UE stores on a list of forbidden LAIs in the UE, a location area identifier (LAI) utilized at the first access point, said method comprising the steps of:
determining whether the LAI stored by the UE on the list of forbidden LAIs is utilized at any other access point where the UE is allowed access; and
if the LAI stored by the UE is utilized at another access point where the UE is allowed access, dynamically changing the LAI at the other access point to a second LAI that is not on the UE’s list of forbidden LAIs.
2. The access control method as recited in claim 1, wherein if the first LAI is utilized at a plurality of access points where the UE is allowed access, the method also includes dynamically changing the first LAI at the plurality of access points to an allowed LAI that is not on the UE’s list of forbidden LAIs.
3. The access control method as recited in claim 1, wherein the step of determining whether the LAI stored by the UE on the list of forbidden LAIs is utilized at any other access point where the UE is allowed access includes querying an access point database by a radio network controller to extract a list of all of the allowed access points for the UE that are currently configured with the LAI stored by the UE.
4. The access control method as recited in claim 3, wherein the step of dynamically changing the LAI at the other access point to a second LAI that is not on the UE’s list of forbidden LAIs includes selecting an allowed LAI, said selecting step including:
accessing by the radio network controller, a list of all possible LAIs that can be selected;
accessing by the radio network controller, a list of rejected LAIs for each UE to determine any unsuitable LAIs for the UE;
eliminating the unsuitable LAIs from consideration; and
selecting as the allowed LAI, an LAI from the LAIs remaining in consideration.
5. The access control method as recited in claim 4, wherein the list of rejected LAIs for each UE includes a UE identifier, a rejected LAI, and an associated timestamp for each occurrence of denied access of a UE in the network, and the method also includes removing a rejected LAI from the list of rejected LAIs for each UE when a predefined time period has elapsed since the associated timestamp.
6. An access control system in a wireless communication network, wherein when a User Equipment (UE) is denied access to the network through a first access point, the UE stores on a list of forbidden LAIs in the UE, a location area identifier (LAI) utilized at the first access point, said system comprising:
means for determining whether the LAI stored by the UE on the list of forbidden LAIs is utilized at any other access point where the UE is allowed access; and
means responsive to a determination that the LAI stored by the UE is utilized at another access point where the UE is allowed access, for dynamically changing the LAI at the other access point to a second LAI that is not on the UE’s list of forbidden LAIs.
7. The access control system as recited in claim 6, wherein if the first LAI is utilized at a plurality of access points where the UE is allowed access, the system also includes means for dynamically changing the first LAI at the plurality of access points to an allowed LAI that is not on the UE’s list of forbidden LAIs.
8. The access control system as recited in claim 6, wherein the means for determining whether an LAI stored by the UE on the list of forbidden LAIs is utilized at any other access point where the UE is allowed access includes:
an access point database for storing a list of all of the allowed access points for the UE that are currently configured with the LAI stored by the UE; and
a radio network controller for querying the access point database to extract the list of allowed access points.
9. The access control system as recited in claim 8, wherein the means for dynamically changing the LAI at the other access point includes means for selecting an allowed LAI, said selecting step including:
accessing by the radio network controller, a list of all possible LAIs that can be selected;
accessing by the radio network controller, a list of rejected LAIs for each UE to determine any unsuitable LAIs for the UE;
eliminating the unsuitable LAIs from consideration; and
selecting as the allowed LAI, an LAI from the LAIs remaining in consideration.
10. The access control system as recited in claim 3, wherein the list of rejected LAIs for each UE includes a UE identifier, a rejected LAI, and an associated timestamp for each occurrence of denied access of a UE in the network, and the system also includes means for removing a rejected LAI from the list of rejected LAIs for each UE when a predefined time period has elapsed since the associated timestamp.
11. An arrangement for controlling access to a wireless communication network, wherein when a User Equipment (UE) is denied access to the network through a first access point, the UE stores on a list of forbidden LAIs in the UE, a location area identifier (LAI) utilized at the first access point, said arrangement comprising:
a radio network controller; and
an access point database accessible by the radio network controller, said database storing a table defining which UEs are allowed to utilize each access point, and a list of rejected LAIs for each UE;
wherein whenever a UE is denied access by an access point, the radio network controller is adapted to:
store the LAI utilized by the rejecting access point in the list of rejected LAIs for each UE;
determine whether the rejected LAI is utilized at any other access point where the UE is allowed access; and
if so, dynamically change the LAI at the other access points to an LAI that the UE is allowed to utilize.
12. The arrangement as recited in claim 11, wherein the list of rejected LAIs for each UE includes a UE identifier, a rejected LAI, and an associated timestamp for each occurrence of denied access of a UE in the network, and the radio network controller includes means for removing a rejected LAI from the list of rejected LAIs for each UE when a predefined time period has elapsed since the associated timestamp.
13. A radio network controller for controlling access to a wireless communication network, wherein when a User Equipment (UE) is denied access to the network through a first access point, the UE stores on a list of forbidden LAIs in the UE, a location area identifier (LAI) utilized at the first access point, said radio network controller comprising:
means for determining whether the LAI stored by the UE on the list of forbidden LAIs is utilized at any other access point where the UE is allowed access; and
means for dynamically changing the LAI at the other access point to a second LAI that is not on the UE’s list of forbidden LAIs, responsive to a determination that the LAI stored by the UE is utilized at another access point where the UE is allowed access.
14. The radio network controller as recited in claim 13, further comprising means for storing the LAI utilized by the rejecting access point in a list of rejected LAIs for each UE.
15. The radio network controller as recited in claim 14, further comprising:
means for determining whether the other access point where the UE is allowed access is controlled by another radio network controller; and
means for instructing the other radio network controller to change the LAI at the other access point, upon determining that the other access point is controlled by the other radio network controller.