WO1994009131A1 - Proteine de liaison specifique recombinee - Google Patents

Proteine de liaison specifique recombinee Download PDF

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Publication number
WO1994009131A1
WO1994009131A1 PCT/GB1993/002133 GB9302133W WO9409131A1 WO 1994009131 A1 WO1994009131 A1 WO 1994009131A1 GB 9302133 W GB9302133 W GB 9302133W WO 9409131 A1 WO9409131 A1 WO 9409131A1
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Prior art keywords
antibody
specific binding
binding protein
domains
regions
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PCT/GB1993/002133
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English (en)
Inventor
William Joseph Harris
Stephen Charles Emery
Gregory Paul Winter
Francis Joseph Carr
Duncan Patrick Mcgregor
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Scotgen Limited
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Priority to GB9507442A priority Critical patent/GB2286189A/en
Priority to JP6509777A priority patent/JPH08505761A/ja
Priority to AU52837/93A priority patent/AU5283793A/en
Publication of WO1994009131A1 publication Critical patent/WO1994009131A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to recombinant bispecific (heterodimeric) and/or monodimeric bivalent specific binding proteins, for example antibodies.
  • Bispecific antibodies may be described as recombinant antibodies capable of binding two different antigenic sites and thus contain antigen binding domains derived from two different sources, and which are brought into association by complementary interactive domains within the antibody molecule.
  • Bivalent antibodies of a monospecific nature may be derived from hybridomas and similarly, bispecifics by the fusion of two hybridoma lines expressing antibodies with different specificities.
  • the application of bispecifics has been limited by the difficulty in efficiently producing and purifying such molecules and additionally, the effector functions intrinsic to complete antibody molecules (such Fc receptor and complement binding) have led to undesirable interactions.
  • Dimerisation techniques which promote the formation of bivalent complexes may therefore be of great importance when one considers constructs, for example F v or Fab fragments, in which the monovalency of the product precludes polyvalent binding to the antigen, providing an avidity factor.
  • each subunit containing different V domains (each subunit containing different V domains) .
  • bispecific antibodies can be effective in cross-linking cytotoxic effector cells to target cells and stimulating the cytotoxic destruction mechanism.
  • bispecific antibodies may be utilized to associate and bring into close proximity certain molecules eg. a drug or a toxin, a radiolabelled hapten or inactivating protein to other entities, such as a particular protein or cell type, via the specific recognition and binding of the individual binding domains.
  • such "bifunctional" antibodies may also be used to develop novel immunoassays and/or diagnostic assays. Since the bispecific antibodies are capable of binding to two distinct antigens, they may be designed to bind enzymes, therapeutic agents, radiolabels or cells to a target without the need for chemical modification. Hence bispecific entities are likely to demonstrate more efficient and specific cell killing than antibodies directly conjugated to cytotoxic agents and furthermore avoid any of the adverse immune responses which may be elicited by chemically modified antibodies.
  • Bispecific antibodies are likely also to prove useful for accelerating and promoting the association/dimerization of other molecules which may have themselves signalling, effector or reporter functions when in a associated/dimeric state. Therefore, bifunctional antibodies may also have an important role as "molecular switches” as well as “cross- linkers” together with a multitude of other uses (both diagnostic or therapeutic) to which a dual binding specificity may be applicable.
  • bispecific antibodies Although the possible roles for which bispecific antibodies may be advantageous are numerous, the clinical applications and other uses for bispecific antibodies have been limited by the difficulty in efficiently producing and purifying such molecules.
  • Methods used to assemble bispecific or other dimeric antibodies include chemical cross-linking, disulphide exchange or the utilization of hybrid-hybridomas or heterotransfectomas. These methods have proved as yet unsatisfactory due to the purity of the products required for successful construction, the production of heterogeneous and ill defined products and especially in the case of Fab fragments the low affinity of the partners (Fd,v L C L ) for each other.
  • heterodimeric F(ab) 2 molecules To address these problems a recent development for the production of heterodimeric F(ab) 2 molecules has employed the C-terminal fusion of peptide sequences corresponding to the leucine zipper regions of the Fos and Jun transcription factors (Kostelny et al., J. Immunol. 148, 1547-1553, 1992) (reflO) . These sequences preferentially form heterodimers and therefore are effective in promoting bispecific formation when fused to two different Fab fragments.
  • a specific binding protein having first and second binding regions which specifically recognise and bind to target entities, said binding regions being contained at least in part on respectively first and second polypeptide chains, said chains additionally incorporating respectively first and second associating domains which are capable of binding to each other, causing the first and second polypeptide chains to combine, thereby providing a single protein incorporating the binding specificities of said first and second binding regions.
  • said first and second binding regions recognise different target entities.
  • said associating domains are derived from an antibody (eg IgA, IgD, IgE, IgG, IgM) , and much of the description which follows uses antibody domains by way of illustration. However, they could be derived from other molecules which are capable of associating, such as natural ligand/receptor combinations or binding regions of natural dimeric proteins.
  • the associating domains are derived from a human protein (ie one which has been exposed to the human immune system) .
  • Said associating domains may be two identical domains which are capable of association, even if they do not normally associate in nature.
  • said associating domains are selected from: antibody V H and V L regions, antibody C H 1 and C L regions, antibody V H .C H 1 and V L .C L regions.
  • the first and second binding regions are antibody antigen-binding domains, eg comprising V H and V L regions contained in a Fab fragment or in a single-chain Fv fragment.
  • either or both of the binding domains could be derived from just one of the V H or V L regions of an antibody, most suitably from the V H region of an antibody (ref 13) .
  • the invention also includes DNA encoding the polypeptides of such a specific binding protein; optionally contained in one or more expression vectors; host cells containing such recombinant DNA and capable of expression of the DNA to produce the polypeptides of the specific binding protein.
  • the invention also provides a process which comprises expressing the recombinant DNA in such a host cell to produce the polypeptides encoded thereby, and where necessary performing post-translation manipulation or processing of the polypeptides, to produce the specific binding protein.
  • the invention further provides a process for producing a specific binding protein as set forth above, which comprises:
  • the invention provides recombinant bispecific (heterodimeric) and/or monodimeric bivalent specific binding proteins, for example antibodies, in which the specific association of the component modules is accomplished by using the recognition and natural homo- or hetero-dimerization of additionally fused associating domains.
  • bispecifics and/or dimerics and variants thereof are also disclosed.
  • antibody and “antibody fragments” are hereinafter used synonymously. Similarly the terms “antibody” and “antibody fragments” are hereinafter used synonymously. Similarly the terms “antibody” and “antibody fragments” are hereinafter used synonymously. Similarly the terms “antibody” and “antibody fragments” are hereinafter used synonymously. Similarly the terms “antibody” and “antibody fragments” are hereinafter used synonymously. Similarly the terms “antibody” and “antibody fragments” are hereinafter used synonymously. Similarly the terms “antibody” and
  • immunoglobulin are to be treated in a likewise manner.
  • Fig 1 a general scheme for bivalent and bispecific antibody formation
  • Fig 3 an example of minimal configuration bispecific recombinant antibody formation
  • Fig 10 shows the arrangement of genes in the various vectors used for antibody fragment expression in E.coli. All coding regions were cloned downstream from a lac promotor in pUC 19. VH and VK and CH and CK are the antibody fragment variable (V) and constant (C) domains respectively, Pb denotes a Pel B leader sequence and the
  • Tag gene encodes a peptide for antibody fragment detection with a secondary antibody.
  • the Tag gene product was not used in these studies.
  • the linker and termination signal were engineered into the vectors as described in the materials and methods.
  • pS l-Fab/Pa is identical to the
  • pDMl is a derivative of pSWl-Fab/Pa.
  • Fig 11 shows denaturing SDS-PAGE of affinity purified anti-P. aeruginosa Fab (lane 2) and ScF v * (lane 3). 2-5 mg of each sample were electrophoresed through a standard denaturing 10% SDS-PAGE gel.
  • Fig 12 show the relative antigen binding capacities of affinity purified anti-P. aeruginosa Fab ( ⁇ ) ScF v * (•) and the original chimeric antibody (o) .
  • Fig 13 shows a Western blot showing the cross- reactivity of the anti-P. aeruginosa with a number of Gram- ve bacteria.
  • Fig 14 shows the different conformational forms of anti-P. aeruginosa ScF v * and Fab.
  • (a) A 7.5% non- denatruring polyacrylamide gel showing multimeric forms (I- III) of ScFv* (lanes 1-3) and a single monomeric form of Fab (lane 4) . HPLC purification of monomeric (III) , dimeric (II) and trimeric (I) forms of ScF v *.
  • Fig 15 shows a comparison of the ability of HPLC purified monomeric ScF v * ( ⁇ ) , dimeric ScF v * (Q) and the original chimeric antibody (o) to bind P. aeruginosa.
  • the advantage of the present invention for the association of the bispecific heterodimer or simple homodimeric bivalent formation, over existing techniques lies in the given nature of the fused domains utilized for this purpose.
  • One of the major disadvantages of chemical modification or the Jun/Fos type approaches concerns their potential to elicit an immune response against "foreign" chemical constituents and peptide sequences when used in human therapy.
  • the technique of using antibody domains to achieve dimerization of antibody constituents avoids this problem by using natural antibody domains which should not induce an immune response in humans especially where the antibody domains are reshaped (humanised) or derived from natural human antibodies.
  • Such dimeric antibodies ought to closely approach the immunogenic characteristics of a natural human antibody and thus should have an extended half-life in circulation compared to bispecifics prepared by other means as discussed previously.
  • the present invention relates to the development of bivalent and other dimeric antibodies especially for use in therapy or for in vivo diagnosis.
  • the successful targetting of antibody molecules to sites of disease upon repeated administrations is dependant on these antibodies provoking little or no immune reaction. Maximisation of the natural human antibody sequence content of the bispecific antibodies will prospectively enhance the perspective for long-term repeat administration of these antibodies, for example in the treatment of chronic disease. Notwithstanding this, other applications as yet undetermined or not described herein for which mono-, bi-, or multi-specific antibodies/antibody fragments (produced via the means of association described in this invention) may be applied will be also encompassed by this patent.
  • the general concept of association of specific binding chains which is applicable to the present invention may be illustrated by reference to figure 1. In this diagram, the entity has been divided into four components A, B, C and D in order to simplify discussion of the inventive process.
  • the components B and D may be nominally seen as additionally fused domains, although in certain configurations they may themselves be part(s) of the same antibody from which A and C are derived.
  • the fragments or domains may be derived from one or more sources depending again on the chosen format and foreseen application of the particular construction.
  • a further augmentation, also foreseen in this invention, is that for particular molecular configurations and destined applications it may be advantageous to introduce or use existing cysteine residues to create inter-domain disulphide bridges in order to further stabilize the constructs.
  • the reduction to produce these covalent bonds may be performed in vivo or in vitro depending on the construct and relative merits of this additional process.
  • any particular type of antibody or antibody fragment is not fundamental to the inventive concept described here.
  • any immunogobulin which provides the desired specificity may be employed.
  • An extension of the invention also foresees the use of any natural molecules (or fragments thereof) which form specific associations (such as cell surface receptors and their ligands) which have been exposed to the immune system and show little or no immunogenicity within the said system.
  • a valuable embodiment of this invention foresees the dimerization of the constituent partners via the homodimeric association of additionally fused antibody domains (or other immuno-silent molecules) .
  • Such a strategy may be used to produce dimeric antibodies.
  • This embodiment is expected to be more suited towards the dimerisation of single antibody species to form homodimeric, bivalent antibodies, since is recognised that a mix of product assemblies may arise when this technique is used for the co-expression and association of two different antibody species to form a heterodimeric, bispecific antibody.
  • the following specific description illustrates how the invention may be carried out.
  • the "Reference example” provides an illustration of the basic technology by which specific binding and associating fragments can be fused and caused to associate, while Examples 1 and 2 which follow provide specific embodiments of the invention to whose manner of execution can draw on the technology of the Reference example.
  • the concept of using dimeric association of fused domains to enable formation of a bivalent species may be simply illustrated by the following example designed for production of a bivalent homodimeric (scF v ) 2 antibody, with reference to figure 1 , in this embodiment, the components A and D are V H and V L domains respectively fused via a linker to a cognate V L and V H domain (components B and C respectively) .
  • This format for the production homodimeric bivalent antibodies has been experimentaly tested using a simple model system (see Fig. 2) in which V H and V L domains of an anti-Pseudomonas aeruginosa antibody were fused via a linker peptide.
  • Bacterial strain All vectors were transformed and expressed in the E. coli strain XL-1-Blue (supE44 hsdR17 recAl endAl gyrA46 the relAl lacF' [proAB+ lacl9 lacZ M15 TnlO (tet r )].
  • the tetacycline selectable F 1 pilus allows strict control of expression of pUC based vectors.
  • the PSV scF v * expression vector was constructed form a pSWl-VHD1.3-VKD1.3-TAGl vector derivative (pSWl-Fab/Pa) using the polymerase chain reaction (PCR) mutagenesis method of Higuchi (1989) (ref16) .
  • the linker was incorporated using a two stage procedure. Two separate amplifications were carried with the primers VHBA :5 « -AGGT(C/G) (C/A)A(G/A)CTGCAG(G/C)AGTC(T/A)GG with LINKFOR:5» -CGATGTCATCCACTTTAGATTCAGAGCCAGAGCCAGAAGATT
  • TGCCTTCTGAGGAGACGG and VKFO 5 ⁇ -GTTTGATCTCGAGCTTGGTGCC with LINKBAK:5• -GTCACCGTCTCCTCAGAAGGCAAATCTTCTGGCTCTGGCTC TGAATCTAAAGTGGATGACATCGAGCTG.
  • the PCR contained 2 units of Taq polymerase (BCL,
  • the purified products of these reactions were mixed and seven cycles of PCR were performed without primers (94'C, 1 minute; 72 * C, 1 minute) . This reaction was then maintained at 94 * C while VHBACK and VKFOR primers were added. A further 30 cycles of PCR were then performed (94 * C, 1 minute; 65 * C, 1 minute; 72'C, 1 minute).
  • the reaction products were electrophoresed through a 2% (w/v) agarose- TAW gel and the 650 bp product purified into lO ⁇ l of de- ionised water by the Prep-a-gene procedure (Bio-Rad Ltd, Hemel Hempsted, Herts., England). The product was digested with PstI and Xhol then ligasted into PstI/Xhol digested ⁇ pSWl-Fab/Pa under standard conditions to construct the pDMl vector (fig 10) .
  • the expression vectors pDMl encoding the anti-P. aeruginosa scF v * antibody fragment and pSWl-Fab/Pa encoding the equivalent Fab fragment (each with the fused light chain constant region domain for detection purposes) were assessed. Expression conditions were modified from Ward et al, (1989) (ref 13): XLl-blue transformed with one of the above vectors was grown in 5ml 2xTY cultures containing 1% glucose, lOO ⁇ g/ml ampicillin and 12.5 ⁇ g/ml tetracycline at 37 * C, overnight. Ten microlitres of overnight culture was then used to inoculate fresh medium for expression of antibody fragments.
  • Anti-P. aeruginosa scF v * and Fab fragments were purified by affinity chromatography. Five hundred millilitre cultures of bacteria producing either anti-P. aeruginosa Fab or scF v * were centrifuged at 4000 rpm for 20 minutes. The supernatant was discarded and the cell pellet sonicated for 1 minute in 10ml of PBS to release periplasmic antibody fragments. This solution was concentrated to a 1ml volume in a Centricon-10 column (Amicon, Stonehouse, Glos, England) and loaded onto an anti-human FAb affinity column (Pierce, warriner, Cheshire England) prepared according to the manufactures instructions. Seven 1ml fractions were eluted in 0.1M glycine buffer pH2.8. The fractions were dialysed overnight against PBS and analyzed by polyacrylamide gel electrophoresis.
  • Bacterial supematants and antibody fragments (FAb and scF v *) purified from cell pellets were assayed in 96 well flat bottomed polystyrene plates (Nunc, Denmark) . The plates were coated overnight at 4 * C with l ⁇ g affinity purified goat anti-human IgG Fab antibody (Sigma Chemical Co., Poole, Dorset, England) in 50 ⁇ l phosphate buffered saline (PBS) . The plates were blocked for 1 hour at 37 * C with 200 ⁇ l of 2% (w/v) BSA (fraction V, Sigma) in PBS and then washed twice with 200 ⁇ l PBS.
  • FBS phosphate buffered saline
  • the plates were then washed six times in 200 ⁇ l Tw20/PBS and the assay developed with 50 ⁇ l lmg/ml 0- phenylendiamine dilydrochloride (Sigma) and l ⁇ l/ml 30% (v/v) hydrogen peroxide (Sigma) in 0.1M citrate-phosphate buffer pH 6.0.
  • the reaction was stopped with lOO ⁇ l 0.5M citric acid and the optical density at 450nm was read using a Bio-Rad M450 plate reader.
  • Positive control anti-P pseudomonas mouse-human chimeric IgG ! antibody was provided by Scotgen Ltd, Aberdeen. This antibody was derived from the original murine patent immunoglobulin from which the Fab and scFv* variable domains were obtained.
  • This assay was performed essentially as the ELISA described above but with the following modifications.
  • P. aeruginosa were grown overnight in Luria broth, pelleted an resuspended in PBS as a volume representing half of the volume of the original culture. The cells were then heat treated at 65 * C for 10 minutes.
  • 96-well polystyrene plates were coated overnight with 50 ⁇ l of heat killed P. aeruginosa. After blocking the plates with Tw20/PBS and washing with PBS, 50 ⁇ l of bacterial supernatant, purified antibody fragments or the mouse/human chimeric anti-P. aeruginosa antibody supernatant were added to each well and incubated at 37 * C for one hour. After the plates were washed four times with PBS the assay proceeded as described in the previous section.
  • the specificity of the scF v * expressed was investigated by Western blotting.
  • P. aeruginosa, P. fluorescens, Al. xylosidans, Ac. calcoaticus and O. anthropi were electorphoresed through a standard 10% SDS polyacrylamide gel with Rainbow size markers (Amersham Int., Aylesbury, Bucks, England).
  • the gel was electorblotted at 0.8 mA/cm 2 in a Hoeffer T70 semi-dry blotter onto Immobilion-P membrane (Millipore Corp., Bedford, Mass, USA) .
  • the membranes were blocked overnight in 5% (w/v) milk powder in PBS.
  • scF v * (l ⁇ g/ml) was incubated for one hour in 0.1% (v/v) Tween 20 in PBS followed by three 10 minute washed in 1% (v/v) Tween 20 in PBS. The membrane was then incubated with a 1:5000 dilution of an anti-human kappa chain or anti-human Fab antibody conjugated to horse radish peroxidase in 5% (w/v) milk powder, 1% (v/v) Tween 20 in PBS for 30 minutes at 37 * C. scF v * binding was detected using the ECL chemiluminescent system (Amersham Int.).
  • Affinity purified Fab and scF v * were separated on a 7.5% non-denaturing polyacrylamide gel using the method of Omstein (1964) (ref 17) to determine the conformation of the molecules.
  • scF v * Forty microgram samples of scF v * were analyzed using a Zorbax GF250 size exclusion column on a Gilson HPLC comprising a model 302 pump, an 802L manometric module, a 811 dynamic mixer, a 116 UV detector and a 201 fraction collector controlled by Gilson 714 software.
  • the analysis was done using both PBS and 0.2M sodium phosphate buffer at a flow rate lml/minute. Eluate was monitored at 280nm, 01AUFS and 0.5 ml fractions were collected and analyzed by ELISA and non-denaturing polyacrylamide gel electrophoresis.
  • the bivalent component thus shows similar binding characteristics to the intact antibody while the monomeric fragment shows greatly reduced binding.
  • Dimeric and monomeric forms can be easily separated by gel filtration, offering a simple method for preparing pure dimeric antibody.
  • the scF v * dimers dissociate into monomers in non- reducing SDS gels and appear, therefore, not linked by disulphide bonds (data not shown) .
  • Our interpretation of the data is that the dimer formation of the (scF v *) 2 is due to non covalent intermolecular V H /V L domain association; the association occurring between domains of different scF v * polypeptides as indicated in figure 2.
  • the resulting dimer is bivalent and shows a binding affinity to the chimeric antibody for the P. aeruginosa antigen.
  • the present invention discloses novel bispecific antibodies in which dimerization of the constituent partners is achieved via the heterodimeric association of additionally fused natural antibody domains.
  • antibodies may consist of two different Fab or scF v antibody fragments (or any other antibody/antibody fragment combination) linked to either a V H or V L polypeptide by gene fusion.
  • the desired bispecific antibody is therefore specifically associated by the recognition and natural heterodimerization of the fused V H or V L domains.
  • the present invention also discloses methods for the production of novel bispecific antibodies.
  • the simplest format envisaged for the production of a bispecific antibody would be the association of two single chain antibodies scF v l and scF v 2. If one relates to the general scheme shown in figure 1, the domains A and C would be V H 1 and V L 2 respectively, and domains B and D; V L 1 and
  • a preferred embodiment of this invention is a bispecific antibody, formed by a C-terminal fusion of either a V H or
  • bispecific F(ab) 2 heterodimers either the V H or V L (components B and D) could be added by C- terminal fusion to the V H /C H 1 polypeptide chains of the Fab fragments (components A and C) .
  • Fab dimerization to form the bispecific antibody, should be promoted by the spontaneous and specific association of the attached V H and V L domains. See Figure 5.
  • Examples of other alternative embodiments of this invention may involve the use of other naturally occuring antibody domains which form heterogeneous (dimers such as V H .C H 1/V L .C L or C H 1/C L ) as C-terminal fusions (components B and D) which are illustrated in figure 6-9. This and other possible conformations have been alluded to previously in the text.
  • any particular type of antibody or antibody fragment is not fundamental to the inventive concept but it is clear that the specificity and affinity of the C- terminal domains chosen will greatly influence the end product(s). Any domain(s) which provides the desired dimerization and recognition specificity required may be employed. However, it is recognised that, for example, specific V H domains will associate more efficiently with certain V L domains than others (K D values for F v 's varying from 10 "4 M - 10 "7 M) (ref 18) and thus the V H /V L binding pair of a specific bifunctional should possibly be optimised to promote heterodimer formation and also to minimise homodimer formation (especially when producing bispecifics) .
  • molecules may be modified in order to improve the specificity and/or binding affinity of the molecules for each other and thus improve their dimerisation properties (ref 19) .
  • This may be achieved via engineering, eg mutation or chemical modification, of the inter-domain hydrophobic contacts, introduction of a metal (or other molecule binding site) between the domains to stabilize association, introduction of strategic cysteine residues to form disulphide bridges, etc.
  • the antibody may, in fact, be trivalent.
  • This extra antigen binding site may be useful itself. If the binding site recognizes a different type of antigen or ligand than the other sites, this property may be used for purification (ligand bound to matrix) , stability (ligand added and bound to site thereby "cross-linking" the two domains of the F v ) or as a label
  • the present invention provides an antibody with a minimum of two F v domains each comprising of structural framework with the relevant CDRs which provide the antibody with the capability to bind specific molecules such as antigens.
  • the invention may be exemplified ,but not limited, in a configuration in which the antigen recognition and binding domains (and any other affiliated sequence such as constant regions etc) are fused at the C- terminal end to "association" domains such as either a V H or V L antibody domain respectively. Association of the constituent partners is achieved via the natural heterodimerisation of the fused V H and V L antibody domains (see figs 4 and 5) .
  • a method to produce bispecific (scFv) 2 .v H /v L or F(ab) 2 .V H /v L entities (see figs, 4 and 5) or derivatives of these with either C H 1/C L or V H .C H 1/V L .C L fused domains (see figs.6-9) .
  • This method comprises the following basic scheme:
  • Example 1 The invention is illustrated but not limited by the following examples.
  • Example 1 The invention is illustrated but not limited by the following examples.
  • This example illustrates the production of a bispecific antibody from two different scFv fragments expressed in Escherichia coli.
  • Complete human V H or V L domains can be added by C-terminal gene fusion, one to either of the two constituent scF v constructs.
  • the completed genes can then be cloned into an appropriate expression vector(s) depending on whether they are to be expressed as in a two cistron system on one vector under a single promotor, expressed singularly from each carried on its own vector yet together in a co- transformed host or each individual grown in different cultures.
  • appropriate expression vector(s) may be obtained from the literature of Skerra et al., Science, 240 1038-1041, 1988 (ref 3), Ward et al., Nature, 341, 544-546, 1989 (ref 13), Bird et al., Science 242, 423-426, 1988 (ref 21), Hoogenboom et al., Nuc. Acid Res. 19, 4133-4137, 1991 (ref 23)., etc. Further changes to obtain vectors suited to the needs of bispecific production may be necessary.
  • F(ab) 2 .v H .v L fragments can be produced in E.coli by similar means and the V H /V L association technique may utilized for for other antibody fragments and other dimerization purposes (see fig 5)
  • the construction of the bispecific shown in fig.5, could be made by the same technique as was used for the F(ab) 2 .Jun.Fos. construction as described by Kostelny et al., J. Immunol. 148, 1547-1553, 1992 (ref 10). in which the one the additional dimerization domains were fused to the first few residues of the C H 2 intron such that it would be spliced to the C H 1 of the V H gene thus replacing the normal C H 2 and C H 3.
  • the V L /C L genes are expressed from a separate vector which is co-transfeeted with the V H carrying plasmid.

Abstract

Protéine de liaison spécifique possédant une première et une deuxième régions de liaison, par exemple des fragments Fv d'anticorps, qui reconnaissent et se lient spécifiquement à des entités cibles. Lesdites régions de liaison sont contenues respectivement, au moins en partie, sur une première et une deuxième chaînes de polypeptides. Lesdites chaînes comprennent respectivement un premier et un deuxième domaines d'association, par exemple des domaines d'anticorprs VH et VL pouvant se lier l'un à l'autre, entraînant ainsi la combinaison de la première et de la deuxièmes chaînes de polypeptides. Ceci permet d'obtenir une seule protéine incorporant les spécificités de liaison desdites première et deuxième régions de liaison. Les première et deuxième régions de liaison peuvent reconnaître différentes entités cibles, donnant ainsi une protéine de liaison bispécifique. Les domaines d'association sont de préférence dérivés d'une protéine humaine (c'est-à-dire une protéine ayant été exposée au système immunitaire humain), de sorte que la protéine présente moins de risques de déclencher le système immunitaire humain lorsqu'elle est administrée thérapeutiquement. La protéine de liaison est obtenue de manière adaptée par expression de l'ADN recombiné.
PCT/GB1993/002133 1992-10-15 1993-10-15 Proteine de liaison specifique recombinee WO1994009131A1 (fr)

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GB9507442A GB2286189A (en) 1992-10-15 1993-10-15 Recombinant specific binding protein
JP6509777A JPH08505761A (ja) 1992-10-15 1993-10-15 組換え特異的結合タンパク質
AU52837/93A AU5283793A (en) 1992-10-15 1993-10-15 Recombinant specific binding protein

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GB929221657A GB9221657D0 (en) 1992-10-15 1992-10-15 Recombinant bispecific antibodies
GB9221657.1 1992-10-15

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Cited By (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0739984A1 (fr) * 1995-04-26 1996-10-30 San Tumorforschungs-Gmbh Polypeptides bivalents contenants aux moins deux domaines
WO1997038102A1 (fr) * 1996-04-04 1997-10-16 Unilever Plc Proteine, polyvalente et a specificites multiples, de fixation sur un antigene
WO2001085795A1 (fr) * 2000-05-05 2001-11-15 Universität Heidelberg Anticorps de recombinaison trivalents a regions variables stabilisees par des ponts disulfure
WO2002008293A2 (fr) * 2000-07-25 2002-01-31 Immunomedics Inc. Proteine de liaison cible multivalente
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