WO1995001438A1 - Sbp members with a chemical moiety covalently bound within the binding site; production and selection thereof - Google Patents
Sbp members with a chemical moiety covalently bound within the binding site; production and selection thereof Download PDFInfo
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- WO1995001438A1 WO1995001438A1 PCT/GB1994/001422 GB9401422W WO9501438A1 WO 1995001438 A1 WO1995001438 A1 WO 1995001438A1 GB 9401422 W GB9401422 W GB 9401422W WO 9501438 A1 WO9501438 A1 WO 9501438A1
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/1034—Isolating an individual clone by screening libraries
- C12N15/1037—Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0002—Antibodies with enzymatic activity, e.g. abzymes
Definitions
- the present invention relates to members of specific binding pair (sbp) which comprise a binding site for complementary second sbp member. More particularly, it relates to sbp members, especially repertoires thereof, wherein a chemical moiety is incorporated specifically at an amino acid residue within the binding site. It also relates to the production of such repertoires and selection of such repertories and selection from a repertoire of first sbp member with binding specificity for a second sbp member of interest.
- the sbp member may be one wherein the binding site is formed by binding regions of immunoglobulin heavy and light chain variable domains.
- V gene repertoires for display on bacteriophage may be made in vi tro by combining un-rearranged V genes, with D and J segments.
- Antibodies against a variety of antigens have been selected from such artificially rearranged V gene repertoires displayed on phage (H.R. Hoogenboom & G. Winter J. Mol. Biol. 227 381-388 1992; and as disclosed in WO 93/06213 and WO 93/11236) .
- the chemical diversity of these encoded libraries is restricted to natural amino acids. It would be desirable to be able to incorporate other reactive groups at the binding site of sbp members such as antibodies. These would have a number of applications.
- catalytic antibodies (reviewed by R.A. Lerner et al. Science 252 659-667, 1991) would be facilitated by the incorporation of nucleophilic groups and non-peptidyl cofactors such as metal ions, haems and flavins, a common feature of many enzymes, into the antibody binding site. These modifying groups would ideally be incorporated covalently at the antigen binding site, thus becoming integral parts of the paratope. Such chemically modified antibodies could then be used directly as detection agents in immunoassay applications, such as time resolved fluorescence immunoassay, or directly in catalysis.
- Barbas et al started with a preexisting antibody Fab fragment with specificity for tetanus toxoid which they mutagenised and displayed on phage and selected from the libraries Fab fragments which bind to metal. They then propose diversifying the isolated metal binding Fab fragments, by chain shuffling or by mutagenesis of another CDR, and then selecting to obtain specificity for the substrate but have not as yet reported whether this can be accomplished successfully.
- Example 2 we describe the construction of a library of scFv fragments prepared synthetically from human V genes can be made where the antigen binding sites contain an amino acid residue which may be specifically modified to introduce a functional group. The residue is specifically chemically derivatized before every selection process so that antibody fragments are identified which bind to antigen, with a non-protein element incorporated at the antigen binding site.
- sbp members eg antibody fragments
- complementary sbp member eg antigen
- the present invention provides a novel approach to the obtention of first spb members with a binding site for second sbp member, ameliorating problems or difficulties associated with the prior art.
- antibody or “antibody fragment” means a first sbp member which has its binding site formed by association of a first polypeptide domain which comprises a binding region of an immunoglobulin heavy chain variable domain (VH) and a second polypeptide domain which comprises a binding region of an immunoglobulin light chain variable domain (VL) and includes the Fab fragment consisting of VL, VH, CL and CHI domains, the Fv fragment consisting of the VL and VH domains of a single antibody, single chain Fv (scFv) comprising a VL domain and a VH domain linked by a peptide linker, F(ab')2 fragments, a bivalent fragment comprising two linked Fab fragments, bispecific single chain Fv dimers (PCT/US92/09965) and diabodies, bivalent or bispecific fragments constructed by gene fusion (P. Holliger et al, supra; PCT/GB93/02492) .
- VH immunoglobulin heavy chain variable domain
- the term "repertoire” is used to indicate diversity, ie variety in sequence, and generally implies a large number of different sequences, perhaps of the order of millions (eg 10 7 -10 9 -10 12 -10 14 ) .
- a repertoire of antibodies or antibody fragments may have a diversity which is representative of that found in an organism such as mouse or human.
- the invention provides a repertoire, which is genetically diverse, of first sbp members each having a binding site which comprises a chemical moiety bound covalently at one or more amino acid residues within the binding site.
- the chemical moiety is not encoded by nucleic acid used to express the first sbp members, instead being introduced by a covalent modification following production of the polypeptides.
- One or more first sbp members with binding specificity for a second sbp member (antigen) of interest may be selected from the repertoire, e.g. employing binding affinity.
- a chemically modified sbp member may bind second sbp member of interest with greater affinity than unmodified, genetically identical sbp member when bindjng is compared under the same conditions.
- the chemical moiety forms an integral part of the binding site, being essential for the second sbp member (antigen in the case of antibody) to form non-covalent bonds with it to obtain high affinity binding.
- a chemically modifiable amino acid residue is an amino acid residue susceptible to modification with a chosen chemical reagent under specified conditions.
- the amino acid may be unique in the binding site, or it may be uniquely modifiable, or selectively or preferentially modifiable over other amino acids present.
- a cysteine residue may be introduced into the binding site and be available for chemical modification via its thiol group.
- cysteines There may be other cysteines in the molecule (eg in a VH domain) but generally those would be paired by disulphide bridges and so not available for chemical modification, or at least not so available as the one introduced into the binding site which is therefore selectively or preferentially modifiable.
- an amino acid preferentially modifiable compared with other amino acids of the same type within the sbp member by engineering its environment, eg by positioning it within the molecule adjacent another amino acid with particular properties. For instance, an amino group next to a carboxlate group would be rendered more nucleophilic and selectively modifiable even if not unique within the binding site.
- the repertoire may contain a unique amino acid in each first sbp member, an amino acid which is uniquely modifiable in each first sbp member or more than one preferentially modifiable amino acid residue in each first sbp member.
- the repertoire needs to be modifiable reproducibly at one or more specific amino acid residues to that reproducible modification may be made of selected repertoires and of polypeptides expressed from clones selected from a repertoire.
- the chemical moiety is incorporated at the site covalently and may form a critical determinant of the binding site. This covalent modification allows a wider variety of moieties to be incorporated, particularly reporter groups or cofactors for catalysis.
- one or more amino acids which are specifically modifiable are incorporated at the binding site.
- the incorporation of a covalent modification to generate a chemisynthetic repertoire involves a number of difficulties.
- introduction of a chemical moiety into a binding protein, such as antibody, with pre-existing binding proteins is likely to cause alterations in the properties of binding. Modification at a site outside the binding site is likely to make the introduced group much less useful as a reporter or catalytic group.
- the present invention overcomes these difficulties by allowing selection of binding proteins ("first sbp members") which can bind second sbp member of interest when the introduced group is present in the binding site.
- Many of the binding proteins eg antibodies
- only bind the target of interest eg antigen
- show greatly improved binding when chemically modified. This differs from previous approaches involving modification of a single antibody known, initially, to bind the antigen of interest.
- the chemical group is present in the binding site, its properties are more likely to be modified by binding of antigen.
- Cofactors for catalysis will also need to be close to where substrate binds in catalytic antibodies. One embodiment of this would be to provide the cofactor on a fixed light chain and select heavy chains which supply substrate specificity. Groups may be incorporated at the antigen binding site which favour high affinity binding of the antigen or promote a particular selectivity of binding for instance to discriminate between antigen molecules of different sizes.
- binding modules allows the in vi tro modification of these structures to include non-peptidyl elements.
- synthetic moieties could be engineered via disulphide linkage at any accessible surface exposed cysteine residue
- the antigen binding CDR regions are the obvious targets for modification. Modification of the light chain CDR3, should result in the synthetic element forming an integral part of the binding site and yet still permit antigen contacts to be formed by the dominant heavy chain CDR3. The diversity and functionality of antibodies might therefore be increased beyond that possible with existing antibody libraries by inclusion of these non-encoded elements.
- the methods described in this application will allow virtually any chemical moiety to be incorporated into the binding site and be an essential component for efficient binding activity.
- the first sbp members in the repertoire may be fused to a surface component of any organism for display at the surface.
- each clone expresses a first sbp member as a fusion protein on the phage surface by inserting the corresponding gene into the gene coding for a surface component such as the cpIII viral coat protein.
- Nucleic acid encoding the binding protein displayed on the surface of an organism may be packaged within the organism for easy recovery following selection of first sbp member able to bind second sbp member of interest. Selection of a first sbp member from a repertoire is preferably by binding with second sbp member of interest.
- the nucleic acid may be recovered from the organism and used, or other nucleic acid molecules with the same sequence, or other nucleic acid molecules encoding the same amino acid sequence, or a mutant or derivative thereof, used in the production of first sbp member with a binding site able to bind the second sbp member of interest.
- Individual first sbp members with the desired specificity eg for an antigen can be isolated from the complex library using the conventional screening techniques (e.g. as described in Harlow, E., and Lane, D., 1988, supra Gherardi, E et al. 1990. J. Immunol , meth. 126 p61-68) .
- Selection will often be elution from an affinity matrix with a ligand. Elution with increasing concentrations of ligand should elute displayed binding molecules of increasing affinity.
- An affinity matrix which has retained the strongly bound first sbp member displayed on the surface of an organism and extract the DNA, for example by boiling in SDS solution. Extracted DNA can then be used directly to transform E. coli host cells or alternatively the encoding sequences can be amplified, for example using PCR with suitable primers, and then inserted into a vector for expression.
- a preferred strategy is to bind a population of phage to an affinity matrix which contains a low amount of ligand.
- affinity matrix which contains a low amount of ligand.
- Phage displaying high affinity protein is preferentially bound and low affinity protein is washed away. The high affinity protein is then recovered by elution with the ligand or by other procedures which elute the phage from the affinity matrix.
- the package can be simply eluted, it can be eluted in the presence of a homologous sbp member which competes with said package for binding to a complementary sbp member; it could be removed by boiling, it could be removed by proteolytic cleavage of the protein; and other methods - -.11 be apparent to those skilled in the art eg. destroying the link between the substrate and complementary sbp member to release said packaged DNA and sbp member.
- the objective is to obtain the DNA from the package so that it can be used directly or indirectly, to express the sbp member encoded thereby.
- binding of the selected first sbp member to the second sbp member may be enhanced compared with binding of the same first sbp member without the chemical moiety covalently bound at an amino acid (one or more) in the binding site.
- the binding may be dependent on the presence of the chemical moiety.
- a method of providing a diverse repertoire of a first specific binding pair (sbp) member according to the present invention comprises a step of chemical modification of first sbp members to introduce a chemcial moiety bound covalenty to an amino acid residue in the binding site of each first sbp member. Provision of the repertoire of first sbp member before the step of chemical modification may comprise expression from a population of nucleic acid molecules collectively encoding the repertoire.
- Provision of the population of nucleic acid molecules may comprise a step of mutation of nucleic acid encoding first sbp member, or a polypeptide component part thereof (eg one polypeptide chain of a heterodimeric binder such as a Fab fragment) , to introduce a codon encoding the amino acid residue.
- the nucleic acid may be constructed by joining together, eg in a combinatorial fashion, of gene fragments. These may be done using PCR.
- One approach aims at creating a semisynthetic library on phage by the covalent incorporation of synthetic moieties on to the whole phage-binding protein population prior to each selection step.
- Semisynthetic phage-antibodies isolated with binding activity are shown to tolerate or even to require the presence of the synthetic group into their antigen-binding sites. In the latter case, these antibody fragments may be the best candidates for use in single phase immunoassays and catalysis.
- example 1 we report how we tested the reactivity of a unique cysteine free thiol functionality in the light chain CDR3 of a scFv expressed as s soluble protein or as a fusion product to filamentous phage. Having assessed the specificity of the semisynthesis, we then in example 2 selected semisynthetic scFv's activities against phOx with two different synthetic moieties, using disulfide exchange or alkylation reaction.
- cysteines are the CDR3 of the heavy or light chain, they could in principle be incorporated at any position in the chains using mutagenesis or joining together of gene fragments. Although cysteine may be present elsewhere in a VH domain they may form disulphide bonds and not be available for chemical modification.
- the group introduced may be linked to the displayed binding protein by a cleavable group such as a disulphide bond or a vicinal diol.
- a cleavable group such as a disulphide bond or a vicinal diol.
- phage may then be eluted from complementary second sbp member using the cleavage reagent.
- Those phage where binding is dependent on the present of the introduced group should be preferentially eluted, whereas those whose binding is independent will be retained.
- the linker length between the introduced group and the binding site may be varied. This allows the exploration of the space of the binding site to find the position of the introduced group which best allows it to fulfil its function as, for instance, a reporter or a catalytic group.
- Cysteine groups may be introduced at more than one site on the molecule, for example at different CDR residues in an antibody or antibody fragment.
- Modification may be performed for instance on both heavy and light chains allowing derivatization with two introduced groups.
- Cysteines may be introduced at specific points within varying CDRs by incorporating cysteine encoding codons, for instance at specific positions within random oligonucleotides. Even if in some fragments this leads to derivatization at more than one site, selection by binding to antigen will allow those fragments where derivatization is compatible with binding to be selected.
- There is also the possibility of incorporating two (or more) residues for modification with the same reagent or two (or more) different reagents, or more preferably different residues may be modified with different reagents to incorporate different chemical moieties into the binding site. This is useful eg for catalytic antibodies where the presence of two chemical moieties such as flavin and haem may promote catalysis of a redox reaction.
- the modification may be performed on a protein chain, e.g. light chain, in solution, eg using the procedures described by M. Figini et al., J. Mol . Biol . 239, 68-78, 1994.
- the light chain may be then associated with a population of heavy chains on phage and antigen binders selected. This association would be repeated at each round of selection prior to contacting the phage population with the antigen.
- the present invention provides a novel way of introducing metal ions at the binding site of a first member of a specific binding pair. Chelating groups such as iminodiacetic acid may be incorporated at the binding site e.g. at a cysteine residue, and then a metal containing solution added.
- the reactive group of these reagents may be combined with the functional group in a modifying reagent.
- a modifying reagent For instance, if it is desired to modify a protein with the fluorophore 7-amino-4-methylcoumarin-3- acetic acid, the N-hydroxysuccinimidyl ester of the molecule may be used to modify amino groups, whereas N- [6- (-amino-4-methylcoumarin-3-acetamido)hexyl] -3' - (2' - pyridyldithio)propionamide may be used to modify cysteine groups.
- Specific modification at an antigen binding site of residues which are found more commonly than cysteine, such as lysine, glutamate, histidine or tyrosine may be achieved by using mutated synthetic segments, such as V genes, to construct the library.
- mutated synthetic segments such as V genes
- the library may be constructed from gene segments of VH and VL domains where all lysine residues have been mutated to another amino acid such as arginine. The lysine in VH CDR3 may then be specifically chemically modified.
- transglutaminase which catalyzes an acyl- ransfer reaction between the gamma-carboxyamide group of glutamine residues and primary amines (E. Bendixen et al, J. Biol. Chem. 26821962-21967, 1993; K.N. Lee et al Biochim. Biophys . Acta 1202 1-6 1993; T. Kanaji et al J " . Biol . Chem. 268 11565-11572 1993) .
- This enzyme could therefore introduce amino acid residues from a peptide into a glutamine residue at the binding site through a peptide lysine epsilon amino group or into a lysine group at the antigen binding site via a peptide glutamine group.
- the enzyme could also catalyse derivatization of binding site glutamine residues with a primary amine.
- glutamine residues and lysine residues are common in antibodies, it would be advantageous to construct the library from gene segments where these residues had been mutated to other residues except for those where modification was desired.
- a further approach is to introduce chemical moieties to either the N or C terminus of polypeptides displayed on phage using reverse proteolysis or chemical conjugation or a combination of the two (I. Fisch et al, Bioconj . Chem. 3, 147-153, 1992; H. F. Gaertner et al, Bioconjug. Chem. 3, 262-268, 1992; H. F. Gaertner et al, J " . Biol . Chem. 269, 7224-7230, 1994; J. Bongers et al, Biochim. Biophys . Acta, 50, S57-162, 1991; R. Offord, Protein Engineering, 4, 709-710, 1991) .
- fluorophores which may be introduced are fluorescein, phycoerythrin, coumarin, NBD, Texas Red and chelated lanthanide ions.
- catalytic groups which may be introduced are flavin adenine dinucleotide (FAD) , flavin mononucleotide (FMN) , cytochromes and chelated metal ions such as zinc and copper.
- Figure 1 shows ELISA signals of individual phage from Library 1 which are unmodified or derivatized with NBD-1A or F-IA.
- Figure 2 shows ELISA signals of individual phage from Library 2 which are unmodified or derivatized with NBD-1A or F-IA.
- Figure 3 shows ELISA signals of individual phage from Library 3 which are unmodified or derivatized with NBD-1A or F-IA.
- Figure 4 shows the effect of modification with IA- NBD of soluble scFv fragments on the ELISA signal obtained for the two clones SSL-32 and SSL-34. Soluble single chain Fv fragments were purified by FPLC gel filtration on Superdex 75 to give monomeric fragments and modified with IA-NBD (black bar) or left unmodified (shaded bar) .
- Figure 5 shows the specificity of soluble scFv fragments derived from clone SSL-34 as determined by the ELISA signal obtained.
- Soluble scFv fragments were purified by FPLC gel filtration on Superdex 75 to given monomeric fragments and modified with IA-NBD (left hand plots) or left unmodified (right hand plots) .
- the antigens are (left to right) phOx-BSA (black bar) , phOx- CSA, phOx-KLH and phOx-polylysine, BSA.
- the NIP12 heavy chain variable domain was excised as a Ncol-Xhol fragment from the corresponding clone that was affinity selected against the 3-iodo-4-hydroxy- 5-nitrophenylacetate hapten (NIP) .
- NIP12 clone derives from a library wherein 49 human VH germline sequences were linked by PCR to a synthetic library of randomized CDR3 (of length 5 and 8) and cloned into the pHENl-V ⁇ phagemid vector (Hoogenboom & Winter, J. Mol. Biol. 227 381-388 1992) .
- NIP12 heavy chain fragment was then recloned into the corresponding sites of pHENl- VX3-C93 for soluble expression of NIP12-C93 scFv, a protein identical to the NIP12 scFv except that it carries the engineered cysteine residue at position 93 in the V ⁇ 3 light chain.
- NIP12 and its mutant NIP12-C93 scFv were prepared.
- the gene of the latter as assembled by excising from the pHENl-V ⁇ 3 cloning vector by Ncol-Xhol digestion and recloning it into the corresponding sites of pHENl-V ⁇ 3-C93 (same vector as pHENl-V ⁇ 3 with the Ser93 to Cys93 mutation in the light chain V ⁇ 3 introduced by site directed mutagenesis) .
- the yields of purified protein were similar for the two clones (about 1.5 mg per culture litre) as were their retention times on Superdex G-75 column.
- the soluble ELISA signal on NIP-coated plate was slightly less intense for the mutant protein than for NIP12. Thus, the introduction of a fifth cysteine into a scFv is tolerated.
- the cpIII-fused NIP12 and NIP12-C93 are equally expressed as detected by Wester blots using antiserum against gene III protein.
- the phage-ELISA signals were in accordance with the soluble ELISA results mentioned above. Because of their insolubility at higher concentration, phage particles usually do not exceed IO 12 TU (for fd vector) to IO 13 TU (for phagemid) per ml. In comparison to the soluble scFv concentration used for modification (+5 ⁇ M) .
- cpIII-fused scFv are thus considerably less concentrated ( ⁇ 2nM for both fd phage and phagemid since the latter packages only 10% of cpIII-fused scFv) . Therefore, we also decided to lower the concentration of modification reagent down to 30 ⁇ M. This is still a large excess (about 1.5 10* times) but, as the reacting groups (iodoacetamide and disulfide exchanger) are thiol-specific, it enabled us to limit the reaction to two hours.
- a chemisynthetic library was prepared with a fixed light chain and a repertoire of heavy chains and antibodies specific for 2-phenyloxazol-5-one then selected.
- each selection step is preceded by semisynthesis on the whole phage-antibody library amplified after the previous selection round.
- the two unselected synthetic libraries (1.0 x IO 7 combinations each) described in Hoogenboom &. Winter (1992; supra) were mixed and CsCl-grade plasmid DNA was prepared.
- the synthetic heavy chain library fragment was excised from this DNA, purified on agarose gel and ligated into the pHENl-V ⁇ 3- C93 expression vector prealably cut with Ncol and Xhol.
- the ligated DNA was then purified by GeneClean (BiolOl) and electroporated into E.coli TGI.
- a library of 2.6 IO 7 clones were obtained wherein greater than 83% of the clones had insert.
- Phage-antibody culture in 50 ml 2XTY-Amp- Glul%, phagemid particles were rescued from the exponentially growing library by superinfection at 37°C for 30 min with VCSM13 helper phage (at a ratio of 20 phage units per cell) . Cells were then spun down (4K rpm for 15 min) and resuspended in 250 ml of prewarmed (37°C) 2XTY-Amp-Kan medium. After incubation for 1 hour at 37°C with shaking, the culture was grown for 16-18 hours at 30°C with shaking.
- scFv cloned into fd vector 250 ml of 2XTY-Tet were inoculated with 100 ⁇ l of an overnight culture and grown for about 20 hours at 30°C.
- Phage-antibody purification after the removal of the cells (7K rpm for 25 min) . the phage particles were concentrated by a first PEG/NaCl precipitation (7K rpm for 25 min) and resuspended in 5 ml of a fresh and degassed 1 mM DTT solution.
- reaction mixture was purified by gel filtration on G-25 Sephadex fine (9 ml bed volume) equilibrated with PBS.
- the semisynthetic scFv was collected in 2 ml and used as such for fluorescence titration.
- Semisynthetic Phage-Antibody and ScFv ELISA Semisynthetic Phage-Antibody and ScFv ELISA.
- Semisynthetic phage-antibody stocks were first 100- fold diluted before ELISA analysis as described by Clackson et al (1991) .
- Semisynthetic scFv ELISA were done according to Marks et al (1991,-supra) .
- the purified phage particles or scFv were mixed with an excess of DTT-quenched reactant before analysis.
- ELISA plates were coated with a 100 ⁇ g/ml phOx-BSA solution in PBS overnight at room temperature.
- HELISA For specificity ELISA (BSA, ovalbumin, phOx-KLH, phOx-CSA, phOx-polylysine, chymotrypsin A, insulin and hen-egg white lysozyme (HEL) ) , the same antigen concentration was used except for HEL which was coated at 3 mg/ml.
- Neither soluble Cys93 scFv nor phage-displayed Cys93 scFv can be efficiently modified in crude culture supernatant. Therefore, to accelerate the search for antibodies where antigen binding depended on the introduced chemical moiety, polyclonal phage-ELISA were performed with purified phage particles (10 ml cultures) issued from libraries of decreasing size (first, the whole library, then mini-libraries made of 28 to 210 clones) . To define the importance of the introduced moiety to the binding activity, negative-control ELISA were done with polyclonal phage particles that were either not modified or modified with another synthetic moiety (usually F-IA) .
- IA-NBD is part of the antigen binding site.
- the phage-ELISA signals of twelve Lib3 clones are presented in figure 3. Again, the clones could be separated into two groups. The majority of the clones (10,12) first group) showed no marked preference for being modified or not. The second group included only two clones where PDEA affected binding properties: the PDEA modification enhanced their ELISA signals by a maximum factor 3.4 times.
- the ELISA signals of Libl and Lib2 clones clearly indicated that, for some clones, the covalently bound synthetic moiety is an integral part of the antigen- binding site.
- the presence of the introduced chemical group is not essential for strong binding of the hapten but in others it is essential for strong binding to occur.
- Such clones from chemisynthetic repertoires would be particularly valuable when, for example reporter groups are incorporated.
- the semisynthetic library selections thus produced phage antibodies with different binding properties, and different tolerances to modification (Table 1) .
- Individual clones of different ELISA profiles were selected for DNA sequencing, and the VH-CDR3 sequence, and the VH germline gene determined (Table 1) .
- the VH- CDR3 sequences of the clones indifferent to the presence or type of modification display a strong similarity to those obtained from the synthetic repertoire by Hoogenboom & Winter (1992, supra) .
- the VHCDR3 sequences of clone SSL14 from the unmodified library, and clone SSL-41 from the PDEA modified library (LSGVRDFY) are identical to ⁇ .Ox-18 from the original study.
- clones SSL-18 from the NBD modified library and SSL-44 from the PDEA modified library are identical to ⁇ .Ox-18 from the original study.
- clones SSL-32 and SSL-34 from the IA-NBD selected library were of VH3 origin and were purified on protein.
- the modification process did not appear to induce any change in the multimerisation of the antibody as judged by the FPLC trace of unmodified and modified protein (data not shown) .
- the binding specificity of the modified and unmodified scFv material was determined by ELISA on microtitre plates coated with phOx-BSA, a number of irrelevant antigens, and a number of other phOx-protein conjugates.
- the soluble SSL-32 scFv was found to bind to phOx-BSA as an unmodified scFv to a similar extent as the phage antibody, and was not characterised further (Figure 4) .
- the diversity of the semi-synthetic clones selected here is rather narrow and improvements in the library may be made by inclusion of longer VH-CDR3 sequences, use of different light chains and chemical modification with a population of different cofactors or chemical groups.
- the location and number of modifiable (e.g. cysteine) residues is likely to have a significant effect on the properties of the chemisynthetic library and may be varied in a controlled way.
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU70068/94A AU691817B2 (en) | 1993-06-30 | 1994-06-30 | Sbp members with a chemical moiety covalently bound within the binding site; production and selection thereof |
DE69426649T DE69426649T2 (en) | 1993-06-30 | 1994-06-30 | SPECIFIC AND PAIRED BINDING COMPOUNDS, WITH A COVALENT, CHEMICAL GROUP TIED IN THE BINDING POINT; YOUR PRODUCTION AND SELECTION |
EP94918979A EP0706569B1 (en) | 1993-06-30 | 1994-06-30 | Sbp members with a chemical moiety covalently bound within the binding site; production and selection thereof |
AT94918979T ATE199024T1 (en) | 1993-06-30 | 1994-06-30 | SPECIFIC AND PAIR-BINDING COMPOUNDS, HAVING A COVALENT CHEMICAL GROUP BONDED IN THE BONDING SITE; YOUR PRODUCTION AND SELECTION |
JP7503366A JPH09500016A (en) | 1993-06-30 | 1994-06-30 | Sbp members with covalently bound chemical moieties within the binding site; their production and selection |
US08/564,207 US6017732A (en) | 1993-06-30 | 1994-06-30 | Bacteriophage library displaying immunoglobulin repertoires with a chemical moiety covalently bound within the binding site: production and selection thereof |
DK94918979T DK0706569T3 (en) | 1993-06-30 | 1994-06-30 | Members of specifically binding pairs with a chemically bonded covalent within the binding site, preparation of selection a |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB9313509.3 | 1993-06-30 | ||
GB939313509A GB9313509D0 (en) | 1993-06-30 | 1993-06-30 | Chemisynthetic libraries |
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WO1995001438A1 true WO1995001438A1 (en) | 1995-01-12 |
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PCT/GB1994/001422 WO1995001438A1 (en) | 1993-06-30 | 1994-06-30 | Sbp members with a chemical moiety covalently bound within the binding site; production and selection thereof |
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US (1) | US6017732A (en) |
EP (1) | EP0706569B1 (en) |
JP (1) | JPH09500016A (en) |
AT (1) | ATE199024T1 (en) |
AU (1) | AU691817B2 (en) |
CA (1) | CA2163979A1 (en) |
DE (1) | DE69426649T2 (en) |
DK (1) | DK0706569T3 (en) |
ES (1) | ES2156154T3 (en) |
GB (1) | GB9313509D0 (en) |
WO (1) | WO1995001438A1 (en) |
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US6017732A (en) | 2000-01-25 |
EP0706569A1 (en) | 1996-04-17 |
JPH09500016A (en) | 1997-01-07 |
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EP0706569B1 (en) | 2001-01-31 |
DK0706569T3 (en) | 2001-04-02 |
DE69426649D1 (en) | 2001-03-08 |
AU691817B2 (en) | 1998-05-28 |
CA2163979A1 (en) | 1995-01-12 |
AU7006894A (en) | 1995-01-24 |
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ATE199024T1 (en) | 2001-02-15 |
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