WO1992016562A1 - Humanised antibodies having modified allotypic determinants - Google Patents
Humanised antibodies having modified allotypic determinants Download PDFInfo
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- WO1992016562A1 WO1992016562A1 PCT/GB1992/000445 GB9200445W WO9216562A1 WO 1992016562 A1 WO1992016562 A1 WO 1992016562A1 GB 9200445 W GB9200445 W GB 9200445W WO 9216562 A1 WO9216562 A1 WO 9216562A1
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- constant region
- amino acid
- molecule
- allotypic
- immunoglobulin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
Definitions
- the present invention relates to binding molecules .
- it relates to recombinantly produced antibodies .
- Monoclonal antibodies are made by establishing an immortal cell line which is derived from a single immunoglobulin producing cell secreting one form of a biologically functional antibody molecule with a particular specificity.
- the simplest antibody comprises four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulphide bonds (see figure 1).
- the light chains are of two types, either kappa or lambda.
- Each of the H and L chains has a region of low sequence variability, the constant region (C) giving rise to allotypes and a region of high sequence variability, the variable region (V) giving rise to idiotypes.
- the antibody has a tail region (the Fc region) which comprises the C regions of the two H chains.
- the antibody also has two arms (the Fab region) each of which has a V L and a V H region associated with each other. It is this pair of V regions (V L and V H ) that differ from one antibody to another, and which together are responsible for recognising the antigen.
- each V region is made up from three complementarity determining regions (CDR) separated by four framework regions (FR).
- CDRs are the most variable part of the variable regions, and they perform the critical antigen binding function.
- the CDR regions are derived from many potential germ line sequences via a complex process involving recombination, mutation and selection. It has been shown that the function of binding antigens can be performed by fragments of a whole antibody. Binding fragments are the Fv fragment which comprises the V L and V H of a single heavy chain variable domain (V H ).
- the Fc tail of a non-human antibody is exchanged for that of a human antibody.
- the FRs of the non-human antibody are exchanged for human FRs. This process is carried out at the DNA level using recombinant techniques.
- these humanised immunoglobulins do not solve all the problems, because an immune response may still be mounted against the treatment antibody even when a patient is treated with a human antibody, as it may show certain sequence differences in the V (ie idiotypic differences) and C (ie allotypic differences) regions when compared with the patients own equivalent antibodies.
- IgG immunoglobulin G
- IgM immunoglobulin A
- IgD immunoglobulin D
- IgE immunoglobulin E
- the allotypes represent alternative amino acid substitutions found at discrete sites in the protein sequence. These different allotypic determinants are found in different combinations within given allelic forms of genes, but not all possible combinations which theoretically might exist are in practice observed.
- the four different allotypes of IgG1 can be seen (ie distinguished) by the immune system. These are G1m 1, 2, 3 and 17. Alternatively, combinations thereof, such as G1m (1, 17 ) , can also be distinguished. The four different single allotypes are depicted in figure 2.
- Antisera can be raised in other non-human species which can see the alternative isoallotypes provided that the antibody is purified away from the other human isotypes.
- Such isoallotypes for which such an antisera exists have been called non-allotypes and given the designation for example, nG1m(1) which is the isoallotype of G1m(1).
- nG1m(1) which is the isoallotype of G1m(1).
- the sequence of the human allotype of IgG1 G1m (1, 2, 17) is shown aligned with sequences for the other human IgG, isotype sub-classes in figure 4 (a, b, c and d). It can be seen that the four isotypes are extremely homologous for the domains CH1, CH2 and CH3, and that the major isotypic differences are in the hinge region which varies in both, length and sequence between isotypes.
- the allotypic residues of IgG1 G1m (1, 2, 17) have been marked in figure 4. However, for the purposes of clarity the sequences around the allotypic sites G1m (1) (2) and (17) are shown below for each isotype.
- IgG1 may exist as several allotypes depending on whether aspartic acid or glutamic acid at position 356, or leucine or methionine at position 358 are present.
- IgG1 may exist as either of two allotypes depending on whether glycine or alanine is present at position 431.
- IgG1 may exist as either of two allotypes depending on whether lysine or arginine is present.
- the allotypes (17) and (3) cannot co-exist as they represent alternative substitutions at the same position.
- the alternative alleles of G1m (1) and (2) do not provoke a human allotype response because of the homology of these alleles with the other IgG sub-classes in this region. These alleles are therefore called isoallotypes because they are only recognisable by xenoantisera (antisera from a different species) and only when the isotype is purified away from the other sub-classes.
- the present applicants propose the creation of a new IgG1 allele by site-directed mutagenesis of the gene, for example, an existing CAMPATH-1H monoclonal antibody gene described below, so that the new allele consists entirely of isoallotypic determinants.
- the preparation of IgG1 mutants according to the teaching provided by the present applicants is shown schematically in figure 3.
- IgG1 is specifically directed to IgG1 and in particular, the CAMPATH-1H monoclonal antibody
- the same approach can be used to create isoallotypes of the other human isotypes such as IgG2, IgG3 and kappa.
- the present invention provides a first binding molecule derivable from a second binding molecule; which second binding molecule is an immunoglobulin, or a derivative, structural or functional analogue thereof, a member of a family of homologous molecules, and has one or more sites which are structurally distinctive from equivalent sites in the other family members;
- said first binding molecule is more closely homologous to the other family members than to said second binding molecule, at at least one of said one or more sites.
- the first binding molecule may also be an immunoglobulin or a derivative, structural or functional analogue thereof.
- the one or more sites which are structurally distinctive from the equivalent sites in the other family members may be in the constant region giving rise to an allotypic difference.
- the first binding molecule may comprise entirely isoallotypic determinants.
- the second binding molecule may be selected from the group consisting of IgG1, IgG2, IgG3, lgA2, IgE, kappa light chains or derivatives, structural or functional analogues thereof.
- the allotypic differences may be present at one or more of sites (1) (2) (3) or (17) as described herein.
- the second binding molecule is IgG2
- the allotypic difference may be present at site (23).
- the second binding molecule is IgG3
- the allotypic differences may be present at one or more of the sites (11) (5) (13) (14)
- the allotypic differences may be present at one or more of the sites (1) and (2).
- the second binding molecule is kappa light chain, the allotypic differences may be present at one or more of the sites (1) (2) or (3).
- the present invention also provides pharmaceutical preparations comprising a first binding molecule as defined above or described herein together with one or more excipients.
- the pharmaceutical preparation may comprise a cocktail of said first binding molecules.
- Also provided by the present invention are methods for making a first binding molecule as defined above or described herein.
- the first binding molecule may be made by providing a gene sequence encoding the second binding molecule and altering those parts of the gene sequence encoding said one or more sites.
- the gene sequence may be altered by site directed mutagenesis using oligonucleotide primers.
- the altered gene sequence may be incorporated into a cloning vector or expression vector.
- the expression vector may be used to transform a cell. The cell may be induced to express the altered gene sequence.
- the present invention therefore provides cloning vectors and expression vectors incorporating the altered gene sequence. Also provided are cells transformed by expression vectors defined above. Also provided are cell cultures and products of cell cultures containing the first binding molecules. Also provided are recombinantly produced said first binding molecules.
- the present invention provides a molecule which comprises an amino acid sequence derivable from part or all of the constant region of an immunoglobulin heavy chain which constant regions are of a particular isotype and have one or more allotypic determinants
- amino acid sequence is substantially homologous to the amino acid sequence of said constant region, but has been altered so that it is without at least one of said allotypic determinants, by making the amino acid residues at the site of an allotypic determinant identical to the amino acid residues from the corresponding position in another equivalent immunoglobulin constant region of a different isotype.
- the molecule may comprise an amino acid sequence derivable from part or all of a human immunoglobulin constant region.
- the molecule may also comprise one or more polypeptides together with said amino acid sequence.
- the polypeptide may comprise a functional biological domain.
- the domain may be such that it mediates any biological function.
- the functional biological domain may comprise a binding domain.
- the binding domain will have an ability to interact with another polypeptide. The interaction may be non-specific or specific.
- the polypeptide, biological domain, binding domain and immunoglobulin-like binding domain may derive from the same source or a different source to the constant region.
- the constant region may be from an immunoglobulin of the isotype IgG.
- the isotype subclass may be IgG1 and the molecule may no longer have one or more of the allotypic determinants 1,2,3 and 17.
- the isotype subclass may be IgG2 and the molecule may no longer have the allotypic determinant 23.
- the isotype subclass may be IgG3 and the molecule may no longer have one or more of the allotypic determinants 11,5,13,14,10,6,24,21,15, 16, 26 and 27.
- the constant region may be from an immunoglobulin of the isotype IgA2 and the molecule may no longer have either or both of the allotypic determinants 1 and 2.
- the present invention also provides a pharmaceutical preparation which comprises a molecule as defined.
- the present invention also provides a reagent which comprises a molecule as defined.
- the present invention also provides a nucleotide sequence encoding a molecule as defined.
- the present invention also provides cloning and expression vectors comprising a nucleotide sequence as delivered above.
- the present invention also provides host cells comprising a cloning or expression vector as defined above.
- the present invention also provides a method of preparing a molecule as defined above which comprises the steps of:
- the present invention also provides a method of treating a patient which comprises administering a pharmaceutical preparation as defined above.
- Genes encoding therapeutically useful antibodies are generally available in one of several different forms. They may be available as a cloned variable region DNA sequence with restriction sites at each end, suitable for recloning along with a chosen cloned constant region DNA sequence into a suitable expression vector. This is the strategy described herein for the constructs TF57-19, MTF121 and MTF123. Alternatively, they may be available as complete immunoglobulin DNA sequences including the V and C regions together, e.g. a cDNA clone of a complete humanised or human antibody.
- the next step is to predict the amino acid sequence of the constant region from the DNA sequence.
- the DNA sequence can be obtained using a variety of strategies familiar to molecular biologists.
- the predicted amino acid sequence would then be checked for the amino acids known to vary as allotypes. Any isoallotypes present within the sequence can be left unaltered. Any allotypes present can be mutated.
- the next step is to decide what amino acid sequence to mutate the allotype to, in order to imitate an isoallotype. This is done by lining up the sequence with the corresponding region of the other immunoglobulin isotypes. For all known allotypes, it has been found that one or more of the other isotypes have invariant sequences for the homologous region. One of these sequences can then be chosen to form the basis for the changes to be made in the allotype in question. Having predicted the new amino acid sequence for the constant region, it is necessary to alter the existing DNA clone or to create a new DNA clone which will encode this sequence. Again there are several strategies available to molecular biologists in order to achieve this.
- the gamma-1 constant region was cloned in an M13TG131 single stranded phage vector. Mutagenic oligonucleotides were synthesised which were largely homologous to the single strand, but which contained base changes necessary to alter the codons for the critical amino acids. The mutagenesis was carried out using a commercial kit from Amersham International, High Wycombe, Bucks. Alternatively it would be possible to synthesise a complete artificial gene which encodes the predicted sequence.
- the gene is ready for expression.
- expression vectors There are many different expression vectors available. Some of these are more suitable for expression in restricted cell types. Again it is within the standard technical expertise of one skilled in this field to choose and adapt expression vectors for this purpose.
- modifications of the pSVgpt and pSVneo vectors have been used. These vectors have convenient cloning sites for the immunoglobulin variable and constant region, encoding DNA fragments adjacent to suitable promoter and enhancer sequences to allow expression in lymphoid cells.
- the vector allows the easy independent replacement of variable or constant region encoding DNA fragments.
- any suitable variable region can be subcloned into the vector, to give rise to a new specificity, or the variable region can be kept and the constant region changed to give rise to a new isotype or allotype.
- Alternative vector systems are readily available.
- the most common kappa light chain allotype is Km(3) in the general population. Therefore it may be sufficient to utilise this common kappa light chain allotype, as relatively few members of the population would see it as foreign.
- the allotype Km(1,2) could first be mutated to the allotype Km(1).
- the light chain allotype Km(1) is often only weakly recognized in combination with certain heavy chain classes and subclasses, and so may not cause a major problem in therapeutic use.
- figure 1 illustrates the structure of an IgG antibody
- FIG 2 shows the allotypes for the IgG1 antibody CAMPATH-1H
- FIG. 3 shows schematically the preparation of IgG1 mutants
- figure 4 shows the IgG1 G1m (1,2,17) allotype sequence aligned to single allotypic examples of IgG2, 3 and 4 (none of these other subclasses have allotypic residues which cover the same residues as for the IgG1 allotypes);
- figure 5 shows the M13TG131 cloning vector containing the human gamma-1 constant region, showing cloning sites and modified polylinker;
- figure 6 shows the original Hu4vH HuG1 pSVgpt expression vector and its modified version
- figure 7 shows the result of an ELISA assay testing different dilutions of the antibodies of mutants 1, 2 and wild type CAMPATH-1H for IgG1 specificity
- figure 8 shows the result of an autologous complement mediated lysis test using human peripheral blood lymphocytes
- FIG 9 illustrates an antibody-dependent cell- mediated cytotoxicity assay (ADCC) using CD3 activated interleukin-2 expanded human blastocytes cell effectors (E) and targets (T).
- ADCC antibody-dependent cell- mediated cytotoxicity assay
- the starting antibody used for site-directed mutagenesis was CAMPATH-1H, a monoclonal antibody with a kappa light chain containing the human constant region sequence for IgG1 which carries the G1m (1, 17) allelic determinants.
- the whole IgG1 encoding region exists as approximately 2.3 kb HindIII-SphI restriction fragment cloned in an M13 vector.
- the M13TG131 cloning vector containing the human gamma-1 constant region showing cloning sites and modified polylinker is shown in figure 5.
- the IgG1 encoding region is entered in the EMBL Sequence Database under the code number HS1GCC4.
- the accession number is AC J00228 (the printout from the database is provided herein as Appendix 1).
- This sequence is for the G1m (1, 17) allotype. It covers 2009 bases from the 5' Hindlll site (A)AGCTT including all of the coding region. It does not however, include some of the 3' non-coding region up to the SphI site.
- the sequence provided by the EMBL Database is that of the upper strand of DNA.
- the CH1 domain starts at nucleotide 210 and ends at nucleotide 503.
- the mutagenic oligonucleotides MO1 and MO4 hybridise to nucleotides 486 to 510.
- the hinge region starts at nucleotide 892 and ends at nucleotide 936.
- the CH2 domain starts at nucleotide 1481 and ends at nucleotide 1803.
- the mutagenic oligonucleotide MO2 hybridises to nucleotides 1515 to 1543.
- the essential signal for the poly A tail is provided by nucleotides 1902 to 1908.
- the IgG1 coding region exists as a 2260 nucleotide fragment, of which the final 251 nucleotides are non-coding and therefore, inessential. Therefore, an embodiment of the invention could be carried out using the sequence information provided by the EMBL Sequence Database. It should be noted however, that the Sph1 restriction site referred to above, is present in the 3' end inessential non-coding region. Therefore, if the sequence data as provided by the EMBL database were being used, alternative restriction sites would have to be utilised.
- mutagenic oligonucleotides were:
- oligonucleotides were synthesised and then purified using an automated synthesizer and oligo purification columns supplied by Applied Biosystems (Applied Biosystems, 850 Lincoln Drive, Foster City, California, 94404 USA) following the manufacturers recommended protocols. Mutations were checked by Sanger Dideoxy sequencing (Sanger, F.S., Nicklen, S., and Coulson, A.R., (1977) Proc. Natl. Acad. Sci., USA, 74, 5463) using standard protocols and kits. As this newly formed allotype sequence is found in all humans, there should be no immunological response to this alternative form of G1m (1). Additionally and similarly, the lysine residue responsible for the G1m (17) allotypic determinant was converted to an arginine residue corresponding to the G1m allele (Lys 214-Arg; mutant 1).
- mutant 1 The gene for this new constant region of mutant 1 carrying these three changes has been sequenced, incorporated into an expression vector containing the CAMPATH-1H V-region and expressed together with the CAMPATH-1H light chain which had been introduced by co-transfection.
- a further mutant has been made by replacing the critical arginine residue associated with G1m (3) of mutant 1 with a threonine residue, to produce a heavy chain which is the equivalent of IgG2 and which should fail to react with both anti-G1m (17) and anti-G1m (3) antisera (mutant 2).
- Mutant 2 has also been sequenced, re-cloned in an expression vector containing the CAMPATH-1H light chain.
- the supernatants of growing cultures containing either of the two mutants were subsequently assayed for the expression of a human IgG1 kappa product.
- the mutations were introduced with the oligonucleotides listed above.
- the modified Hu4vHG1pSVgpt vector shown in figure 6 was used to simplify the subcloning of all the new mutants into the expression vector, owing to the possibility of use of two different "sticky ends" Bam HI and NotI.
- the expression vectors and V H region sequences and expression, along with the light chains, in YO rat plasmacytoma cells are all as described in Riechmann L., Clark, M.R. Waldman H., Winter G. (1988) Nature 332, 323-327.
- Example 1 From the positive cultures, the producers of the largest amount of the IgG1 product were selected to obtain purified antibody for biological assays to determine their allotypes and biological effector functions.
- Example 1 From the positive cultures, the producers of the largest amount of the IgG1 product were selected to obtain purified antibody for biological assays to determine their allotypes and biological effector functions.
- Human peripheral blood mononuclear cells from a healthy donor were isolated from 60 ml defibrinated blood on a Lymphoprep gradient (Nyeggard & Co., AS, Oslo, Norway). The cell pellet was washed in IMDM (Iscove's Modification of Dulbecco's Medium, Flow Laboratories, Scotland), and the cells were labelled with 51 Cr.
- the starting dilution of antibodies used in the test was 50 ⁇ g/ml in PBS, 10 ⁇ g/ml BSA (dilution 1). Dilution 1 was further diluted 8 times two-fold to a final dilution of 1/128. Wild type antibody diluted in the same manner was used as a control.
- ADCC antibody-dependent cell-mediated cytotoxicity
- Unlabelled blastocytes (2 ⁇ 10 6 ) were diluted 100:1 and 30:1 in IMDM 1% BSA medium.
- the ratios 100:1 and 30:1 refer to the final absolute ratios of effectors to 5 1 Cr labelled targets in the assay.
- Assays were performed in microtitre plates with a total volume of 200 ⁇ l per assay well. Thus 100 ⁇ l of targets at a concentration of 2 ⁇ 10 4 were put in each well ie 2 x 10 3 total cells.
- E:T of 100:1 100 ⁇ l of effectors at 2 x 10 4 were plated per well ie 2 ⁇ 10 5 .
- For E:T of 30:1 100 ⁇ l of effectors at 6 ⁇ 10 5 were put into each well ie 6 x 10 4 total cells.
- cpm radioactive counts per minute as measured on a counter.
- FIG. 9 The result is shown in figure 9. The figure shows that all of the antibodies tested released chromium. Wild type TF 57-19 and mutant 2 (MTF 123) released at about equal levels, whereas mutant 1 (MTF 121) shows a slightly higher release.
- the antibodies were tested in an assay specific for their G1m (3) allotypes reactivity using a monoclonal reagent from Oxoid (WHO/IVISS recognised agent, Study
- Microtiter plates were coated with the anti-CAMPATH idiotype YID 13.9.4 antibody captive, and divided into three arrays of 4 ⁇ 4 wells. Into each of the three arrays, 4 ⁇ 5 fold dilutions of the antibody TF 57-19, MTF 121 and MTF 123 (50 ⁇ g/ml) in PBS 1% BSA and a control solution of PBS/BSA each were added.
- the microtiter plate was developed with streptavidin horseradish peroxidase.
- the result is illustrated in Table 1.
- the numbers in the results represent the optical density (O.D) as measured in an ELISA plate reader multiplied by 100 ie 12 represents an O.D of 0.12 and 70 an O.D of 0.70.
- the antibodies were tested in a conventional allotyping experiment using inhibition of red cell agglutination.
- the experiment was carried out using reagents supplied by the Central Laboratory of the Netherlands Red Cross, Blood Transfusion Service (PO Box 9190, 1006 AD Amsterdam, Netherlands).
- coated red blood cells were washed four times with PBS and stored at 4°C in preservation fluid (although coated red blood cells can be stored at 4°C in PBS for one week). These coated red blood cells were then agglutinated with four antisera to the IgG1 allotypes as follows using the recommended dilution for each antiserum.
- anti-G1m(z) anti-G1m(17) 1 in 30 dilution
- anti-G1m(a) anti-G1m(l) 1 in 30 dilution
- anti-G1m(f) anti-G1m(3) 1 in 30 dilution
- CAMPATH-1H constructs (MTF 121, MTF 123) with the altered gamma-1 constant regions were then tested for their abilities to inhibit the agglutination of the red cells by the above antisera.
- the inhibiting antibodies were tried at concentrations of 0.5mg/ml, 0.25mg/ml and 0.125mg/ml in phosphate buffered saline containing 5% foetal bovine serum.
- Control sera containing IgG1 of allotype G1m(zax) or G1m(f) [G1m(1,2,17) or G1m(3)] were also included in the experiment and were used at dilutions of 1 in 10,20 and 40.
- Allotype CAMPATH-1H constructs Control sera TF57-19 MTF121 MTF123 G1m(1,2,17) G1m(3) G1m(1) + - - + - G1m(2) - - - +
- binding molecules hereby provided to make pharmaceuticals according to standard techniques.
- pharmaceuticals can be used in accordance with standard practices.
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Priority Applications (1)
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JP4505594A JPH06510659A (en) | 1991-03-12 | 1992-03-12 | Humanized antibodies with altered allotypic determinants |
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GB919105245A GB9105245D0 (en) | 1991-03-12 | 1991-03-12 | Binding molecules |
GB9105245.6 | 1991-03-12 |
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JP (1) | JPH06510659A (en) |
CA (1) | CA2105980A1 (en) |
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WO (1) | WO1992016562A1 (en) |
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Also Published As
Publication number | Publication date |
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CA2105980A1 (en) | 1992-09-13 |
GB9105245D0 (en) | 1991-04-24 |
JPH06510659A (en) | 1994-12-01 |
EP0575407A1 (en) | 1993-12-29 |
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