WO1991003493A1 - CONJUGUES F(ab)3 ou F(ab)4 bi ou trispécifiques - Google Patents

CONJUGUES F(ab)3 ou F(ab)4 bi ou trispécifiques Download PDF

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Publication number
WO1991003493A1
WO1991003493A1 PCT/GB1990/001335 GB9001335W WO9103493A1 WO 1991003493 A1 WO1991003493 A1 WO 1991003493A1 GB 9001335 W GB9001335 W GB 9001335W WO 9103493 A1 WO9103493 A1 WO 9103493A1
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Prior art keywords
antibody
fab
bispecific
trispecific
arms
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PCT/GB1990/001335
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English (en)
Inventor
Martin John Glennie
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The University Of Southampton
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Priority claimed from GB898919485A external-priority patent/GB8919485D0/en
Application filed by The University Of Southampton filed Critical The University Of Southampton
Publication of WO1991003493A1 publication Critical patent/WO1991003493A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07K16/34—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood group antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2806—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]

Definitions

  • Antibodies which are bispecific with respect to the antigen they recognize have been used successfully in a number of applications. In immunochemistry they have been used to cross-link cellular antigen and detecting agent such as ferritin or horseradish peroxidase, doing away with the antibody conjugates used in more conventional methods. Similarly they have been used as
  • heterobifunctional protein cross-linkers for the immobilization of enzymes in a number of assays. Perhaps their greatest potential lies in their therapeutic use for the targeting of unwanted cells or pathogens by cytotoxic effector cells or pharmacologic agents such as drugs or toxins.
  • bispecific F(ab' ⁇ ) 2 antibodies in which one Fab' ⁇ aim is directed at a lymphoma cell and the other binds to a riboscme-inactivating protein, such as ricin A chain or saporin, can target a toxic agent to tumour cells both in vitro and in vivo and prevent further growth.
  • a riboscme-inactivating protein such as ricin A chain or saporin
  • bispecific antibodies have usually have been employed which cross-link the T cell receptor complex or the Fc receptor, respectively, onto the target cell and thereby mediate high levels of specific lysis.
  • the bispecific antibodies do not simply serve to "glue" the two cell populations together, but in linking the effector and target cell actually trigger the lytic process.
  • bispecific antibodies have also been useful as tools for understanding some of the molecular interactions which occur when resting T cells are activated for
  • effectors for lysis activation of effectors for lysis and the activation for proliferation is not clear.
  • effectors such as
  • T cells are not cytotoxic when resting but become cytotoxic when profilterating.
  • certain effector populations can be
  • TCR-CD3 antigen receptor complex
  • T cell molecules such as CD2 CD4 or CD8, are more potent in this respect.
  • a trimeric or tetraireric antibody preferably bispecific or trispecific.
  • antibody is meant a moiety capable of binding to one or more specific sites on one or more specific antigens.
  • Trimeric antibodies consist of three structurally similar arms, such as three Fab arms, linked together. Tetrameric antibodies consist of four such arms.
  • Bispecific antibodies of the invention consist of two arms having a first antigen specificity, the third, and fourth if present, having a
  • Trispecific antibodies of the invention consists of three arms having, respectively, first, second and third antigen specificities, if present, the fourth arm has the same
  • antibodies of the invention are F(ab) 3 or F(ab) 4 antibodies, such as a bispecific or trispecific F(ab') 3 or F(ab') 4 antibody and
  • Fab' antibody is meant an Fab antibody
  • Mtibody specificity in antibodies according to the invention may, however, be provided by antibody fragments from any source, including genetically engineered Fv fragments, which may have engineered on multiple residues suitable for forming links between fragments. Such fragments will form Fv 3 and Fv 4 antibodies.
  • Antibodies of the invention may have specificities for any antigens against which antibodies can be raised or engineered. They find particular application in therapy, especially against tumour cells, but also have applications in assay techniques.
  • At least one arm of the antibody specific for a marker on a target which may be a target cell such as tumour cell
  • at least one arm is specific for a marker on an effector, which may be an effector cell such as a T cell, lymphocyte or macrophage, or it may be another cell toxin such as a ribosome-inactivating protein, for example saporin, ricin A chain or intact ricin, or another therapeutic agent to which antibodies can be raised or engineered, such as daunomycin or adriamycin.
  • the trispecificity allows it to at once bind to an effector cell and to activate it.
  • the third arm binds to the target cell. It is preferred that two arms of the trispecific antibody are specific to T cells, one of the CD3 molecule and the other to an accessory surface molecule such as the CD2, CD4 or CD8. Alternatively, both arms may be specific for CD2. In that event, the two arms are specific for different epitopes on CD2 such as T11 2 and T11 3 or T11 2 and T11 3 .
  • step (v) linking the bispecific F(ab) 2 antibody from step (iii) to the Fab arm from step (iv) to give specific F(ab) 3 .
  • the Fab fragments are generated by treating the antibodies providing the fragments with a proteolytic enzyme such as pepsin to give a monospecific F(ab) 2 fragment.
  • a proteolytic enzyme such as pepsin
  • This is split by reaction with, for example, 2-merc-aptcethanol to give Fab SH fragments, in which the -S-S- links between the Fd chains of the F(ab) 2 fragments in the original antibody have been broken and reduced to -SH groups.
  • Fab SH fragments are prepared from two antibodies to give FabAg SH and FabB SH fragments.
  • the linkage of the Fabg jj fragments is effected by treating FabA SH fragments with o-phenylenediamine (oPDM) to give FabA mal fragments. These are combined with untreated FabB SH fragments, in a 2:1 weight ratio, under cross-linking conditions to give bispecific FabAAB.
  • the product was, reduced and alkylated with 20mM 2-mercaptoethanol and 25mM iodoacetamide respectively to remove any minor products which may have formed by oxidation or disulphide exchange, before fractionating an Ultrogel AcA44.
  • oPDM o-phenylenediamine
  • Fab SH fragments are prepared from three antibodies to give FabA SH FabB SH and FabC SH fragments.
  • the linkage of the Fab SH fragments is effected by treating FabA SH fragments with oPDM to give FabA mal fragments. These are combined with untreated FabB SH fragments under cross-linking conditions to give bispecific F(ab)2AB, as shown in Fig. 1.
  • FabC SH fragments are similarly treated with oPDM, to yield FabC mal fragments, which are combined with the F(ab)2AB by means of an -SH group on the F(ab)2AB to give trispecific F(ab) 3 ABC antibody (see Fig. 2).
  • a conjugate comprising an antibody according to the first aspect of the invention and an effector for which at least one of the arms of the antibody is specific.
  • the invention also contemplates a process for the preparation of such a conjugate, in which the antibody is mixed with the effector.
  • the invention further contemplates a pack coirprising an
  • Figure 1 shows the postulated reaction between two Fab fragments to produce a bispecific F(ab) 2 antibody
  • Figure 2 shows the proposed structure of a trispecific antibody according to the invention
  • Figure 3 shows typical chromatography profiles obtained during the preparation of bispecific F(ab' ⁇ ) 3 and trispecific F(ab' ⁇ ) 3 ;
  • Figures 4 (a) and (b) are graphs showing redirected cellular cytotoxicity of 51 Cr-labelled chicken red blood cells (CRBC) mediated by normal peripheral blood lymphocyte (PBL) and bispecific F(ab' ⁇ ) 2 antibody;
  • CRBC chicken red blood cells
  • PBL peripheral blood lymphocyte
  • bispecific F(ab' ⁇ ) 2 antibody bispecific F(ab' ⁇ ) 2 antibody
  • Figure 5 is a graph showing redirected cellular cytotoxicity of 51 Cr-labelled CRBC by PBL and one or two bispecific
  • Figure 6 is a graph showing redirected cellular cytotoxicity of 51 Cr-labelled CRBC by bispecific F(ab' ⁇ ) 2 and F(ab' ⁇ ) 3 derivatives;
  • Figure 7 shows the blocking of redirected cellular
  • Figure 8 is a graph showing redirected cellular cytotoxicity of 51 Cr-labelled CRBC by trispecific F(ab' ⁇ ) 3 .
  • Figures 9(a) and (b) are graphs showing the case of blocking of trispecific antibodies
  • Figure 10 is a graph showing proliferation (activation) responses of PBL to different Fab' ⁇ derivatives
  • FIG. 11 shows proliferation responses of PBL to different
  • Figure 12 shows the redirected cellular cytotoxocity of human tumour cells (Namalwa) with trispecific antibody; and Figure 13 shows the redirected cellular cytotoxocity of human tumour cells with a trispecific antibody triggering through CD2.
  • FCS myoclone
  • a mouse IgGl monoclonal antibody, E 11 C 12 , reacting with chicken red blood cells (CRBC) was raised using conventional hybridoma
  • mice were immunized in a protocol which delivered CRBC (approx 10 9 ) s.c. in CFA and IFA (Difco, Detroit, MI) on days 0 and 14 respectively, and i.p. in DMEM on day 24.
  • CRBC CRBC
  • IFA IFA
  • DMEM DMEM
  • splenic mononuclear cells were fused with the NS-1 (P3/NS-1/1-Ag4.1) mouse myeloma line at a ratio of 2:1 by using a standard somatic fusion protocol with polyethylene glycol 4000 (E.Merck, Darmstadt, Germany).
  • Hybridoma cells secreting anti-CRBC antibody were identified by immunofIuorescence staining and flow cytometry as described previously and cloned by limiting dilution.
  • hybridoma cell lines producing the antibodies OKTI (CD5), OKT3 (CD3) and OKT11 (CD2) were obtained from the American Type Culture Collection (ATCC, Rockville, Maryland), and the hybridoma 3G8 (CD16) was a gift from Dr. D. Segal, NIH, Bethesda, Maryland. All hybridoma cells were expanded as ascitic tumors in pristaneprimed (BALB/c ⁇ CBA) Fl mice. The 7S IgG fraction of monoclonal ascites was isolated as described by precipitation in 2 M amronium sulfate, followed by ion exchange chromatography on Trisacryl-M-DEAE (LKB-Adapter AB, Bromma, Sweden) .
  • Antibody F(ab'( ⁇ ) 2 fragments from IgG were prepared by limited proteolysis with pepsin at pH 4.1-4.2 in 0.1 M sodium acetate. The reaction being monitored at regular intervals by rapid fractionation of 100 ⁇ gg samples on a GF 250 HPLC column (Zorbac), and then, when less than 10% of the IgG remained, the digestion was stopped by adjusting the pH to 8.0 with saturated Tris-base and the products fractionated on Ultrogel AcA44 (LKB).
  • Example 1 Preparation of bispecific F(ab' ⁇ ) 3 antibodies:
  • F(ab' ⁇ ') 2 from the two chosen mouse antibodies at 10 mg/ml in 0.2 M Tris-HCI buffer, pH 8.0, containing 10 mM EDTA was reduced by addition of 20 mM 2-mercaptoethanol for 30 min at 30°C.
  • both reduced Fab' ⁇ (Fab' ⁇ SH ) samples were chilled to 4°C, a temperature which was maintained throughout the remainder of the preparation including the chromatography stages, before running through Sephadex G-25 equilibrated in a buffer of 50 irM sodium acetate, pH 5.3, containing 0.5 mM EDTA.
  • bispecific F(ab' ⁇ ) 2 antibodies were made by a similar method to that of Example 1, except that the Fab' fragments of Example 1 were mixed in a 1:1 molar ratio, to give bispecific F(ab' ⁇ ) 2 .
  • Bispecific F(ab' ⁇ ) 2 was conjugated with a Fab' ⁇ mal from a third antibody. This latter reaction relies on having free -SH groups available in the bispecific F(ab' ⁇ ) 2 derivative.
  • the procedure and reaction conditions for linking the Fab' ⁇ mal to the F(ab' ⁇ ) 2SH were similar to those used Example 1: bispecific F(ab' ⁇ ) 2 and Fab' ⁇ 2 fragments from the third antibody at 5 mg/ml in 0.2 M Tris-HCl buffer, pH 8.0, containing 10 mM EDTA were reduced by addition of 20 mM 2-mercapoethanol for 30 min at 30°C.
  • Trispecific F(ab' ⁇ ) 4 was also generated during the trispecific F(ab' ⁇ ) 3 preparation. It emerged from the AcA44 column at a position which corresponded to that of a protein with a molecular weight of approximately 200 kDa. This size is consistent with the joining of four Fab' ⁇ fragments during the reaction. Apparently, the bispecific F(ab' ⁇ ) 2 has conjugated with two Fab' ⁇ mal fragments from the third antibody.
  • the final products in the reaction mixtures were reduced and alkylated with 20 mM 2-mercaptoethanol and 25 mM iodoacetamide respectively to remove any minor products which may have formed by oxidation or disulphide exchange, before fractionating on Ultrogel AcA44.
  • ** toxin ribosome inactivating proteins such as saporin or ricin
  • CRBC Chicken red blood cells
  • Namalwa lymphoma cells were used as targets throughout the study.
  • fresh blood was collected from Rhode Island Red
  • Ficoll-Hypaque (Lymphoprep, Nyeguard, Oslo, Norway). Cells collected at the interface were washed in phosphate-buffered saline (PBS) and resuspended in supplemented DMEM for use in cytotoxicity or proliferation assays.
  • PBS phosphate-buffered saline
  • Cytotoxicity was measured by a standard 51 Cr-release assay in 96-well, U-bottomed, microculture plates (Gibco). Each well received 50 ⁇ l of antibody diluted in supplemented DMEM, followed by 10 4 5 1 -Cr-labeled CRBC (50 ⁇ l) or 10 4 51 Cr-labeled Namalwa cells (50 ⁇ l) and 2 ⁇ 10 5 or 5 ⁇ 10 5 PBL
  • effectors 100 ⁇ l respectively in supplemented DMEM.
  • the cell mixtures were then sedimented by centrifugation (230xG for five min) before incubating at 37 ° C in a humidified atmosphere of 5% CO 2 in air for 4, 8 or 21 hours to allow lysis. Finally the cells were sedimented at 420 ⁇ G for five min and 100- ⁇ l aliquots of supernatant removed to assess the release of 51 Cr from target cells. Percentages of specific 51 Cr release were calculated by the usual method using detergent lysis with 1% Nonidet P40 to give maximum 51 Cr release.
  • Fig. 4 shows lytic activity of the CD3 ⁇ CRBC antibody (100 ng/ml) in 4 and 8 hour assays using fresh PBL from six healthy donors.
  • (b) shows lysis of CRBC using PBL from one healthy donor and various concentrations (as indicated) of CD3 ⁇ CRBC and CD16 ⁇ CRBC in 4, 8 or 21 hour assays.
  • the assay time is indicated on each of the CD3 ⁇ CRBC titration curves, but is emitted from those of the CD16 ⁇ CRBC derivative due to their proximity.
  • FIG. 5 A graph showing redirected antibody dependent cellular cytotoxicity of 51 Cr-labeled CRBC by PBL and one or more bispecific F(ab' ⁇ ) 2 antibodies is shown in Fig. 5. Lysis was measured in an 8 hour assay using fresh PBL from one donor and the derivatives indicated.
  • Fig. 6 shows that the redirected cellular cytotoxicity against 51 Cr-labelled CRBC is considerably higher for bispecific F(ab' ⁇ ) 3 derivatives than for bispecific F(ab'#) 2 derivatives.
  • the CD3 ⁇ CD3 ⁇ CRBC trimsr was found to be up to 125 times more potent than the equivalent dimer, CD3 x CRBC, giving significant activity at concentrations below 0.1ng/ml. The efficiency of these bispecific trimers is not dependant upon two
  • CD3 ⁇ CRBC ⁇ CRBC gives a similar cytotoxicity result.
  • Fig. 7a shows a comparison of the cytotoxicity of CD2 ⁇ CRBC antibody with that of CD2 ⁇ CD2 ⁇ CRBC antibody, blocked with CD2 antibody.
  • Fig. 7b shows a comparison of the cytotoxicity of CD3 ⁇ CRBC
  • bispecific trimers still showed cytotoxic activity with blocking
  • FIG. 8 A graph showing redirected antibody dependent cellular cytotoxicity of 51 Cr-labelled CRBC by trispecific F(ab' ⁇ ) 3 is shown in Fig. 8.
  • Lysis was measured in an 8 hour cytotoxicity assay using fresh PBL from one donor and the derivatives indicated.
  • bispecific F(ab) 2 antibodies This has clear advantages both in cost of treatment and directly to the patient who will take a lower dosage of antibody.
  • Figure 9(a) shows the cytotoxicity of the CD2 ⁇ CD3 ⁇ CRBC antibody in the presence of, respectively, CD2 antibody, CD3 antibody and a mixture of CD2 antibody and CD3 antibody as blocker.
  • the graph shows that when using CD2 antibody CD3 antibody at 500 ⁇ g/ml, a concentration known to be sufficient to block bispecific derivatives (Fig. 7) no reduction in the activity of this trispecific reagent was observed. It was only when both these blocking antibodies were included in the assay that any reduction in activity occurred.
  • PBL Peripheral blood lymphocytes isolated from Ficoll-Hypaque were cultured at 37°C in 96-well, U-bottomed, microculture plates (10 5 /well) in supplemented RPMI containing the various antibody derivatives, together with or without CRBC (200 ⁇ l /well). After 48 hours each well was pulsed for 16 hours at 37°C with 1 ⁇ Ci [%]thymidine (Amersham) and the incorporated radioactivity harvested onto glass microfibre filters and assessed as described previously. All experimental points were determined in triplicate. A graph showing proliferation (activation) responses of PBL to different Fab' ⁇ derivatives is shown in Figs. 10 and 11. Fresh PBL from one donor were cultured for 48 hours with the Fab' 2fderivative or mixture of derivatives indicated.
  • CD2 ⁇ CD2 ⁇ CRBC and a mixture of CD2 ⁇ CRBC + CD3 ⁇ CRBC were highly mitogenic.
  • Bispecific or trispecific F(ab) 3 antibodies with the appropriate specificities can be constructed which will first activate cellular effectors, such as T cell or monocytes, and then target them to destroy any unwanted cell.
  • effectors such as T cell or monocytes
  • trispecific antibodies efficient activation would appear to benefit from two antibody specificities reacting with molecules on the surface of the effector cell.
  • the third Fab specificity of the trispecific F(ab) 3 is then available to target against any unwanted cell.
  • Target cells in this system could include neoplastic cells, virally infected host cells (including HIV), autoreactive host cells (B or T lymphocytes) or invading pathogens, including bacteria and viruses.
  • the bispecific F(ab' ⁇ ) 3 antibodies approximately 100 times more potent than the equivalent bispecific F(ab' ⁇ ) 2 antibodies.
  • CD3 ⁇ CD3 ⁇ CRBC antibody was still fully active at below lng/ml. This surprising increase in performance does not appear to arise from more efficient triggering of cytotoxic T cells, at least as judged by triggering of mitosis.
  • An F(ab' ⁇ ) 3 antibody containing two CRBC specific Fab' ⁇ arms and one T cell specific Fab' ⁇ arm also demonstrated a similar improvement in performance.
  • bispecific F(ab' ⁇ ) 3 antibodies because they bind to one cell surface through two Fab'o arms, couple target and effector cells together with an increased avidity over equivalent bispecific F(ab' ⁇ ) 2 antibody. Blocking studies were consistent with this interpretation, showing that the two arms of a bispecific F(ab' ⁇ ) 3 required at least 20 times more free Fab'o from the appropriate antibody to inhibit cytotoxicity than did equivalent F(ab' ⁇ ) 2 reagent.
  • Fab arms reacting with the target cell and one Fab arm recruiting either a cellular effector or a pharmacological agent such as a toxin.
  • a cellular effector or a pharmacological agent such as a toxin.
  • a pharmacological agent such as a toxin.
  • other cells including B cells and monocytes, can be activated when bound by two antibodies reacting with the appropriate surface molecules.
  • Activiated cells which show a high proliferative rate are also often more susceptible to destruction by pharmacological agents such as cytotoxic drugs and toxins; the more rapidly growing tumours, such as childhood acute lymphoblastic leukaemia, are often the most sensitive to conventional chemotherapy.
  • pharmacological agents such as cytotoxic drugs and toxins
  • tumours such as childhood acute lymphoblastic leukaemia
  • a trispecific antibody, with two Fab arms directed at the target cell and one at a pharmacological agent could first activate the target cell and then deliver a poison while it remained in a hypersensitive state.
  • trispecific antibodies In addition to the advantages of being able to activate effector or target cells, trispecific antibodies, because they have two Fab arms binding to one surface, also display an increased avidity for that surface.
  • a trispecific F(ab) 3 derivative will cross-link two cell surfaces together significantly more strongly than a mixture of two bispecific F(ab) 2 antibodies.
  • This advantage may also be applied to immunoassays including enzyme-linked immunosorbent assays or radio-immunoassays. In this situation a trispecific antibody with two different binding sites for a single antigen, such as an enzyme, protein or peptide, and a third Fab arm for a second protein, can be used as a single step cross-linker increased avidity.
  • a trispecific F(ab) 3 derivatives may be useful include situations where it is necessary to capture three different immunogenic antigens, such as enzymes, proteins or peptides, into a tight immune complex.
  • An enzyme and its substrate could be captured directly from solution onto a solid surface in this wayy Redirected cellular cytotoxicity (RCC) of human tumour cells (Namalwa) with trispecific antibody.
  • RCC Redirected cellular cytotoxicity
  • the differentiation antigen CD37 was used as a tumour marker for delivering effectors to the Namalwa cells.
  • the results are shown in Figure 12 of four RCC assays, using PBL from different donors (donor 1-4).
  • the trispecific antibody [anti-CD2 ⁇ anti-CD3 ⁇ anti-CD37] is far more active than any bispecific antibody. Note that this enhance lysis is specific in that the
  • T11 3 is as, or more, active than the original trispecific antibody [anti-CD2 ⁇ anti-CD3 ⁇ anti-CD37].
  • three other trimeric antibodies, [anti-CD3 ⁇ anti-CD3 anti-CD37], [anti-CD3 ⁇ anti-CD4 ⁇ anti-CD37] and [anti-CD3 ⁇ anti-CD5 ⁇ anti-CD37] which are not mitogenic to T cells do not show the enhance activity of the [CD2 ⁇ CD3 ⁇ CD37] and [CD2 ⁇ CD2' ⁇ CD37] derivatives, but are probably more active than a bispecific F(ab') 2 [anti-CD3 ⁇ anti-CD37],

Abstract

Sont décrits de nouveaux anticorps trimères ou tétramères comprenant des anticorps F(ab)3 et F(ab)4 bispécifiques et trispécifiques. On a mis point un procédé simple et efficace de production d'anticorps F(ab'η)3 purs, selon lequel on joint les fragments individuels d'anticorps F(ab)' par l'intermédiaire de liaison de thioéthers stables. On a formé des molécules hybrides provenant d'anticorps monoclonaux de souris, présentant des spécifités pour des effecteurs cytotoxiques (globules sanguins T périphériques humains) ciblés contre des globules rouges de poulet marqués au 51Cr. On a couplé, premièrement, des anticorps Fab' provenant de deux des anticorps choisis par leurs groupes SH de région charnière, à l'aide de o-phénylènedimaléimide (oPDM), puis on a lié ce fragment bispécifique, à nouveau par l'intermédiaire de la région charnière à l'aide de oPDM à un troisième fragment Fab'.
PCT/GB1990/001335 1989-08-29 1990-08-29 CONJUGUES F(ab)3 ou F(ab)4 bi ou trispécifiques WO1991003493A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB8919485.6 1989-08-29
GB898919485A GB8919485D0 (en) 1989-08-29 1989-08-29 Novel antibody and preparative method therefor
GB9001949.8 1990-01-29
GB909001949A GB9001949D0 (en) 1989-08-29 1990-01-29 Novel antibodies and preparative method therefor

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WO1991003493A1 true WO1991003493A1 (fr) 1991-03-21

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EP0517024A2 (fr) * 1991-06-03 1992-12-09 BEHRINGWERKE Aktiengesellschaft Récepteurs tétravalents bispécifiques, leur préparation et utilisation
EP0516953A1 (fr) * 1991-04-19 1992-12-09 Tanox Biosystems, Inc. Conjugués de liposomes ou micro-billes et anticorps spécifiques pour lymphocytes T
WO1992022583A2 (fr) * 1991-06-11 1992-12-23 Celltech Limited Proteines monospecifiques tri- et tetravalentes de liaison aux antigenes
EP0637593A1 (fr) * 1993-08-02 1995-02-08 MERCK PATENT GmbH Molécules de déclenchement bispécifiques pour reconnaître l'antigène lymphocytaire CD2 et des antigènes tumorales
US5573920A (en) * 1991-04-26 1996-11-12 Surface Active Limited Antibodies, and methods for their use
WO1997008205A1 (fr) * 1995-08-25 1997-03-06 GSF - Forschungszentrum für Umwelt und Gesundheit GmbH Anticorps presentant deux specificites ou plus pour l'elimination specifique de cellules in vivo
US5837243A (en) * 1995-06-07 1998-11-17 Medarex, Inc. Therapeutic compounds comprised of anti-Fc receptor antibodies
WO1999002567A2 (fr) * 1997-07-08 1999-01-21 Board Of Regents, The University Of Texas System Compositions et procedes destines a des homoconjugues d'anticorps qui induisent l'arret de la croissance ou l'apoptose de cellules tumorales
US5872222A (en) * 1991-04-19 1999-02-16 Tanox Biosystems, Inc. Conjugates of polymers and antibodies specific for T lymphocytes, and their use as adjuvants
EP1005494A1 (fr) * 1997-03-27 2000-06-07 Commonwealth Scientific And Industrial Research Organisation Reactifs polyvalents presentant une avidite elevee et une specificite multiple
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