SK12782001A3 - Antibody and chemokine constructs that are directed to ccr5, and their use for treating autoimmune diseases - Google Patents

Abstract

The invention relates to antibody and chemokine constructs against chemokine receptor expressing cells, especially against monocytes/macrophages expressing the chemokine receptor CCR5 and CCR5<+> T cells. The invention further relates to the use of antibody and chemokine constructs for destroying cells expressing the chemokine receptor for treating autoimmune diseases and allergic diseases, especially for treating chronic inflammatory diseases of the joints. The inventive antibody and chemokine constructs facilitate the specific depletion of chemokine receptor expressing cells and thus a specific immunosuppressive therapy of autoimmune diseases.

Description

ANTIBODY AND CHEMOKINE CONSTRUCTS AND THEIR USE IN THE TREATMENT OF AUTOIMMUNE DISEASES

Technical field

The present invention relates to antibody and chemokine constructs acting against cells expressing a chemokine receptor, in particular against monocytes / macrophages expressing a chemokine receptor CCR5 and against CCRS * T cells. Furthermore, the invention relates to the use of antibody and chemokine constructs for the breakdown of cells expressing a chemokine receptor for the treatment of autoimmune diseases and allergic diseases, in particular for the treatment of chronic inflammatory joint diseases. The antibody and chemokine constructs of the invention allow targeted killing of cells expressing chemokine receptors and thereby allow targeted immunosuppressive therapy of autoimmune diseases to be performed.

BACKGROUND OF THE INVENTION

In Germany, about 1% of the population suffer from rheumatoid arthritis. In addition, a number of other rheumatic-type diseases also result in joint inflammation. Three groups of drugs are currently used for the treatment of inflammatory joint diseases: non-family antirheumatic drugs, cortisone preparations, basisterapeutics and TNFα blockade. The focus of the current therapy consists in local injections of cortisone preparations together with a systemic dose of anti-inflammatory drugs and basisterapeutics.

Non-steroidal anti-rheumatic drugs have mild pain-relieving and inflammatory effects, but with frequent use they are characterized by a high incidence of side effects (eg gastric ulcers, kidney damage). At high doses, cortisone preparations have a strong anti-swelling and pain effect, but a rapid relapse occurs after discontinuation. In addition, cortisone preparations cannot in any way stop the joint disease process. Long-term cortisone treatment is usually associated with severe α7ft4 / H T side effects (infection, Cushing's syndrome, osteoporosis, parchment skin, metabolism disorders, and hormonal disorders). Similarly, local cortisone injections have a major disadvantage, since the entrapped white blood cells have only reduced activity and are not destroyed, therefore a rapid relapse occurs following discontinuation of treatment, as has already been reported for systemic use. Rarely, when cortisone injection occurs, the onset of inflammation induced by the irritating action of cortisone crystals. The duration of exposure to a single cortisone injection varies greatly from primary inactivity to several weeks of action.

Basisterapeutics are used in rheumatology for the long-term suppression of inflammation and to reduce the dose of cortisone preparations. Due to their considerable toxicity (allergy, infection, malignant diseases, renal deterioration, blood pressure problems, lung diseases), strict monitoring of the patient by a specialist must be ensured. The onset of efficacy cannot be expected earlier than 3 months after the start of treatment. There are currently 4 to 5 different basistherapeutics available, which can be used on their own or combined if therapy fails. There is little known about the mechanism of action of these basisterapeutics. It is not unequivocally demonstrated whether the use of these basisterapeutics can reduce joint destruction. In recent years, a new class of substances has been introduced in the treatment of rheumatoid arthritis, which is based on the blockade of cellular delivery substances (mainly TNFα) by monoclonal antibodies or soluble receptor constructs.

In addition, patients are generally not satisfied with the therapy currently available; in other cases, normal treatment should be discontinued for unacceptable side effects.

This means that it is necessary to find a new therapeutic principle for the treatment of chronic joint inflammatory diseases resp. rheumatic diseases in general and also for the treatment of other autoimmune diseases.

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SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide novel therapeutic active ingredients for the treatment of joint inflammatory diseases and other autoimmune diseases that overcome the disadvantages of the present state.

The solution of this object is set forth in the independent claims.

Preferred embodiments are defined in the respective subclaims.

The above task has been accomplished using antibody and chemokine constructs that are capable of binding to a chemokine receptor on the surface of a target cell, and binding of the construct to the chemokine receptor causes destruction of the target cell.

The antibody and chemokine constructs of the invention cause selective killing of target cells expressing a chemokine receptor, particularly leukocytes. Constructs of the invention include bispecific antibodies, antibody constructs, chemokine constructs, murine, chimerized or humanized antibodies, and bind either to target cells expressing a chemokine receptor and to an antigen on the surface of effector cells, particularly a CD3-antigen, or contain a toxin. The effector cells are primarily leukocytes, in particular monocytes / macrophages or T cells or dendritic cells.

In one study conducted in 40 patients with various joint diseases, it was found that there was a very high increase in monocyte / macrophage content expressing the chemokine receptor CCR5 and T lymphocytes in the inflammatory joint. In the joint, more than 90% of monocytes and T lymphocytes express the chemokine receptor CCR5, whereas in the blood it is only about 10 to 20%. According to this expression sample, the chemokine receptor CCR5 and chemokine receptor are generally very useful as targets for cell destruction therapy. Almost all monocytes and T lymphocytes were affected by CCR5 destruction, while only a small fraction of these cells were destroyed in the bloodstream.

31784 / H T cells. Monocytes and T-lymphocytes are the dominant cell types in chronic inflammation of the joints, mainly destruction of the joints by monocytes.

Surprisingly, it has now been shown that with the newly developed antibody and chemokine constructs it was possible to specifically destroy chemokine receptor-expressing leukocytes, particularly CCR5-expressing leukocytes.

While the current treatment strategy is essentially a symptomatic therapy that can have little effect on joint disease and its destruction and, for example, basistherapeutics do not develop their efficacy for several months and yet, like other drugs, exhibit considerable long-term toxicity, several hours in the joint nearly complete destruction of monocytes / macrophages expressing the chemokine receptor CCR5 ⁺ and T-lymphocytes. These types of cells cause chronic inflammation and induce joint destruction. Since monocytes can be removed very effectively, the use of the antibodies of the invention has a beneficial effect on joint destruction. Due to the non-selective inhibition of the immune system using basisterapeutics and TNFα blockade, there is a suspicion of an increased tendency to infections and tumor formation. By contrast, due to the breakdown of cells expressing chemokine receptors, in particular leukocytes expressing CCR5, they are predominantly removed by leukocytes that are involved in the inflammatory process without substantially affecting the immune defense system. Antibodies of the invention generally allow therapy with a small spectrum of side effects while improving the course of joint disease and preventing its destruction.

In a preferred embodiment, it is a bispecific antibody construct whose specific action is directed against a chemokine receptor, in particular against a human chemokine receptor, and in particular against a human chemokine receptor CCR5 and with a different specific action against an antigen on the effector cell surface, especially CD3 on the T cell surface. Antibody constructs with identical or similar epitope specificity are also included in the invention.

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In a particularly preferred embodiment of the invention, the bispecific antibodies are single-chain-Antikorper.

In another preferred embodiment, the antibody construct is a bispecific antibody whose specific action is directed against a chemokine receptor, in particular against a human chemokine receptor, and in particular against a human chemokine receptor 5 (CCR5) and with a different specific action against a toxin. Again, in a particularly preferred embodiment of the invention, the bispecific antibodies are single chain antibodies.

In another preferred embodiment of the invention, the construct is a chemokine toxin chemokine construct, which is a fusion of a modified or unmodified chemokine with a modified or unmodified toxin. Particularly preferred are CCR5-coupled chemokine toxins, such as e.g. MIP 1 β, MIP 1a, MCP-2, MCP-3, and RANTES constructs.

In the chemokine construct of the invention, the chemokine may be covalently bound to the toxin, but the linkage between the chemokine and the toxin may also be formed in another way. The chemokine may be bound via an multimerization domain to an antibody which, in addition to containing a compatible multimerization domain, exhibits specific activity against an antigen on the surface of an effector cell, preferably against CD3 on the surface of a T cell and / or against a toxin. Likewise, a chemokine can be linked via a multimerization domain with a toxin through a compatible multimerization domain bound to a toxin. This linking through the multimerization domains can take place in vitro or in vivo.

In another embodiment, the antibody construct is an antibody against a chemokine receptor, preferably CCR5, which is covalently bound to the toxin. This is a so-called immunotoxin.

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Particularly suitable toxins are fused pseudomonastoxin, fused diphterotoxin and similar toxins.

The invention also encompasses antibody constructs comprising an antibody against a chemokine receptor, in particular against CCR5, which can be bound in vitro and / or in vivo via a multimerization domain in homo / heterodimers with a second antibody directed against an antigen on an effector cell, particularly against CD3 and / or or against a toxin.

Also contemplated are antibody constructs in which an antibody against a chemokine receptor, in particular against CCR5, may be bound via a multimerization domain with a toxin with a compatible multimerization domain in vitro and / or in vivo.

Generally, the antibody constructs, chemokine constructs and murines, chimerized or humanized antibodies of the invention are substances that have the ability to kill cells expressing chemokine receptors, particularly leukocytes, and the selective kill is used to treat inflammatory diseases (autoimmune disease, allergic diseases, etc.).

In the context of the present invention, the term antibody or antibody construct also includes antibody fragments that exhibit the specificity of the antibodies or antibody constructs of the invention, the so-called active fragments.

Bispecific antibodies can be prepared as described below or by conventional methods; for example, chemically coupled antibodies or antibody fragments prepared by the hybridhybridone technique, such as bispecific single chain antibodies, diabodies, and binding of two antibodies via multimerization domains.

Preferably, the bispecific antibodies are single chain antibodies. In doing so, different portions of these antibodies can be coupled using conventional methods, or prepared as a contiguous protein using recombinant DNA technology, for example by expressing the molecule

31784 / H T nucleic acid encoding a chimeric or humanized antibody chain to produce a contiguous protein (see, e.g., Mack et al. (1995) Proc.Natl.Acad.Sci USA, Vol. 92, pp. 7021-7025).

In a particularly preferred embodiment of the invention, it is a single chain antibody with the following Fv fragments: sc-Fv fragment of a monoclonal antibody against a chemokine receptor, preferably CCR5, as well as an sc-Fv fragment of a monoclonal antibody against CD3. Here, the Fv fragment against the chemokine receptor as well as the Fv fragment against CD3 can be located at the N-terminal position. Preferably, the Fv fragment against CCR5 is in the Nterminal position. The arrangement of the VL and VH domains of the antibodies can be different for both constructs, preferably the Fv fragment against CCR5 has a VL-VH arrangement and the Fv fragment against CD3 has a VH-VI arrangement. Linkers between the variable domains as well as between the two Fc fragments consist of peptide linkers, preferably hydrophilic flexible linkers containing glycine and serine of 0 to 25 amino acids in length. In addition, histidine chains of 6xHis may also be at the C or N-terminal position for easier purification and detection.

Bispecific single chain antibodies have the advantage over conventional bispecific antibodies that they consist of only a single protein chain so that their composition can be precisely defined. They have a low molecular weight, typically less than 60 kD, and can be readily prepared in large quantities by recombinant techniques in suitable cell lines, e.g. in CHO cells. Their essential advantage is that they do not contain any permanent antibody domains and thus can only activate lymphocyte lesions when bound to their target cells, i.e. cells expressing chemokine receptors. Single chain antibodies are therefore often preferred over conventional bispecific antibodies, since their clinical use is associated with smaller or smaller antibodies. very small side effects.

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The invention further relates to a cell of eukaryotic or prokaryotic origin that produces an antibody construct of the invention, in particular a bispecific antibody of the invention, or is used for an in vitro protein production process.

Chemokine toxins formed by combining a chemokine with a toxin of the invention can be prepared e.g. by chemically binding, preparing a fusion protein from a chemokine and a modified or unmodified precaryotic or eukaryotic toxin, or by linking the chemokine and the toxin via a multimerization domain.

In a particularly preferred embodiment, the recombinantly produced fusion protein is formed from a chemokine bound to a human chemokine receptor CCR5 (MIP 1β, MIP 1a, RANTES, MCP-2, MCP-3) and fused versions of pseudomonasexotoxin A (e.g. PE38, PE40). The chemokine is coupled to the pseudomonas toxin via a short peptide linker. This linker preferably consists of a flexible and hydrophilic amino acid sequence, in particular of glycine and serine molecules, and has a length of 0 to 20 amino acids.

It was further an object of the present invention to provide a pharmaceutical composition comprising at least one antibody and chemokine construct of the invention, in particular comprising at least one bispecific antibody in sufficient quantity to destroy cells expressing chemokine receptors, optionally using a suitable pharmaceutical carrier.

Pharmaceutical preparations containing the bispecific antibodies of the invention are suitable for parenteral administration, i. for subcutaneous, intramuscular, intravenous, intra-articular, or intraperitoneal administration, the preparations for parenteral administration typically consisting of an antibody solution or a cocktail thereof dissolved in a suitable environment, e.g. in the aquatic environment. Suitable aqueous media are e.g. water, NaCl and glycine solution. In addition, these preparations may also contain conventional pharmaceutically acceptable excipients such as pH adjusters, buffers and the like.

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The concentration of the bispecific antibody in the pharmaceutical preparation can vary widely, i.e., it can range from less than about ^10-7 wt. % up to 1 wt. %. Concentrations of from 10 to ⁴ wt. % to 10 ^-1 wt. %. For intra-articular administration, the dose of the bispecific antibody should be 1 mg to 0.001 mg, particularly preferably about 0.02 mg of the single chain bispecific antibody.

Thus, a pharmaceutical preparation for intra-articular administration, for example to the knee joint, should contain about 20 µg of the bispecific antibody or chemokine toxin of the invention dissolved in about 2-5 ml of sterile sodium chloride buffer, e.g. phosphate buffer or Tris buffer. The composition for intravenous administration should be similar.

Another object of the present invention is to draw attention to the new application possibilities of the antibodies of the present invention.

This task has been accomplished by using at least one antibody or chemokine toxin of the invention to destroy cells expressing a chemokine receptor. In one preferred embodiment, the antibodies of the invention and the chemokine toxin of the invention, respectively, are used to treat chronic inflammation of the joints and other autoimmune diseases or to treat allergic diseases.

The selective destruction (depletion) of chemokine receptors, particularly CCR5, has two significant advantages over existing immunosuppressive therapies: on the one hand, the current therapies are not aimed at destroying the infiltrating leukocytes, but only reduce their activity. This leads to near-recurrence after discontinuation of treatment and continuous immunosuppression is required. In contrast, the reduction of the respective leukocytes directly in the joint gives hope that after one or a few treatments, long-term remission will occur. A second advantage of killing chemokine receptors is that, according to the distribution of cells expressing chemokine receptors, particularly CCR5, only cells that are involved in the inflammatory process are removed and other cells remain largely spared.

Mechanism of action of the bispecific antibodies of the invention, the specific action of which is directed against the chemokine receptor and which

31784 / HT have other specific anti-antigen activity on the surface of T cells than effector cells, as shown in FIG. 1 (above) and FIG. 2 according to a preferred embodiment of the invention. As shown in FIG. 1 (above), the bispecific antibody binds both arms to two different antigens. These are in one preferred embodiment a chemokine receptor CCR5 and a CD3 surface molecule on T cells. As shown in FIG. 2, this bispecific antibody causes cross-linking of T cells and CCR5 expressing cells. Cross-linking causes the T-lymphocytes to activate the lesion and destroy the lymphocytes with bound CCR5 cells. This means that CCR5 ⁺ cell lesions are only performed when T cells are present. These occur in large numbers in all forms of joint inflammation. Therefore, by injecting the bispecific antibody into the inflamed joint, it is possible to specifically eliminate the cells that cause this inflammation.

Further embodiments of the invention and their mechanism of action are shown in the accompanying Figures 1 to 9.

Due to the possibility of targeted killing of cells expressing chemokine receptors, an advantageous conception for the treatment of not only chronic joint inflammation but also other rheumatic diseases and autoimmune diseases has been found, which has been found to similarly increase the number of cells expressing chemokine receptors, especially CCR5.

Potential areas of use for bispecific antibodies in tumor therapy have been described (e.g., in Kroesen, BJ et al. (1993) Cancer Immunol. Immunother. 37: 400-7; Nitta, T. et al. (1990) Lancet 335: 368 -71; Bolhuis, RL et al (1992) Int.J.Cancer Suppl 7: 78-81; Canevari, S. et al (1995) J. Natl Cancer Inst 87: 1463-9; , G. et al (1995) J. Hematother 4: 433-437, Kroesen, BJ et al (1994) Br.J.Cancer, 70: 652-61, Tibben, JG et al (1993) J Natl.Cancer Inst. 85: 1003-4), however, the use of bispecific antibodies for immunopression has not been described so far.

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BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 depicts the antibody and chemokine constructs of the invention that cause cross-linking of target cells (Targetzellen), in this case CCR5 expressing cells and effector cells, in this case CD3 surface T cells. Top: Bispecific antibody with specific activity against both CCR5 and CD3; in the middle: a chemokine construct consisting of a chemokine and an anti-CD3 antibody; bottom: a chemokine construct in which it is possible to attach a chemokine with a multimerization domain to an anti-CD3 antibody via a compatible multimerization domain.

The cross-linking results, as schematically shown in FIG. 2, in that T lymphocytes are activated for lesions and those lymphocytes that are cross-linked with CCR5-positive cells are destroyed.

Fig. 3 depicts the antibody and chemokine constructs of the invention that induce binding between target cells, in this case cells expressing CCR5 and a toxin. Top: bispecific antibody with specific activity against both CCR5 and toxin; bottom: a chemokine construct consisting of a chemokine and an anti-toxin antibody.

Crosslinking of the target cell and the toxin causes the CCR5-positive target cell to be killed, as shown in FIG. 4th

In FIG. 5 are similar to FIG. 3 shows antibody and chemokine constructs that induce binding between the target cells and the toxin, but in this case the toxin is not bound via a specific function of the anti-toxin antibody because it is bound either covalently to the anti-chemokine receptor, particularly CCR5 (FIG. 5 above) or with a chemokine (FIG. 5 in the middle) or via a multimerization domain with a single antibody directed against a chemokine receptor with a compatible multimerization domain (FIG. 5 below).

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Also in this case, as shown in FIG. 6, the association of the target cell and the toxin results in the death of the target cell.

Fig. 7 shows the result of a single FACS analysis (performed according to the method described by Mack et al. (1998) J.Exp.Med 187, pp 1215-1224), which demonstrates the destruction of CCR5-positive T cells and synovial fluid monocytes from the inflamed knee patient with chronic polyarthritis resp. cultured peripheral blood leukocytes (PBMC).

Fig. 8 shows the cytotoxicity of Ra-PE38 chemokine toxin, more precisely, the destruction of CHO cells expressing CCR5 by RaPE38 chemokine toxin (10 ng / ml) after 24-hour incubation (bottom right). CHO cells that expressed the CXCR4 chemokine receptor instead of CCR5 were not damaged by RaPE38 (above) because RANTES is not bound to CXCR4. Incubation with the medium does not destroy CHO cells. Ra-PE38 is a fusion protein of RANTES and fused pseudomonosexotoxin with a molecular weight of 38 kD.

Fig. 8 shows the course of FIG. 5 in the middle.

Fig. 9 shows incubation of synovial fluid with CD3-CCR5 bispecific antibodies for an additional 48 hours. Fig. 9 thus relates to FIG. 7 above. There is a concentration-independent destruction of T lymphocytes and monocytes. At a concentration of 125 ng / l, the number of monocytes and T-lymphocytes decreased by 96 and 96%, respectively. 97.5%.

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DETAILED DESCRIPTION OF THE INVENTION

The examples below serve to illustrate the present invention and do not mean any limitation to certain embodiments, respectively. field of use. Rather, a number of other application possibilities of the present invention could be mentioned

Example 1

Preparation of bispecific antibody

For the preparation of a bispecific antibody, e.g. single-chain technology (Mack et al. (1995) Proc. Natl. Acad. Sci. USA 92: 7021-7025; Mack et al. (1997) J. Immunol. 158: 3965-3970). In this case, as shown schematically in FIG. 1 (top) and 3 (top), linking the different domains of the light (VL) and heavy (VH) immunoglobulin chains of two different antibodies into one sequence, and optionally, the histidine chain of 6xHis can still be attached. This fusion takes place in the DNA-plane, so that upon expression a protein chain with four different variable domains is formed (see Fig. 1 (above) and 3 (below)). The attached histidine chain allows simple and efficient purification in one step using immobilized Nions. Fig. 1 (below) shows a preferred form of a bispecific antibody bound to a CD3-antigen on the surface of an effector cell and to human CCR5 on the surface of leukocytes as target cells.

Various antibody domains were amplified by RT-PCR from hybridoma cells producing the desired antibody. The PCR fragments thus obtained were cloned and sequenced in a vector. Finally, a single chain antibody with a certain specificity was generated by fusion PCR, with a linker consisting of (Gly4Ser-i) ₃ inserted between the two different antibody domains. In a further fusion PCR, the anti-CCR5 antibody fragment was fused to the already published CD3 antibody fragment and inserted

31784 / HT linker consisting of Gly ₄ Ser ₁ (see Mack et al., Supra). The arrangement of domains was as follows. VL (1) -VH (1) -VH (2) -VL (2), wherein (1) corresponds to a specific action against CCR5 and (2) corresponds to a specific action against CD3.

Example 2

Expression and purification of the bispecific antibody of Example 1

For expression of the bispecific antibody, the appropriate DNA sequence was subcloned in a eukaryotic expression vector (e.g. PEF-DFHR, Mack et al. (1995), PNAS, supra) and transferred by electroporation to DHFR-deficient CHO cells from the supernatant of stable transfected CHO- cells, the bispecific antibody was isolated by affinity chromatography on Ni-NTA. eluting at a reduced pH. Finally, the pH was adjusted and the protein concentration was adjusted to the desired value.

Example 3

In vitro blood leukocyte and leukocyte tests in inflammatory joints

In vitro assays, joint fluid, including contained cells, was incubated with the bispecific antibody for one or several days. Almost 24 hours later, almost complete disappearance of CCR5-positive lymphocytes and monocytes was observed. After a longer incubation, the control medium differentiated the monocytes into macrophages that settled at the bottom of the culture vessel. No macrophages were seen when incubated with the bispecific antibody.

31784 / HT • • · · · · · · r t »· · erf» e · e pf rr »· _rr.

A similar result was obtained when incubating PBMC with a bispecific antibody. Here, almost complete destruction of CCR5-positive monocytes occurred and extensive destruction of CCR5-positive T cells. The destruction of CCR5 positive T cells and monocytes is shown in FIG. 7th

These results show that the construct of the invention of Example 1 has the ability to completely destroy CCR5-positive monocytes. This applies to both monocyte from articular pactate and blood monocytes that express CCR5 when differentiated into macrophages. Monocytes / macrophages are destroyed within a few hours (less than 24 hours). Destruction of monocytes / macrophages in the joint is of great therapeutic importance since these cells cause joint destruction. In addition, interaction with macrophages is essential for the activation of T lymphocytes, so that T cell function is suppressed at the same time.

In addition to the destruction of monocytes / macrophages, a significant decrease in the number of CCR5-positive T-lymphocytes was observed.

Claims (17)

PATENT CLAIMS An antibody or chemokine construct having the ability to bind to a chemokine receptor on the surface of a target cell, wherein binding of the construct to the chemokine receptor results in the destruction of the target cell, and active fragments of the construct. The antibody or chemokine construct of claim 1, wherein the chemokine receptor is a human chemokine receptor. The antibody or chemokine construct of claim 1 or 2, wherein the chemokine receptor is chemokine receptor 5 (CCR5). The antibody construct according to any one of the preceding claims, wherein the construct is a bispecific antibody having the ability to bind to a chemokine receptor as the first antigen and to a CD3-antigen on the surface of the effector cell as the second antigen. The antibody construct of any one of claims 1 to 3, wherein the construct is a bispecific antibody having the ability to bind to a chemokine receptor as the first antigen and to a toxin as the second antigen. The antibody construct of any one of claims 1 to 3, which is covalently bound to a toxin 31784, 1H An antibody construct according to any one of claims 1 to 3, which via a multimerization domain can bind to a second antibody construct having the ability to bind to a CD3 antigen on the surface of an effector cell and / or a toxin, or which can bind to a toxin via a compatible multimerization domain in vitro and / or in vivo. The chemokine construct according to any one of claims 1 to 3, wherein it is a fusion construct of a modified or unmodified chemokine with a modified or unmodified toxin. The chemokine construct according to any one of claims 1 to 3, wherein the chemokine construct can bind via a multimerization domain with an antibody construct having the ability to bind to CD3antigen on the surface of an effector cell and / or a toxin, or which can bind to a toxin via a compatible multimerization domain in vitro and / or in vivo. The chemokine construct of any one of claims 1 to 3, wherein the chemokine is covalently bound to an antibody construct having the ability to bind to a CD3-antigen on the surface of an effector cell and / or a toxin. The chemokine or antibody construct according to any one of claims 4, 7, 9 or 10, wherein the effector cell is a leukocyte, in particular a monocyte / macrophage or a T-cell or a dendritic cell. The antibody construct of any one of claims 1 to 7 or 9 to 11, which is a single chain construct. 31783 / H T A cell of eukaryotic or prokaryotic origin that produces an antibody or chemokine construct according to any one of the preceding claims. A pharmaceutical composition comprising at least one antibody or chemokine construct according to any one of claims 1 to 12 in an amount sufficient to destroy the cells expressing the chemokine receptor, and optionally a pharmaceutically acceptable carrier. Use of at least one antibody or chemokine construct according to any one of claims 1 to 12 for the destruction of cells expressing a chemokine receptor Use of at least one antibody or chemokine construct according to any one of claims 1 to 12 for the treatment of chronic joint inflammation and other autoimmune and allergic diseases. Use of at least one antibody or chemokine construct according to any one of claims 1 to 12 for the preparation of a pharmaceutical composition for the treatment of chronic joint inflammation and other autoimmune and allergic diseases.