CA2060384C - A pharmaceutical composition containing an antibody recognizing the cdw52 antigen - Google Patents

Abstract

The invention relates to a method of treatment of a human or animal subject suffering from T-cell mediated inflammation of the joints, such as rheumatoid arthritis, which comprises administering to said subject an effective amount of an antibody recognising the CDw52 antigen.
Preferably the antibody is CAMPATH-1H administered in an amount of 1 to about 100mg per day for a period between 1 and 30 days.

Description

2060h~~4 The present invention relates to a method of treatment of certain auto-immune conditions in a human or animal subject.
The cells and molecules in an animal body do not normally stimulate an adaptive immune response in that body as a result of a number of mechanisms which ensure a state referred to as "self-tolerance".
However, in certain circumstances these mechanisms may fail to prevent the stimulation of such an immune response and this condition is referred to as "auto-immunity". A number of diseases in humans and animals are now thought to result from autoimmunity.
One such condition is rheumatoid arthritis which is associated with the production by an animal of antibodies against its own IgG. The inflammation of and consequent damage to the joints associated with the disease are probably mediated via immune complexes. Diseases in which inflammation of and damage to the joints arise from autoimmunity are referred to generically herein "T-cell mediated inflammation of the joint synovium".
The CDw52 antigen (a 23kDa glycoprotein also referred to as CAMPATH-1) is strongly expressed on the surface of all human lymphocytes and most monocytes but is absent from other blood cells including stem cells. A number of antibodies have been developed directed against CDw52 which is an unusually good target for complement-mediated attack. Antibodies against CDw52 bind to all lymphocytes and monocytes but lyse only lymphocytes (T and B) in vivo. Antigens similar to CDw52 are expressed in other mammalian species.
Antibodies which have been developed against CDw52 and which have been used in therapy include the following:

CAMPATH-1M is a rat IgM monoclonal antibody which has been used extensively in vitro for purging bone marrow harvests in order to deplete the T cell population prior to bone marrow transplantation.
Marked reductions in the incidence and severity of graft-versus-host disease has been seen with this therapy.
CAMPATH-1G is a rat IgG2b class-switch variant of an IgG2a antibody recognising the CDw52 antigen which has been used in vivo to achieve immunosupression in more than 100 patients undergoing organ and bone marrow transplantation, management of organ rejection and treatment of haematologic malignancies with a high level of success. However, the rapid development of an anti-rat immunoglobulin response, including the possibility of anaphylaxis, is likely to limit the use of rat monoclonal antibodies against the CDw52 antigen in humans in vivo.
CAMPATH-1H is a genetically manipulated IgG
antibody obtained by grafting the complementarity determining regions from CAMPATH-1G into human framework regions. The resulting "humanized" antibody is highly effective in vitro being equivalent to the rat monoclonal antibody at complement lysis and two to four times better in cell-mediated lysis of human lymphocytes. No limiting anti-globulin response is anticipated with this humanized antibody.
Expression of CAMPATH-1H was achieved initially in rat myeloma cells by placing DNA encoding the engineered antibody chains in genomic context under control of the immunoglobulin promoter/enhancer.
CAMPATH-1H has recently been expressed to high levels in Chinese hamster ovary (CHO) cells.

It has now surprisingly been found that antibodies against the CDw52 antigen are effective in the treatment of T-cell mediated inflammation of the joint synovium.
The present invention provides a method of treatment of a human or animal subject suffering from T-cell mediated inflammation of the joint synovium which comprises administering to the said subject an effective amount of an antibody recognising the CDw52 antigen.
The medicament according to the invention is applicable to the treatment of any disease involving T-cell mediated inflammation of the joint synovium.
The most common such disease is rheumatoid arthritis which is a major cause of suffering and disability in the developed world. Other diseases involving T-cell mediated inflammation of the joint synovium include variants of rheumatoid arthritis such as atypical Still's disease. The medicament according to the invention will find most applicability in the treatment of humans but it may also find application in veterinary medicine where animals with disease involving T-cell mediated inflammation of the joint synovium may also be treated with an appropriate antibody.
For the treatment of humans it is preferred to use an anti-CDw52 antibody which does not carry with it the risk of the development of an immune reaction against the antibody itself. Accordingly whilst it is possible to use mouse or rat mono-clonal antibodies it is preferred to use antibodies which have been produced by recombinant DNA technology and which have been engineered to reduce the risk of causing an immune reaction. Thus it is possible to use a . 20fi0;~84 chimeric antibody in which the constant domains of a mouse or rat anti-CDw52 antibody have been replaced by the constant domains of a human antibody. However, it is preferred to use a humanized or CDR-grafted antibody for the treatment of humans, i.e. an antibody in which the complementarity determining regions from a mouse or rat antibody are combined with framework regions and constant domains from one or more human antibodies.
Most preferably the method according to the invention is carried out using the CRD-grafted antibody CAMPATH-1H (see Reichman et al, Nature, 322, 323-327 (1988)). As noted above, the antibody CAMPATH-1H can be produced in rat myeloma cells as originally described or it can be produced in any other expression system, particularly an expression system suitable for the production of a correctly folded, glycosylated, mammalian protein. High yields of CAMPATH-1H have been obtained by expression in a genetically manipulated CHO cell line (Page and Sydenham, Biotechnoloav, 9, 64-68 (1991)).
The dosages of anti-CDw52 antibody, preferably CAMPATH-1H, to be administered to a patient suffering from a disease involving T-cell mediated inflammation of the joint synovium will vary with the condition being treated and the recipient of the treatment. The dose will generally be in the range 1 to about 100mg for an adult patient, usually administered daily for a period between 1 and 30 days. The preferred daily dose is 1 to 10 mg per day although in some instances larger doses of up to 40mg per day may be used.
._ The anti-CDw52 antibody, particularly CAMPATH-1H
will generally be administered to the patient in the form of a pharmaceutical formulation. Such formulations preferably include, in addition to the antibody, a physiologically acceptable carrier or diluent, possibly in admixture with one or more other agents such as other antibodies or drugs, such as an antibiotic. Suitable carriers include, but are not limited to, physiological saline, phosphate buffered saline, phosphate buffered saline glucose and buffered saline. Alternatively the antibody may be lyophilised (freeze dried) and reconstituted for use when needed by the addition of an aqueous buffered solution as described above. Routes of administration are routinely parenteral, including intravenous, intra-muscular, subcutaneous and intraperitoneal injection or delivery.
The anti-CDw52 antibody may be administered in combination with or sequentially with other drugs, in particular other drugs conventionally used in the treatment of T-cell mediated inflammation of the joint synovium, such as steroids, for example, hydro-cortisones, or non-steroidal anti-inflammatory drugs.
Sequential administration of the antibody with another drug may be appropriate in some cases. For example, the anti-CDw52 antibody may re-establish the effectiveness of steroids in patients where steroid therapy has ceased to be effective so that treatment with the antibody may conveniently be followed by steroid therapy.
The invention is illustrated by the following case histories of patients treated with the CDR-grafted anti-CDw52 antibody CAMPATH-1H.
~~1 2a6~384 5a The antibody used in Case No. 1 was produced in rat Y-0 myeloma cells. The antibody used in Case No.

2 was produced by expression in a recombinant CHO cell line (Page and Sydenham, Biotechnoloav, 9, 64-68 (1991)). In both cases the antibodies were extracted from the cell culture medium and subsequently purified.
It is to be understood that these case histories are not intended to be in any way limiting on the scope of the invention.
CASE N0. 1 The patient was a female born in 1940 who was a typical case of a patient with severe aggressive rheumatoid arthritis who had failed to respond or had reacted adversely to several disease modifying anti-rheumatic drugs.
Immediately prior to commencement of treatment with CAMPATH-1H, the patient had restricted joint mobility and had shown a poor response to increasing doses of penicillamine which had been discontinued.
Treatment with CAMPATH-1H commenced September 1988 and the patient was given 12 doses of 2mg CAMPATH-1H
intravenously in 500m1 normal saline over a 14 day period. This brought about a "remarkable" subjective improvement in the condition of the patient. There was also an objective improvement based on a number of conventional clinical criteria and in the sense that she was able to undertake her own self-care and also such activities as walking and knitting. The patient also received 500mg Naprosyn (Trade-mark) twice daily.
The treatment with CAMPATH-1H brought about a i relatively long lasting lymphopenia. By about 20 weeks after treatment the patient's lymphocyte count had returned to above 1.0 which was matched by a reactivation of her disease. Treatment commenced with pyritinol (a second-line anti-rheumatic agent undergoing trials) and this treatment was continued for 12 months. Treatment then commenced with cyclosporin 125mg daily and 25 months after the commencement of treatment with CAMPATH-1H the patient continues to do reasonably well on cyclosporin.
CASE NO. 2 The patient was a female born in 1971 who has been diagnosed as suffering from a particularly severe case of atypical Still's disease (a variant of rheumatiod arthritis occurring in younger patients).
At the age of 15 (in 1986) she developed fever, a brief episode of nausea and vomiting and abdominal pain and then a painful red right ankle. She was admitted to hospital and a small amount of pus was extracted from the ankle joint. At the same time she was found to have a symmetrical synovitis, right hypochondrial pain, pleuritic pain and a rash. These have persisted intermittently ever since, the polyarthropathy being dominant and immobilising.
Over the period 1988 to 1990 various investigations showed anaemia (normochronic, normocytic), thrombocytosis, hyperglobulinaemia, abnormal liver function (both alkaline phosphatase and transferases), fluctuating creatinine clearances (possibly related to NSAID therapy), hypoalbuminaemia (without proteinuria), white cell scan (uptake in joints), respiratory function tests, ECG
(inverted T waves), positive ANCA. ANA, DNAB, Rh factor, complement, bone scans have always been normal as were renal, liver and skin biopsies. A synovial biopsy in June 1990 showed a predominantly T cell infiltrate and peripheral subsets showed these to be mostly T also (T 80%, B 11%).
Therapies during the above period included steroids, i penicillamine, azathioprine, cyclophosphamide, methotrexate, plasma exchange, high dose intravenous gamma-globulin and cyclosporin A. Partial control was achieved with steroids, plasma exchange and cyclosporin A but remissions proved to be short lived. The progression of her disease and her lack of response to conventional and aggressive therapy resulted in her being an inpatient in hospital for long periods during 1990.
The patient commenced treatment with CAMPATH-1H in December 1990 and she received 6 daily doses of 2mg each of CAMPATH-1H followed by 6 doses of l0mg each over a 7 day period. The antibody was administered intravenously in saline. Towards the end of the treatment period a definite symptomatic improvement was noted and by the end of the treatment the patients joints were less inflamed and she had a lower C-reactive protein value and thermographic index as well as lowered erythrocyte sedimentation rate.
Shortly after the end of treatment she developed a skin abscess on her left thigh at the site of subcutaneous injection which was treated with antibiotics. Two and a half weeks after the end of treatment she changed from total parenteral nutrition to oral feeds. Four weeks after the end of treatment her condition was remarkably improved and she was discharged from hospital and allowed to return home.
Approximately 9 months after the initial treatment, she suffered a relapse with multiple joint involvement.
After initial testing for sensitivity with a low dose, she was given a further course of treatment with lOmg/day CAMPATH-1H for 10 days which produced a remission.
In addition to the above two case histories, five further patients suffering from rheumatoid arthritis and refractory to conventional therapies were treated with CAMPATH-1H using a protocol similar to that used for the patient in Case No. 2 above. Four of the five patients responded to treatment although the duration of the effect

Claims (29)

1. Use of an antibody recognizing the CDw52 antigen for the manufacture of a medicament for the treatment of T-cell mediated inflammation of the joint synovium.

2. Use according to claim 1, wherein said anti-body is a humanized antibody.

3. Use according to claim 2, wherein said anti-body is CAMPATH-1H.

4. Use according to claim 1, 2 or 3, for the manufacture of a medicament for the treatment of rheumatoid arthritis.

5. Use according to claim 1, 2, 3 or 4, the antibody being accompanied by instructions directing administration in an amount of from 1 to about 100mg per day for a period between 1 and 30 days.

6. Use according to claim 5, wherein said instructions specify an amount of 1 to 10mg per day.

7. Use according to claim 1, 2, 3, 4, 5 or 6, wherein said medicament is adapted to be administered intravenously.

8. Use of an antibody recognizing the CDw52 antigen in conjunction with a steroid for the manufacture of a medicament for the treatment of T-cell mediated inflammation of the joint synovium.

9. Use of the antibody CAMPATH-1H for the manufacture of a medicament for the treatment of arthritis, the antibody being accompanied by instructions directing administration of CAMPATH-1H in a dose of 1 to about 100mg per day for a period of between 1 and 30 days.

10. An antibody recognizing the CDw52 antigen for use in the treatment of T-cell mediated inflammation of the joint synovium.

11. An antibody according to claim 10, wherein said antibody is a humanized antibody.

12. An antibody according to claim 11, wherein said antibody is CAMPATH-1H.

13. An antibody according to claim 10, 11 or 12, for use in the treatment of rheumatoid arthritis.

14. An antibody according to claim 10, 11 or 12, in a form for intravenous administration.

15. The antibody CAMPATH-1H for use in the treatment of arthritis.

16. Use of an antibody recognizing the CDw52 antigen for the treatment of T-cell mediated inflammation of the joint synovium.

17. Use according to claim 16, wherein said antibody is a humanized antibody.

18. Use according to claim 17, wherein said antibody is CAMPATH-1H.

19. Use according to claim 16, 17 or 18, for the treatment of rheumatoid arthritis.

20. Use according to claim 16, 17 or 18, wherein said antibody is adapted to be administered intravenously.

21. Use according to claim 16, 17 or 18, of said antibody in combination with or sequentially with a steroid.

22. Use of the antibody CAMPATH-1H for the treatment of arthritis.

23. An anti-T-cell mediated inflammation of the joint synovium pharmaceutical composition comprising a pharmacologically effective amount of an antibody recognizing the CDw52 antigen, in association with a physiologically acceptable carrier.

24. An anti-rheumatoid arthritis pharmaceutical composition comprising a pharmacologically effective amount of an antibody recognizing the CDw52 antigen, in association with a physiologically acceptable carrier.

25. A composition of claim 23 or 24, wherein said antibody is a humanized antibody.

26. A composition of claim 23 or 24, wherein said antibody is CAMPATH-1H.

27. A composition of claim 23 or 24, in a form for intravenous administration.

28. A composition of claim 23 or 24, further including a steroid.

29. A composition of claim 26, in a form for intravenous administration.