Method for treating multiple sclerosis

Abstract

A method is provided for administering to a mammal suffering from, or at risk for, multiple sclerosis, an initial dosing of a therapeutically effective amount of an anti-LFA-1 antibody, followed by a subsequent intermittent dosing of a therapeutically effective amount of the anti-LFA-1 antibody wherein the antibody is administered to the mammal no more than once per week in the intermittent dosing.

Description

[0001] This is a continuation application filed under 37 CFR §1.53(b)(1) claiming priority to application Ser. No. 10 / 727,383, filed on 2 Dec. 2003, which is a continuation of application Ser. No. 10 / 208,112, filed on 29 Jul. 2002, which is a continuation application of application Ser. No. 09 / 309,749, filed on 11 May 1999 (now abandoned), which is a divisional application of application Ser. No. 08 / 766,008, filed on 13 Dec. 1996 (now abandoned), which is a continuation application of application Ser. No. 08 / 432,543, filed on 2 May 1995 (U.S. Pat. No. 5,622,700), which is a continuation application of application Ser. No. 08 / 287,055, filed on 8 Aug. 1994 (now abandoned), which is a continuation application of application Ser. No. 08 / 128,329, filed 28 Sep. 1993 (now abandoned), which is a continuation application of application Ser. No. 07 / 933,269, filed on 21 Aug. 1992 (now abandoned) which applications are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] 1. Field...

AI Technical Summary

Benefits of technology

[0029] It is a further object to minimize the toxicity and other adverse effects arising from the use of large doses of immunosuppressants in transplant patients.

[0030] It is a still further object to provide the host with selective tolerance to the antigen or agent causing the specific immune disorder, so that the host has a reduced susceptibility to infections and other assaults on the immune system that are opportunistic when conventional immunosuppressive agents or dosages are employed.

[0033] It was surprisingly found that specific tolerance is induced by adjusting the dose regimen, and that it is not necessary to maintain antagonist dosage at the same initial level over the course of treatment. It was also surprising that the survival of grafts upon transplantation was prolonged using a dosing regimen where a high initial dose is given followed by a continuous maintenance dose. Also unexpected was that this dosing scheme using only one drug resulted in a selective tolerance of the host to the agent causing the disorder, so that the host defense system was not severely depressed.

Problems solved by technology

These alternatives frequently produce severe side effects, including retinal lesions and kidney and bone marrow toxicity.

Immunosuppressive agents such as methotrexate have been used only in the treatment of severe and unremitting RA because of their toxicity.

Corticosteroids also are responsible for undesirable side effects (e.g., cataracts, osteoporosis, and Cushing's disease syndrome) and are not well tolerated in many RA patients.

Additionally, systemic immunosuppression is accompanied by undesirable toxic effects (e.g., nephrotoxicity when cyclosporin A is used after renal transplantation) and reduction in the level of the hemopoietic stem cells.

Immunosuppressive drugs may also lead to obesity, poor wound healing, steroid hyperglycemia, steroid psychosis, leukopenia, gastrointestinal bleeding, lymphoma, and hypertension.

It has been hypothesized that such treatment results in the depletion of passenger lymphoid cells and thus the absence of a stimulator cell population necessary for tissue immunogenicity.

Furthermore, the in vivo administration of anti-CD11a MAb to cynomolgus monkeys prolonged skin allograft survival.

However, these results were not reproducible in leukemic adult grafting with this MAb [Maraninchi et al., Bone Marrow Transplant, 4: 147-150 (1989)], or with an anti-CD18 MAb, directed against the invariant chain of LFA-1, in another pilot study.

Furthermore, a rat anti-murine CD11a MAb, 25-3, was unable to control the course of acute rejection in human kidney transplantation.

The above methods successfully utilizing anti-LFA-1 or anti-ICAM-1 antibodies represent an improvement over traditional immunosuppressive drug therapy; however, they advocate a higher than minimum or fixed dosage of drug that we expect either to unduly suppress the immune system (and create a signficant risk of infection) or to be inadequate for long-term tolerance.

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