Methods of treating inflammatory and autoimmune diseases with natalizumab

Abstract

Natalizumab is a safe and efficacious treatment for inflammatory and autoimmune diseases, such as multiple sclerosis, Crohn's Disease, and rheumatoid arthritis. Chain swapping between natalizumab and IgG4 molecules acts to reduce the level of bivalent natalizumab present following administration of natalizumab, and thus to lower the activity of natalizumab in the patient. Differences in IgG4 levels across patients or within a single patient across time may change the pharmacokinetic profile of natalizumab. Patients with lower levels of IgG4 may experience higher nadir levels of natalizumab during a dosing period. Monitoring IgG4 and / or bivalent natalizumab levels, and determining a dose or dosage period based on the monitoring may improve the safety and / or efficacy of natalizumab therapy.

Description

PRIORITY CLAIM [0001] This application claims priority to U.S. Provisional Patent Application No. 60 / 779,190, filed Mar. 3, 2006, the entire contents of which are hereby incorporated herein.TECHNICAL FIELD [0002] The invention relates to methods of treating inflammatory and autoimmune diseases with a recombinant antibody. These methods improve the safety of treatment by adjusting the dose based on IgG4 antibodies in the patient. BACKGROUND ART [0003] The migration of lymphocytes from the peripheral blood across the blood brain barrier has been reported to initiate the development of several central nervous system (CNS) inflammatory diseases. Lymphocyte entry into the CNS is mediated by cellular adhesion molecules (O'Neill et al., Immunology 72:520-525 (1991); Raine et al., Lab. Invest. 63:476-489 (1990); Yednock et al., Nature 356:63-66 (1992); Baron et al., J. Exp. Med. 177:57-68 (1993); Steffen et al., Am. J. Path. 145:189-201 (1994); Christensen et al., J. Immunol. 154:5293-5301 ...

AI Technical Summary

Benefits of technology

[0015] The invention provides safer methods of using natalizumab to treat patients with inflammatory and autoimmune diseases.

[0016] In a first aspect, the invention provides a method of treating a patient with an inflammatory or autoimmune disease with natalizumab by administering a dose of natalizumab for a first dosage period; monitoring the amount of bivalent natalizumab in the patient's plasma or serum during the first dosage period; determining a second dose of natalizumab based on the level of bivalent natalizumab observed; and administering a second dose of natalizumab for a second dosage period; wherein the second dose improves the safety and / or efficacy of the treatment during the second dosage period. In an embodiment of the method the monitoring shows that the amount of bivalent natalizumab in the patient's plasma or serum remains above a predetermined level during the first dosage period, and the corrected dose of natalizumab administered over the second dosage period is designed to achieve a reduction of the natalizumab level during the second dosage period to below the predetermined level during at least a portion of the second dosage period. In an embodiment the second dose is lower than the first dose. In an embodiment the second dosage period is longer than the first dosage period. In an embodiment the corrected dose is lower than the first dose, and wherein the second dosage period is longer than the first dosage period. In an embodiment the first dose is 300 mg administered by IV infusion and the first dosage period is four weeks. In an embodiment the predetermined level is about 1 μg / ml, and wherein the second dose is less than 300 mg administered by IV infusion and the second dosage period is more than four weeks. In an embodiment the predetermined level is about 0.5 μg / ml, and wherein the second dose is less than 300 mg administered by IV infusion and the second dosage period is more than four weeks. In an embodiment the predetermined level is about 0.1 μg / ml, and wherein the second dose is less than 300 mg administered by IV infusion and the second dosage period is more than four weeks.

Problems solved by technology

Most individuals present with the relapsing-remitting form of the disease and experience recurrent attacks, which, over time, result in accumulating permanent physical disability and cognitive decline.

Current treatments are minimally effective for secondary progressive MS.

The development of neutralizing antibodies to interferons is associated with a loss of efficacy.

As a result, in the United States alone, over 50,000 patients who were previously treated no longer receive therapy.

Thus, there is a large group of patients with active MS who are currently not receiving any approved therapy.

Although a variety of therapeutic strategies are currently used in clinical practice to manage breakthrough disease while on treatment (e.g., switching therapy, changing dose and frequency of interferon, combination therapy), the similar efficacy between available medications and lack of clinical data demonstrating the effectiveness of any of these strategies in breakthrough patients makes the decision of what to do for these patients largely empirical.

Differences in the concentration of IgG4 between patients or within a patient over time may lead to differences in the concentration of bivalent natalizumab delivered over a dosing period.

This may lead to variation in safety and / or efficacy between patients or within a patient over successive dosage periods.

Variation in IgG4 levels may also lead to excessive natalizumab activity in certain patients.

This may lead to an increased risk of infection in those patients.