METHODS OF ADMINISTERING ANTI-TNFalpha ANTIBODIES

Abstract

Methods of treating disorders in which TFNα activity is detrimental via biweekly, subcutaneous administration of human antibodies, preferably recombinant human antibodies, that specifically bind to human tumor necrosis factor α (hTNFα) are disclosed. The antibody may be administered with or without methotrexate. These antibodies have high affinity for hTNFα (e.g., Kd=10−8 M or less), a slow off rate for hTNFα dissociation (e.g., Koff=10−3 sec−1 or less) and neutralize hTNFα activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Kits containing a pharmaceutical composition and instructions for dosing, and preloaded syringes containing pharmaceutical compositions are also encompassed by the invention.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 163,657, filed on Jun. 5, 2002, which claims the benefit of the filing date under 35 U.S.C. §119(e) to U.S. Provisional Application No. 60 / 296,961, filed on Jun. 8, 2001. The entire contents of each of the foregoing applications, including specification, any drawings, and sequence listing, are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Tumor necrosis factor α (TNFα) is a cytokine produced by numerous cell types, including monocytes and macrophages, that was originally identified based on its capacity to induce the necrosis of certain mouse tumors (see e.g., Old, L. (1985) Science 230:630-632). Subsequently, a factor termed cachectin, associated with cachexia, was shown to be the same molecule as TNFα. TNFα has been implicated in mediating shock (see e.g., Beutler, B. and Cerami, A, (1988) Annu. Rev. Biochem. 57:505-518; Beutler, B. and Cerami, A, (19...

AI Technical Summary

Benefits of technology

[0008]The present invention provides methods for biweekly dosing regimens for the treatment of TNFα associated disorders, preferably via a subcutaneous route. Biweekly dosing has many advantages over weekly dosing including, but not limited to, a lower number of total injections, decreased number of injection site tractions (e.g., local pain and swelling), increased patient compliance (i.e., due to less frequent injections), and less cost to the patient as well as the health care provider. Subcutaneous dosing is advantageous because the patient may self-administer a therapeutic substance, e.g., a human TNFα antibody, which is convenient for both the patient and the health care provider.

Problems solved by technology

While these mouse anti-hTNFαantibodies often displayed high affinity for hTNFα (e.g., Kd≦10−9 M) and were able to neutralize hTNFα activity, their use in vivo may be limited by problems associated with administration of mouse antibodies to humans, such as short serum half life, an inability to trigger certain human effector functions and elicitation of an unwarned immune response against the mouse antibody in a human (the “human anti-mouse antibody” (HAMA) reaction).

However, because these chimeric and humanized antibodies still retain some murine sequences, they still may elicit an unwanted immune reaction, the human anti-chimeric antibody (HACA) reaction, especially when administered for prolonged periods, e.g., for chronic indications, such as rheumatoid arthritis (see e.g., Elliott, M. J., et al (1994) Lancet 344:1125-1127; Elliot, M. J., et al.

However, these hybridoma-derived monoclonal autoantibodies were reported to have an affinity for hTNFα that was too low to calculate by conventional methods, were unable to bind soluble hTNFα and were unable to neutralize hTNFα-induced cytotoxicity (see Boyle, et al.

However, because of their relatively fast dissociation kinetics, these antibodies may not be suitable for therapeutic use.

Weekly dosing with antibodies and / or any drug can be costly, cumbersome, and result in an increase in the number of side effects due to the frequency of administration.

Intravenous administration also has limitations in that the administration is usually provided by someone with medical training.

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