Macrogenics, Inc.

The United States of America As Represented by the United States

The United States of America As Represented by the Department of Health

Ronald L Wilder

Leslie Sydnor Johnson

Scott Koenig

Ezio Bonvini

Philip W Gold

Esther M Sternberg

George P Chrousos

Stanley Pillemer

The present invention provides methods of treating, preventing, slowing the progression of, or ameliorating the symptoms of T cell mediated immunological diseases, particularly autoimmune diseases (e.g., autoimmune diabetes (i.e. type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)) and multiple sclerosis) through the use of anti-human CD3 antibodies. The antibodies of the invention of the invention are preferably used in low dose dosing regimens, chronic dosing regimens or regimens that involve redosing after a certain period of time. The methods of the invention provide for administration of antibodies that specifically bind the epsilon subunit within the human CD3 complex. Such antibodies modulate the T cell receptor/alloantigen interaction and, thus, regulate the T cell mediated cytotoxicity associated with autoimmune disorders. Additionally, the methods of the invention provide for use of anti-human CD3 antibodies modified such that they exhibit reduced or eliminated effector function and T cell activation as compared to non-modified anti-human CD3 antibodies.

Methods for the treatment of autoimmune disorders using immunosuppressive monoclonal antibodies with reduced toxicity

The present invention provides methods of treating, preventing or ameliorating the symptoms of T cell-mediated immunological diseases, particularly autoimmune diseases, through the use of anti-CD3 antibodies. In particular, the methods of the invention provide for administration of antibodies that specifically bind the epsilon subunit within the human CD3 complex. Such antibodies modulate the T cell receptor/alloantigen interaction and, thus, regulate the T cell mediated cytotoxicity associated with autoimmune disorders. Additionally, the invention provides for modification of the anti-CD3 antibodies such that they exhibit reduced or eliminated effector function and T cell activation as compared to non-modified anti-CD3 antibodies.

Inbred Lewis (LEW/N) female rats develop an arthritis in response to Group A streptococcal cell wall peptidoglycanpolysaccharide (SCW) which mimics human rheumatoid arthritis. Histocompatible Fischer (F344/N) rats, on the other hand, do not develop arthritis in response to the same SCW stimulus. To evaluate this difference in inflammatory reactivity between the two strains, the function of the hypothalamic-pituitary-adrenal axis and its ability to modulate the development of the inflammatory response was studied. It has been found that, in contrast to F344/N rats, LEW/N rats had markedly impaired plasma ACTH and corticosterone responses to SCW, recombinant human Interleukin-1 alpha (IL-1 alpha), the serotonin agonist, quipazine, and synthetic rat corticotropin-releasing hormone (CRH). In addition, LEW/N rats compared to F344/N rats had smaller adrenal glands and larger thymuses. Treatment of LEW/N rats with replacement doses of dexamethasone decreased the severity of their SCW-induced arthritis. Conversely, treatment of F344/N rats with the glucocorticoid receptor antagonist, RU 486, or the serotonin (5-HT.sub.2) antagonist, LY53857, was associated with development of severe inflammatory disease, including arthritis, in response to SCW. These findings support the concept that susceptibility of LEW/N rats to SCW arthritis is related to abnormal hypothalamic-pituitary-adrenal (HPA) axis responsiveness to inflammatory and other stress mediators and that resistance of F344/N rats to SCW arthritis is regulated by an intact HPA axis-immune system feedback loop.

Evaluative means for detecting inflammatory reactivity

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Rockville, MD, United States of America

Ronald L Wilder