Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1997-09-08
2002-08-27
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S133100, C424S141100, C424S143100, C424S144100, C424S153100, C424S173100, C530S387100, C530S387300, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750
Reexamination Certificate
active
06440418
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to humanized antibodies specific for human gp39, DNA encoding such antibodies, methods for their production, pharmaceutical compositions containing, and the use of such humanized antibodies as therapeutic agents. These antibodies have particular application in the treatment of autoimmune diseases including, e.g., rheumatoid arthritis, multiple sclerosis, diabetes, and systemic lupus erythematosus as well as non-autoimmune diseases including, e.g., graft-versus-host disease and for preventing graft rejection.
BACKGROUND OF THE INVENTION
The immune system is capable of producing two types of antigen-specific responses to foreign antigens. Cell-mediated immunity is the term used to refer to effector functions of the immune system mediated by T lymphocytes. Humoral immunity is the term used to refer to production of antigen-specific antibodies by B lymphocytes. It has long been appreciated that the development of humoral immunity against most antigens requires not only antibody-producing B lymphocytes but also the involvement of helper T (hereinafter Th) lymphocytes. (Mitchison,
Eur. J. Immunol.,
1:18-25 (1971); Claman and Chaperon,
Transplant Rev.,
1:92-119 (1969); Katz et al,
Proc. Natl. Acad. Sci. USA,
70:2624-2629 (1973); Reff et al,
Nature,
226:1257-1260 (1970)). Certain signals, or “help”, are provided by Th cells in response to stimulation by Thymus-dependent (hereinafter TD) antigens. While some B lymphocyte help is mediated by soluble molecules released by Th cells (for instance lymphokines such as IL-4 and IL-5), activation of B cells also requires a contact-dependent interaction between B cells and Th cells. (Hirohata et al,
J. Immunol.,
140:3736-3744 (1988); Bartlett et al,
J. Immunol.,
143:1745-1765 (1989)). This indicates that B cell activation involves an obligatory interaction between cell surface molecules on B cells and Th cells. Such an interaction is further supported by the observation that isolated plasma membranes of activated T cells can provide helper functions necessary for B cell activation. (Brian,
Proc. Natl. Acad. Sci. USA,
85:564-568 (1988); Hodgkin et al,
J. Immunol.,
145:2025-2034 (1990); Noelle et al,
J. Immunol.,
146:1118-1124 (1991)).
It is further known that in a contact-dependent process termed “T cell helper function”, CD4
+
T lymphocytes direct the activation and differentiation of B lymphocytes and thereby regulate the humoral immune response by modulating the specificity, secretion and isotype-encoded functions of antibody molecules (Mitchell et al,
J. Exp. Med.,
128:821 (1968); Mitchison,
Eur. J. Immunol.,
1:68 (1971); White et al,
J. Exp. Med.,
14:664 (1978); Reinherz et al,
Proc. Natl. Acad. Sci. USA,
74:4061 (1979); Janeway et al,
Immunol. Rev.,
101:39 (1988); O'BRIEN et al,
J. Immunol.,
141:3335 (1988); Rahemtulla et al,
Nature,
353:180 (1991); and Grusby et al,
Science,
253:1417 (1991)).
The process by which T cells help B cells to differentiate has been divided into two distinct phases; the inductive and effector phases (Vitetta et al,
Adv. Immunol.,
45:1 (1989); Noelle et al,
Immunol. Today,
11:361 (1990)). In the inductive phase, resting T cells contact antigen-primed B cells and this association allows clonotypic T cell receptor (TCR)-CD4 complexes to interact with Ia/Ag complexes on B cells (Janeway et al,
Immunol. Rev.,
101:39 (1988); Katz et al,
Proc. Natl. Acad. Sci.,
70:2624 (1973); Zinkernagel,
Adv. Exp. Med.,
66:527 (1976); Sprent,
J. Exp. Med.,
147:1159 (1978); Sprent,
Immunol. Rev.,
42:158 (1978); Jones et al,
Nature,
292:547 (1981); Julius et al,
Eur. J. Immunol.,
18:375 (1982); Chestnut et al,
J. Immunol.,
126:1575 (1981); and Rogozinski et al,
J. Immunol.,
126:735 (1984)). TCR/CD4 recognition of Ia/Ag results in the formation of stable T-B cognate pairs and bi-directional T and B cell activation (Sanders et al,
J. Immunol.,
137:2395 (1986); Snow et al,
J. Immunol.,
130:614 (1983); Krusemeier et al,
J. Immunol.,
140:367 (1988); Noelle et al,
J. Immunol.,
143:1807 (1989); Bartlett et al,
J. Immunol.,
143:1745 (1989); and Kupfer et al,
Annu. Rev. Immunol.,
7:309 (1987)). In the effector phase, activated T cells drive B cell differentiation by secreting lymphokines (Thompson et al,
J. Immunol.,
134:369 (1985)) and by contact-dependent stimuli (Noelle et al,
J. Immunol.,
143:1807 (1989); Clement et al,
J. Immunol.,
140:3736 (1984); Crow et al,
J. Exp. Med.,
164:1760 (1986); Brian,
Proc. Natl. Acad. Sci., USA,
85:564 (1988); Hirohata et al,
J. Immunol.
140:3736 (1988); Jover et al,
Clin. Immunol. Immun.,
53:90 (1989); Whalen et al,
J. Immunol.,
141:2230 (1988); Pollok et al,
J. Immunol.,
146:1633 (1991); and Bartlett et al,
J. Immunol.,
143:1745 (1990)), both of which are required for T cells to drive small resting B cells to terminally differentiate into Ig secreting cells (Clement et al,
J. Immunol.,
132:740 (1984); Martinez et al,
Nature,
290:60 (1981); and Andersson et al,
Proc. Natl. Acad. Sci., USA,
77:1612 (1980)).
Although the inductive phase of T cell help is Ag-dependent and MHC-restricted (Janeway et al,
Immun. Rev.,
101:34 (1988); Katz et al,
Proc. Natl. Acad. Sci., USA,
10:2624 (1973); Zinkernagle,
Adv. Exp. Med. Biol.,
66:527 (1976)); the effector phase of T cell helper function can be Ag-independent and MHC-nonrestricted (Clement et al,
J. Immunol.,
132:740 (1984); Hirohata et al,
J. Immunol.,
140:3736 (1988); Whalen et al,
J. Immunol.,
143:1715 (1988)). An additional contrasting feature is that the inductive phase of T cell help often requires CD4 molecules and is inhibited by anti-CD4 mAb (Rogozinski et al,
J. Immunol.,
126:735 (1984)), whereas helper effector function does not require CD4 molecules (Friedman et al,
Cell Immunol.,
103:105 (1986)) and is not inhibited by anti-CD4 mAbs (Brian,
Proc. Natl. Acad. Sci., USA,
85:564 (1988); Hirohata et al,
J. Immunol.,
140:3736 (1988); Whalen et al,
J. Immunol.,
143:1745 (1988); and Tohma et al,
J. Immunol.,
146:2547 (1991)). The non-specific helper effector function is believed to be focused on specific B cell targets by the localized nature of the T-B cell interactions with antigen specific, cognate pairs (Bartlett et al,
J. Immunol.,
143:1745 (1989); Kupfer et al,
J. Exp. Med.,
165:1565 (1987) and Poo et al,
Nature,
332:378 (1988)).
Although terminal B cell differentiation requires both contact- and lymphokine-mediated stimuli from T cells, intermediate stages of B cell differentiation can be induced by activated T cell surfaces in the absence of secreted factors (Crow et al,
J. Exp. Med.,
164:1760 (1986); Brian,
Proc. Natl. Acad. Sci., USA,
85:564 (1988); Sekita et al,
Eur. J. Immunol.,
18:1405 (1988); Hodgkin et al,
J. Immunol.,
145:2025 (1990); Noelle et al,
FASEB J,
5:2770 (1991)). These intermediate effects on B cells include induction of surface CD23 expression (Crow et al,
Cell Immunol.,
121:94 (1989)), enzymes associated with cell cycle progression (Pollok et al, i J. Immunol., 146:1633 (1991)) and responsiveness to lymphokines (Noelle et al,
FASEB J,
5:2770 (1989); Pollok et al,
J. Immunol.,
146:1633 (1991)). Recently some of the activation-induced T cell surface molecules that direct B cell activation have been identified. Additionally, functional studies have characterized some features of activation-induced T cell surface molecules that direct B cell activation. First, T cells acquire the ability to stimulate B cells 4-8 h following activation (Bartlett et al,
J. Immunol.,
145:3956 (1990) and Tohma et al,
J. Immunol.,
146:2544 (1991)). Second, the B cell stimulatory activity associated with the surfaces of activated T cells is preserved on paraformaldehyde fixed cells (Noelle et al,
J. Immunol.,
143:1807 (1989); Cros et al,
J. Exp. Med.,
164:1760 (1986); Pollok et al,
J. Immunol.,
146:1633 (1991); Tohma et al,
J. Immunol.,
146:2544 (1991); and Kubota et al,
Immunol.,
72:40 (1991)) and on purified membrane fragments (Hodgkin et al
Black Amelia
Hanna Nabil
Newman Roland A.
Padlan Eduardo A.
Gambel Phillip
IDEC Pharmaceuticals Corporation
Teskin Robin L.
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