Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1994-11-14
2002-10-29
Gambel, Phillip (Department: 1644)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S350000, C530S866000
Reexamination Certificate
active
06472510
ABSTRACT:
1. INTRODUCTION
The present invention relates to a counter-receptor, (also known as CD40 ligand), for the CD40 B-cell antigen, and to soluble ligands for this receptor, including fusion molecules comprising at least a portion of CD40 protein. It is based, at least in part, on the discovery that a soluble CD40/immunoglobulin fusion protein was able to inhibit helper T-cell mediated B-cell activation by binding to a novel 39 kD protein receptor on helper T-cell membranes. The present invention provides for a substantially purified CD40CR receptor; for soluble ligands of CD40CR, including antibodies as well as fusion molecules comprising at least a portion of CD40 protein; and for methods of, controlling B-cell activation which may be especially useful in the treatment of allergy or autoimmune disease.
2. BACKGROUND OF THE INVENTION
Studies by Mitchison, Benacerraf and Raff first suggested that physical interactions between T
h
and B-cells were essential in the development of humoral immune responses. Later studies documented that T
h
formed physical conjugates with class II major histocompatibility complex (MHC) compatible, antigen-presenting B-cells (Vitetta et al., (1987)
Immunol. Rev
. 99:193-239) and that it was the B-cells within these conjugates that responded to T
h
(Bartlett et al., (1989)
J. Immunol
. 143:1745-1754). With the discovery that T
h
-derived lymphokines exerted potent growth and differentiative effects on B-cells, it was proposed that soluble factor(s) released in proximity by activated T
h
mediated the activation of the interacting B-cell. However, none of the molecularly cloned lymphokines, alone or in combination, manifested the ability to induce B-cell cycle entry. Unlike soluble factors, plasma membrane fractions from activated T
h
induced B-cell cycle entry (Hodgkin et al., (1990)
J. Immunol
. 145:2025-2034; Noelle et al., (1991)
J. Immunol
. 146:1118-1124). Studies using purified plasma membrane fractions from activated T
h
suggested that a protein expressed on the membrane of activated T
h
was responsible for initiating humoral immunity (Noelle et al., (1991)
J. Immunol
. 146:1118-1124; Bartlett et al., (1990)
J. Immunol
. 145:3956-3962).
Purified plasma membranes from activated T
h
(PM
Act
) have been used to investigate the nature of this effector. function (Hodgkinet al. (1990)
J. Immunol
. 145:2025-2034; Noelle et al., (1991)
J. Immunol
. 146:1118-1124). PM
Act
from activated T
h
, but not resting T
h
(PM
rest
) expressed an activity that induced B-cell cycle entry in an antigen-nonspecific, class II-unrestricted manner. In addition, it was shown that the activity expressed by PM
Act
required 4-6 hours of activation, de novo RNA synthesis and was protein in nature (Bartlett et al., (1990)
J. Immunol
. 145:3956-3962).
3. SUMMARY OF THE INVENTION
The present invention relates to a counter-receptor, termed CD40CR, for the CD40 B-cell antigen, and to soluble ligands for this receptor, including fusion molecules comprising at least a portion of CD40 protein. It is based, at least in part, on the discovery that a soluble CD40/immunoglobulin fusion protein was able to inhibit helper T-cell mediated B-cell activation by binding to a novel 39 kD receptor protein (termed “CD40CR” for CD40 counter-receptor) on helper T-cell membranes, and on the discovery that a monoclonal antibody, termed MR1, directed toward this 39 kD receptor was able to inhibit helper T-cell mediated activation of B-cells.
The present invention provides for a substantially purified CD40CR receptor; for soluble ligands of CD40CR, including antibodies as well as fusion molecules comprising at least a portion of CD40 protein; and for methods of controlling B-cell activation.
In particular embodiments of the invention, B-cell activation in a subject may be inhibited by contacting helper T cells of the subject with effective amounts of a soluble ligand of CD40CR. Such inhibition of B-cell activation may be especially useful in the treatment of allergy or autoimmune disease.
One advantage of the present invention is that it enables intervention in an aspect of the immune response which is not antigen specific. Many current therapies for allergy include desensitization to particular antigens, and require that each patient be tested in order to identify antigens associated with sensitivity. Asia practical matter, exhaustive analysis of a patient's response to each and every potential allergen is virtually impossible. Furthermore, in most autoimmune conditions, the causative antigen is, generally, unknown or even irrelevant to the disease process. The present invention, which relates to the antigen nonspecific CD40/CD40CR interaction, circumvents the need to characterize the antigen associated with allergy or autoimmunity. Therefore, the present invention may be used to particular advantage in the treatment of allergic conditions in which the immunogen is not known, or has multiple components, for example, in hay fever or in procainamide induced lupus. It may also be useful in acute treatment of immune activation, for example, in therapy for anaphylaxis.
3.1. ABBREVIATIONS
Ig
immunoglobulin
mab
monoclonal antibody
PM
Act
plasma membranes prepared from
activated helper T-cells
PM
rest
plasma membranes prepared from resting
helper T-cells
PAGE
polyacrylamide gel electrophoresis
rIL4
recombinant interleukin 4
rIL5
recombinant interleukin 5
SN
supernatant
T
h
helper T-cell
T
h
1
refers to D 1.6, a I-A
d
-restricted,
rabbit immunoglubulin specific clone
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Aruffo Alejandro A.
Ledbetter Jeffrey A.
Noelle Randolph
Stamenkovic Ivan
Bristol--Myers Squibb Company
Gambel Phillip
Switzer Joan E.
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