Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1999-12-23
2004-01-27
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S133100, C424S137100, C424S141100, C424S142100, C424S143100, C424S152100, C424S153100, C424S154100, C424S172100, C424S173100, C530S387100, C530S387300, C530S387500, C530S388100, C530S388150, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750
Reexamination Certificate
active
06682736
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Cross-Reference to Related Applications
The present application claims priority to U.S. Provisional Patent Application Ser. No. 60/113,647, filed Dec. 23, 1998, the disclosure of which is hereby incorporated in its entirety herein.
2. Summary of the Invention
In accordance with the present invention, there are provided fully human monoclonal antibodies against human cytotoxic T-lymphocyte antigen 4 (CTLA-4). Nucleotide sequences encoding and amino acid sequences comprising heavy and light chain immunoglobulin molecules, particularly contiguous heavy and light chain sequences spanning the complementarity determining regions (CDRs), specifically from within FR1 and/or CDR1 through CDR3 and/or within FR4, are provided. Further provided are antibodies having similar binding properties and antibodies (or other antagonists) having similar functionality as antibodies disclosed herein.
3. Background of the Technology
Regulation of immune response in patients would provide a desirable treatment of many human diseases that could lead to a specificity of action that is rarely found through the use of conventional drugs. Both up-regulation and down-regulation of responses of the immune system would be possible. The roles of T cells and B cells have been extensively studied and characterized in connection with the regulation of immune response. From these studies, the role of T cells appear, in many cases, to be particularly important in disease prevention and treatment.
T cells possess very complex systems for controlling their interactions. Interactions between T cells utilize numerous receptors and soluble factors for the process. Thus, what effect any particular signal may have on the immune response generally varies and depends on the particular factors, receptors and counter-receptors that are involved in the pathway. The pathways for down-regulating responses are as important as those required for activation. Thymic education leading to T-cell tolerance is one mechanism for preventing an immune response to a particular antigen. Other mechanisms, such as secretion of suppressive cytokines, are also known.
Activation of T cells requires not only stimulation through the antigen receptor (T cell receptor (TCR)), but additional signaling through co-stimulatory surface molecules such as CD28. The ligands for CD28 are the B7-1 (CD80) and B7-2 (CD86) proteins, which are expressed on antigen-presenting cells such as dendritic cells, activated B-cells or monocytes that interact with T-cell CD28 or CTLA-4 to deliver a costimulatory signal. The role of costimulatory signaling was studied in experimental allergic encephalomyelitis (EAE) by Perrin et al.
Immunol Res
14:189-99 (1995). EAE is an autoimmune disorder, induced by Th1 cells directed against myelin antigens that provides an in vivo model for studying the role of B7-mediated costimulation in the induction of a pathological immune response. Using a soluble fusion protein ligand for the B7 receptors, as well as monoclonal antibodies specific for either CD80 or CD86, Perrin et al. demonstrated that B7 costimulation plays a prominent role in determining clinical disease outcome in EAE.
The interaction between B7 and CD28 is one of several co-stimulatory signaling pathways that appear to be sufficient to trigger the maturation and proliferation of antigen specific T-cells. Lack of co-stimulation, and the concomitant inadequacy of IL-2 production, prevent subsequent proliferation of the T cell and induce a state of non-reactivity termed “anergy”. A variety of viruses and tumors may block T cell activation and proliferation, leading to insufficient activity or non-reactivity of the host's immune system to the infected or transformed cells. Among a number of possible T-cell disturbances, anergy may be at least partly responsible for the failure of the host to clear the pathogenic or tumorgenic cells.
The use of the B7 protein to mediate anti-tumor immunity has been described in Chen et al.
Cell
71:1093-1102 (1992) and Townsend and Allison
Science
259:368 (1993). Schwartz
Cell
71:1065 (1992) reviews the role of CD28, CTLA-4, and B7 in IL-2 production and immunotherapy. Harding et al.
Nature
356:607-609 (1994) demonstrates that CD28 mediated signaling co-stimulates murine T cells and prevents the induction of anergy in T cell clones. See also U.S. Pat. Nos. 5,434,131, 5,770,197, and 5,773,253, and International Patent Application Nos. WO 93/00431, WO 95/01994, WO 95/03408, WO 95/24217, and WO 95/33770.
From the foregoing, it was clear that T-cells required two types of signals from the antigen presenting cell (APC) for activation and subsequent differentiation to effector function. First, there is an antigen specific signal generated by interactions between the TCR on the T-cell and MHC molecules presenting peptides on the APC. Second, there is an antigen-independent signal that is mediated by the interaction of CD28 with members of the B7 family (B7-1 (CD80) or B7-2 (CD86)). Exactly where CTLA-4 fit into the milieu of immune responsiveness was initially evasive. Murine CTLA-4 was first identified and cloned by Brunet et al.
Nature
328:267-270 (1987), as part of a quest for molecules that are preferentially expressed on cytotoxic T lymphocytes. Human CTLA-4 was identified and cloned shortly thereafter by Dariavach et al.
Eur. J. Immunol
. 18:1901-1905 (1988). The murine and human CTLA-4 molecules possess approximately 76% overall sequence homology and approach complete sequence identity in their cytoplasmic domains (Dariavach et al.
Eur. J. Immunol
. 18:1901-1905 (1988)). CTLA-4 is a member of the immunoglobulin (Ig) superfamily of proteins. The Ig superfamily is a group of proteins that share key structural features of either a variable (V) or constant (C) domain of Ig molecules. Members of the Ig superfamily include, but are not limited to, the immunoglobulins themselves, major histocompatibility complex (MHC) class molecules (i.e., MHC class I and II), and TCR molecules.
In 1991, Linsley et al.
J Exp. Med
. 174:561-569 (1991), proposed that CTLA-4 was a second receptor for B7. Similarly, Harper et al.
J Immunol
147:1037-44 (1991) demonstrated that the CTLA-4 and CD28 molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. See also Balzano et al.
Int J Cancer Suppl
7:28-32 (1992). Further evidence of this role arose through functional studies. For example, Lenschow et al.
Science
257:789-792 (1992) demonstrated that CTLA-4-Ig induced long term survival of pancreatic islet grafts. Freeman et al.
Science
262:907-909 (1993) examined the role of CTLA-4 in B7 deficient mice. Examination of the ligands for CTLA-4 are described in Lenschow et al.
P.N.A.S
. 90:11054-11058 (1993). Linsley et al.
Science
257:792-795 (1992) describes immunosuppression in vivo by a soluble form of CTLA-4. Linsley et al.
J Exp Med
176:1595-604 (1992) prepared antibodies that bound CTLA-4 and that were not cross-reactive with CD28 and concluded that CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7. Kuchroo et al.
Cell
80:707-18 (1995) demonstrated that the B7-1 and B7-2 costimulatory molecules differentially activated the Th1/Th2 developmental pathways. Yi-qun et al.
Int Immunol
8:37-44 (1996) demonstrated that there are differential requirements for co-stimulatory signals from B7 family members by resting versus recently activated memory T cells towards soluble recall antigens. See also de Boer et al.
Eur J Immunol
23:3120-5 (1993).
Several groups proposed alternative or distinct receptor/ligand interactions for CTLA-4 as compared to CD28 and even proposed a third B-7 complex that was recognized by a BB I antibody. See, for example, Hathcock et al.
Science
262:905-7 (1993), Freeman et al.
Science
262:907-9 (1993), Freeman et al.
J Exp Med
178:2185-92 (1993), Lenschow et al.
Proc Natl Acad Sci USA
90:11054-8 (1993), Razi-Wolf et al.
Proc Natl Acad S
Corvalan Jose Ramon
Davis C. Geoffrey
Gilman Steven Christopher
Hanke Jeffrey Herbert
Hanson Douglas Charles
Abgenix, Inc.
Fish & Neave
Gambel Phillip
Gunnison, Esq. Jane T.
Haley, Jr., Esq. James F.
LandOfFree
Human monoclonal antibodies to CTLA-4 does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Human monoclonal antibodies to CTLA-4, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Human monoclonal antibodies to CTLA-4 will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3261147