Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,... – Conjugated via claimed linking group – bond – chelating agent,...
Reexamination Certificate
1995-06-06
2002-05-07
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
Conjugated via claimed linking group, bond, chelating agent,...
C424S130100, C424S133100, C424S135100, C424S141100, C424S143100, C424S144100, C424S153100, C424S173100, C424S178100, C424S183100, C424S001490, C530S387100, C530S387300, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750, C530S391100, C530S391300, C530S391700
Reexamination Certificate
active
06383487
ABSTRACT:
This invention relates to immunosuppression and more particularly provides monoclonal antibodies and other binding molecules against the CD25 antigen.
In organ transplant surgery, particularly kidney, liver, heart, lung and bone marrow transplant surgery, it is necessary to suppress the immune system of the graft recipient to minimise the likelihood of graft rejection after surgery. Various immunosuppressive drugs have been proposed for this purpose but their use has to be carefully controlled since, in addition to undesirable side-effects arising from the use of certain immunosuppressive agents, there is also the difficulty that the immunosuppressive action makes the graft recipient particularly susceptible to infection by bacteria and viruses that would be controlled by a normal immune system. Immunosuppressive agents that have been used successfully in clinical practice include steroids, azathioprine and cyclosporin A. It is necessary in clinical practice to attempt to balance the degree of immunosuppression necessary to prevent or treat graft rejection episodes with the retention of a certain amount of the recipient's immune system to combat other infectious agents and, at the same time, to keep any possible undesirable side-effects under control.
In addition to the use of immunosuppressive drugs, attention has also focused upon the use of certain monoclonal antibodies (MAbs) to suppress immune reactions, in particular, attention has been paid to monoclonal antibodies that recognise various surface antigens of T-cells. Here too, problems have been encountered in clinical practice, namely that prior art antibodies were either too powerful or not sufficiently effective, and sometimes caused severe side effects such as high fever.
These MAb's are generally designated by a CD (Cluster Determination) number assigned by successive Leucocyte Typing Workshops. Although a term such as CD3 is now frequently applied to the cell surface antigen, and a MAb to this antigen is often described as “anti-CD3”, in the following description terms such as CD3, CD25 etc. will be applied to MAb's and the corresponding cell surface antigens will be described as “CD3 antigen” etc.
In particular, monoclonal antibodies to membrane antigens present on all T-cells (also called pan T-cell antigens) such as the CD3 antigen are very potent antibodies in that they have an overall suppressive activity on the immune system. Therefore, the human body may be deprived of the immediate immune response usually mediated by the memory T-cells once an infection occurs. This is certainly not desirable when attempting to prevent rather than to cure graft rejection episodes. A treatment suitable for use in prophylaxis should be essentially selective, i.e. the pool of memory T-cells should be kept intact while the category of T-cells (activated T-cells) which could be directly involved in a rejection event should be inactivated.
This desirable goal may be achieved using antibodies to activated T-cells. These T-cells are characterised by the presence of the high affinity IL-2 receptor on their membrane surface. The high affinity IL-2 receptor is composed of at least two different polypeptide chains, an &agr;-chain also known as the CD25 antigen, and a &bgr;-chain. Resting T-cells do not express this high affinity receptor but low and intermediate affinity receptors which consist of &agr;- or &bgr;-chain homodimers. A CD25 antibody which interferes with the binding of IL-2 to its high affinity receptor and therefore selectively suppresses the immune response, is an antibody of choice for the prophylaxis of graft rejection episodes.
Natural immunoglobulins or antibodies comprise a generally Y-shaped multimeric molecule having an antigen-binding site at the end of each upper arm. The remainder of the structure, in particular the stem of the Y mediates effector functions associated with the immunoglobulins. The general structure of an antibody of the IgG class is shown schematically in FIG.
1
A. Both heavy and light chains comprise a variable domain and a constant part. An antigen binding site consists of the variable domain of a heavy chain associated with the variable domain of a light chain. The variable domains of the heavy and light chains have the same general structure which is illustrated in FIG.
1
B.
More particularly, the antigen binding characteristics of an antibody are essentially determined by 3 specific regions in the variable domain of the heavy and light chains which are called hypervariable regions or complementarity determining regions (CDRs). As shown in
FIG. 1B
, these 3 hypervariable regions alternate with 4 framework regions, (FRs) whose sequences are relatively conserved and which are not directly involved in binding. The CDRs form loops and are held in close proximity by the framework regions which largely adopt a &bgr;-sheet conformation. The CDRs of a heavy chain together with the CDRs of the associated light chain essentially constitute the antigen binding site of the antibody molecule.
The determination as to what constitutes an FR or a CDR region is usually made by comparing the amino acid sequence of a number of antibodies raised in the same species. The general rules for identifying the CDR and FR regions are given in Table C.
Furthermore, it has been recently found that the contribution made by a light chain variable domain to the energetics of binding is small compared to that made by the associated heavy chain variable domain and that isolated heavy chain variable domains have an antigen binding activity on their own. Such molecules are now commonly referred to as single domain antibodies.
Several murine CD25 MAbs already exist and include 33B3-1 (Immunotech-Merieux), BD&agr;IL-2R (Becton-Dickinson), 2C8 (Amersham), Campath 6 (MRC, Cambridge) and ATH207 (free University, Berlin). However, it has now been found that a novel mouse CD25 antibody of the IgG2a isotype, hereinafter called RFT5-IgG2a, has better properties than the CD25 antibodies of the prior art especially with regard to binding affinity, and that it is possible to construct other CD25 binding molecules having the same hypervariable regions as RFT5-IgG2a.
Accordingly, the invention provides a CD25 binding molecule which comprises at least one antigen binding site comprising at least one domain which comprises in sequence, the hypervariable regions CDR1, CDR2 and CDR3; said CDR1 having the amino acid sequence Arg-Tyr-Trp-Met-His (SEQ. ID. NO: 7), said CDR2 having the amino acid sequence Ala-Ile-Tyr-Pro-Gly-Asn-Ser-Asp-Thr-Ser-Tyr-Asn-Gln-Lys-Phe-Glu-Gly (SEQ. ID. NO: 8), and said CDR3 having the amino acid sequence Asp-Tyr-Gly-Tyr-Tyr-Phe-Asp-Phe (SEQ. ID. NO: 9); and direct equivalents thereof.
In a first aspect of the invention, the CD25 binding molecule comprises a single antigen binding site comprising a single domain.
In a second aspect of the invention, the CD25 binding molecule comprises at least one antigen binding site comprising:
a) a first domain comprising in sequence the hypervariable regions CDR1, CDR2 and CDR3; said CDR1 having the amino acid sequence Arg-Tyr-Trp-Met-His (SEQ. ID. NO: 7), said CDR2 having the amino acid sequence Ala-Ile-Tyr-Pro-Gly-Asn-Ser-Asp-Thr-Ser-Tyr-Asn-Gln-Lys-Phe-Glu-Gly (SEQ. ID. NO: 8), and said CDR3 having the amino acid sequence Asp-Tyr-Gly-Tyr-Tyr-Phe-Asp-Phe (SEQ. ID. NO: 9) and,
b) a second domain comprising in sequence the hypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ having the amino acid sequence Ser-Ala-Ser-Ser-Ser-Ile-Ser-Tyr-Met-Gln (SEQ. ID. NO: 10), said CDR2′ having the amino acid sequence Asp-Thr-Ser-Lys-Leu-Ala-Ser (SEQ. ID. NO: 11), and said CDR3′ having the amino acid sequence His-Gln-Arg-Ser-Ser-Tyr-Thr (SEQ. ID. NO: 12);
and direct equivalents thereof.
Unless otherwise indicated, any polypeptide chain is hereinafter described as having an amino acid sequence starting at the N-terminal extremity and ending at the C-terminal extremity.
When the antigen binding site comprises both the first and second doma
Akbar Arne Nalpon
Amlot Peter Lloyd
Cammisuli Salvatore
Heinrich Günther
Furman Diane E.
Gambel Phillip
Novartis AG
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