WO1988007054A1 - Complement-binding peptide - Google Patents
Complement-binding peptide Download PDFInfo
- Publication number
- WO1988007054A1 WO1988007054A1 PCT/GB1988/000213 GB8800213W WO8807054A1 WO 1988007054 A1 WO1988007054 A1 WO 1988007054A1 GB 8800213 W GB8800213 W GB 8800213W WO 8807054 A1 WO8807054 A1 WO 8807054A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino acid
- polypeptide
- sequence
- lys
- tail
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
Definitions
- This invention relates to a complement binding peptide and to pharmaceutical preparations containing sam
- immunoglobulins particularly IgG and IgM, are able to bind the first component of complement, generally designated Cl.
- Complement comprises a number of protein molecules which are sequentially activated by the binding of Cl to an Ig. Activation of complement is important in the opsonisation and lysis of cell pathogens. The activatio of complement also stimulates the inflammatory response and may be involved in autoimmune hypersensitivity.
- the first component of complement, Cl comprises three proteins which bind tightly together. These proteins are Clq, Clr and Cls. It has been shown that Clq is responsible for binding the three protein complex to the Ig.
- Ig's have two heavy chains linked together with disulphide bonds and two light chains, one light chain being linked to each of the heavy chains by disulphide bonds.
- the general molecular structure of an Ig is show in Figure 1 of the accompanying drawings.
- Each heavy chain has at one end a variable domain followed by a number of constant domains.
- Each light chain has a variable domain at one end and a constant domain at its other end, the variable domain of the light chains being aligned with the variable domain of the heavy chain and the constant domain of each light chain is aligned with the first constant domain of the heavy chain.
- the variable domains of each pair of light and heavy chains form an antigen binding site.
- the portions of the heavy chains extending beyond the ends of the light chains can be separated from the remainder of the Ig by enzymatic cleavage to yield a fragment, known as the Fc fragment. It is known that the Fc fragment inhibits the interaction of Clq with an Ig.
- the constant region of an Ig comprises at least two constant domains, CH2 and CH3, as- shown in Figure 1. . It is possible to cleave the CH3 domain from the rest of the Ig molecule. It has been shown that removal of the CH3 domain from an Ig does not remove its ability to bind Clq.
- the binding site on the Ig for Clq is located within the CH2 domain.
- synthetic peptides corresponding in sequence to short sections of the CH2 domain were tested for inhibition of binding. This work identified two possible binding sites.
- a comparison of the sequences of CH2 domains of several Ig's was made in conjunction with studies of their three-dimensional structure. This lead to the identification of two further proposals for the site of binding Clq.
- An object of the present invention is to provide a peptide binding to the Clq protein of complement.
- polypeptide having the ability to inhibit complement mediated lysis, consisting of or containing the amino aci sequence I;
- X is a polar amino acid
- A is any amino acid; Y is a basic amino acid; ' and, Z is a basic amino acid
- polypeptide having the ability to inhibit complement mediated lysis, having the general formula II:
- X is, Asn, Glu, Thr or Gin
- Y and Z are, independently, Lys, or Arg; • Head' is a hydrogen atom or a sequence of amino acid residues attached to the amino group of the adjacent amino acid X; 'Tail' is a hydrogen atom or a sequence of amino acid residues attached to the carboxyl group of the adjacent amino acid Y; and, each of the groups represented by A, which may be the same or different, is an amino acid residue.
- the group X is Glu or Thr, and Y and Z are both Lys or Arg.
- each A is a non-ionic, preferably polar, most preferably small, amino acid residue.
- the groups represented by 'Head* and 'Tail' may be joined by a peptide bridge to form a cyclic polypeptide or an analogue.
- the polypeptide may be a pentapeptide ('Head' and 'Tail' both being hydrogen atoms) or a longer peptide, for example a sequence of amino acids mimicing the natural sequence- of a complete or incomplete CH2 domain of an Ig.
- 'Head' and 'Tail' comprise identical sequences of amino acids.
- polypeptide of the invention has the sequence:
- the polypeptide may be arranged so that side chains of the residues X Y and Z adopt approximately the configuration which they adopt in the CH2 domain of an Ig. This may be achieved by locating a polypeptide in a 'Head' and 'Tail' which together form a B-pleated sheet. Alternatively, this may be achieved by fixing the polypeptide to a carrier so that the polypeptide adopts a B-sheet-like configuration.
- polypeptide analogue for instance an extended chain having appropriate functional groups attached thereto, it is only necessary to ensure that the functional groups are arranged in the same configuration as are the equivalent residues in the polypeptide.
- the polypeptide analogue may compris an anti-peptide or anti-analogue, having the sequence Y-X-Z-X-z or Z-X-Z-X-Y, depending on being parellel or anti-parallel to the Clq binding sites of complement, wherein Y is a hydrogen bonding residue, each Z is independently a negatively charged residue and each X is independently an amino acid residue.
- Such an anti-peptide would act by masking the necessary residues on an antibody structure, so that Clq would not be bound.
- such an anti-peptide would be produced in two copies connected via a long flexible linker. Each copy in the long molecule would then bind to a respective CH2 domain in a single antibody molecule, thereby inhibiting Clq binding.
- the polypeptide or its analogue of the present invention may be fixed on to a carrier, such as a protein polysaccharide or plastics material, or may be used as formed.
- the polypeptide of the present invention may find application in the therapy of autoimmune diseases, such a lupus erythematosus, which are believed to be caused by non-specific or uncontrolled activation of Clq.
- a polypeptide was synthesised, using standard laboratory techniques for polypeptide synthesis, having the following structure: Acetyl-Ala-Glu-Ala-Lys-Ala-Lys-Ala-Amide
- the present invention has shown that it is possible to synthesise a polypeptide based on the sequence of the Glu318 to Lys322 sequence which can be used directly in, vivo to compete with the binding of Clq. This ability would be expected to have potential as an anti-infammatory drug.
- FIG. 2 there is shown graphically the inhibition of complement lysis by synthetic peptides of this invention.
- the circles represent lysis for the peptide Acetyl-Ala-Glu-Ala-Lys-Ala-Lys-Ala-NH- and squares indicate that same for a control ppeptide of sequence Ser-Asp-Glu-Lys-Ala-Ser-Pro-Asp-Lys-Tyr, which both contain acidic and basic residues.
- Figure 2 was as follows: Peptides were purified by reverse-phase HPLC and the composition checked by amino acid analysis. Freeze dried peptide was weighed and dissolved in CFD (Complement Fixation Diluent - Oxoid) to a concentration of 4mM and serial dilutions of the peptide made into 200 microlitre NIP-derivatized red cells (5 x 7 10 cells/ml), guinea pig serum (1/40 dilution) and antibody (7 microgram/ml), and incubated at 37°C for 30 minutes and then scanned using a Titertek Multiscan (Trade
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A polypeptide, having the ability to inhibit complement mediated lysis, consists of or contains the amino acid sequence (I): -X-A-Y-A-Z-, in which X is a polar amino acid, A is any amino acid; Y is a basic amino acid, and Z is a basic amino acid. In a preferred embodiment the polypeptide has the general formula (II): Head-X-A-Y-A-Z-Tail, in which X is Asn, Glu, Thr or Gln, Y and Z are, independently, Lys or Arg, 'Head' is a hydrogen atom or a sequence of amino acid residues attached to the amino group of the adjacent amino acid X, 'Tail' is a hydrogen atom or a sequence of amino acid residues attached to the carboxyl group of the adjacent amino acid Y, and, each of the groups represented by A, which may be the same or different, is an amino acid residue.
Description
. COMPLEMENT-BINDING PEPTIDE
This invention relates to a complement binding peptide and to pharmaceutical preparations containing sam
It has been known for some time that certain classe of immunoglobulins (Ig's), particularly IgG and IgM, are able to bind the first component of complement, generally designated Cl.
Complement comprises a number of protein molecules which are sequentially activated by the binding of Cl to an Ig. Activation of complement is important in the opsonisation and lysis of cell pathogens. The activatio of complement also stimulates the inflammatory response and may be involved in autoimmune hypersensitivity.
The first component of complement, Cl, comprises three proteins which bind tightly together. These proteins are Clq, Clr and Cls. It has been shown that Clq is responsible for binding the three protein complex to the Ig.
Ig's have two heavy chains linked together with disulphide bonds and two light chains, one light chain being linked to each of the heavy chains by disulphide bonds. The general molecular structure of an Ig is show in Figure 1 of the accompanying drawings.
Each heavy chain has at one end a variable domain
followed by a number of constant domains. Each light chain has a variable domain at one end and a constant domain at its other end, the variable domain of the light chains being aligned with the variable domain of the heavy chain and the constant domain of each light chain is aligned with the first constant domain of the heavy chain. The variable domains of each pair of light and heavy chains form an antigen binding site.
The portions of the heavy chains extending beyond the ends of the light chains can be separated from the remainder of the Ig by enzymatic cleavage to yield a fragment, known as the Fc fragment. It is known that the Fc fragment inhibits the interaction of Clq with an Ig.
The binding of Clq is known to be dependent on ionic strength, suggesting that ionic interactions are involved.
The constant region of an Ig comprises at least two constant domains, CH2 and CH3, as- shown in Figure 1. . It is possible to cleave the CH3 domain from the rest of the Ig molecule. It has been shown that removal of the CH3 domain from an Ig does not remove its ability to bind Clq.
It is also possible to isolate the CH2 domain and it has been shown that such isolated CH2 regions have the same binding affinity for Clq as do isolated Fc fragments.
From this information it may be deduced that the binding site on the Ig for Clq is located within the CH2 domain. Various attempts have been made to identify the particular sequence of amino acids within the CH2 domain which are responsible for the binding to Clq. In one approach, synthetic peptides corresponding in sequence to short sections of the CH2 domain were tested for inhibition of binding. This work identified two possible binding sites. In another approach, a comparison of the
sequences of CH2 domains of several Ig's was made in conjunction with studies of their three-dimensional structure. This lead to the identification of two further proposals for the site of binding Clq.
An object of the present invention is to provide a peptide binding to the Clq protein of complement.
According to the present invention there is provide a polypeptide, having the ability to inhibit complement mediated lysis, consisting of or containing the amino aci sequence I;
-X-A-Y-A-Z- (I)
in which: X is a polar amino acid;
A is any amino acid; Y is a basic amino acid; 'and, Z is a basic amino acid
Also, according to the present invention there is provided a polypeptide, having the ability to inhibit complement mediated lysis, having the general formula II:
Head-X-A-Y-A-Z-Tail (II)
in which; X is, Asn, Glu, Thr or Gin
Y and Z are, independently, Lys, or Arg; •Head' is a hydrogen atom or a sequence of amino acid residues attached to the amino group of the adjacent amino acid X; 'Tail' is a hydrogen atom or a sequence of amino acid residues attached to the carboxyl group of the adjacent amino acid Y; and,
each of the groups represented by A, which may be the same or different, is an amino acid residue.
Preferably the group X is Glu or Thr, and Y and Z are both Lys or Arg.
Preferably each A is a non-ionic, preferably polar, most preferably small, amino acid residue.
The groups represented by 'Head* and 'Tail' may be joined by a peptide bridge to form a cyclic polypeptide or an analogue.
The polypeptide may be a pentapeptide ('Head' and 'Tail' both being hydrogen atoms) or a longer peptide, for example a sequence of amino acids mimicing the natural sequence- of a complete or incomplete CH2 domain of an Ig.
It is also possible that 'Head' and 'Tail' comprise identical sequences of amino acids.
Preferably the polypeptide of the invention has the sequence:
Acetγl-Ala-Glu-Ala-Lys-Ala-Lys-Ala-Amide
Advantageously, the polypeptide may be arranged so that side chains of the residues X Y and Z adopt approximately the configuration which they adopt in the CH2 domain of an Ig. This may be achieved by locating a polypeptide in a 'Head' and 'Tail' which together form a B-pleated sheet. Alternatively, this may be achieved by fixing the polypeptide to a carrier so that the polypeptide adopts a B-sheet-like configuration.
If a polypeptide analogue is used, for instance an
extended chain having appropriate functional groups attached thereto, it is only necessary to ensure that the functional groups are arranged in the same configuration as are the equivalent residues in the polypeptide.
Alternatively, the polypeptide analogue may compris an anti-peptide or anti-analogue, having the sequence Y-X-Z-X-z or Z-X-Z-X-Y, depending on being parellel or anti-parallel to the Clq binding sites of complement, wherein Y is a hydrogen bonding residue, each Z is independently a negatively charged residue and each X is independently an amino acid residue. Such an anti-peptide would act by masking the necessary residues on an antibody structure, so that Clq would not be bound. Preferably, such an anti-peptide would be produced in two copies connected via a long flexible linker. Each copy in the long molecule would then bind to a respective CH2 domain in a single antibody molecule, thereby inhibiting Clq binding.
The polypeptide or its analogue of the present invention may be fixed on to a carrier, such as a protein polysaccharide or plastics material, or may be used as formed.
The polypeptide of the present invention may find application in the therapy of autoimmune diseases, such a lupus erythematosus, which are believed to be caused by non-specific or uncontrolled activation of Clq.
It is believed that the ability of the peptide of the invention to inhibit lysis is indicative of its binding to the Clq component of complement. This view i supported by related research into the affinity of Clq fo mutant IgG antibodies, which is the subject of a related International Patent Application, in the name of Medical
esearch Council, filed on the same day as the present application, under the title "Improvements in or relating to altered anti- bodies". From that work, it may be explained that the binding site of IgG to Clq was localised to three side chains on residues 318, 320 and 322 of the CH2 domain of IgG. The peptide of this invention aims to mimic the Clq binding ability of the amino acid sequence spanning residues 318 to 322. By systematically altering the side chains at the three "motif" locations the significance of the acids at each location was determined. The following Table sets forth the results of this investigation which summarises the Affinity of human Clq for mutant mouse IgG2b antibodies
Loca :ion Natural Mutant Lys: Affinit A Ammiinnoo A Ammiinnoo for Clq
Acid Acid (nM)
318 Glu Ala - >300
318 Glu Thr + 11
318 Glu Val - 110
3 32200 L Lyyss A Allaa - >300
320 Lys Arg + 11
322 Lys Ala - 300
322 Lys Arg + 11 wild type + 11
The invention will now be described, by way of illustration, by the following Example.
EXAMPLE
A polypeptide was synthesised, using standard laboratory techniques for polypeptide synthesis, having the following structure:
Acetyl-Ala-Glu-Ala-Lys-Ala-Lys-Ala-Amide
The ability of this polypeptide to inhibit haemolysis of NIP-kephalin-derivatised sheep red blood cells was measured by the method of eltzien [Molec. Immunol., 21, 801 (1984)]. Using mouse anti-NP IgG2b antibody at 15 microgram/ml and guinea pig complement, th red blood cells are completely lysed. However, the polypeptide above was found to inhibit lysis at 166 micromolar. This compared well with the known affinity for Clq of monomeric IgG (which has two CH2 domains) of 7 micromolar.
It has been previously shown that modification of tryptophan residues in antibodies destroys their ability to lyse cells by complement. However, it has also been shown that such modification does not affect the ability of Clq to bind to the antibody. Based on these previous findings it was proposed that a Clq binding site occurred at Trp 277 (a buried residue) . Several peptides corresponding to this region were previously tested for their role in complement activation and one peptide did appear to play some part.
Previous work also included the preparation of peptides to inhibit antibody-mediated haemolysis of red cells by complement. At 175 micromolar, the peptide Val-Gln-Val-His-Asn-Ala-Lys-Thr-Lys-Pro-Arg gave 50% inhibition. Dimers of the peptide were made by cross- linking at the N-terminus through terephthaloyl-bis- (iminodiacetic acid) and gave 50% inhibition at 77 micromolar.
The results found with polypeptides of this invention are similar to those found with the peptide defined in the immediately preceding paragraph and are consistent with the concept underlying the present invention that the spatial configuration of the residues
involved in binding Clq comprise: hydrogen bonding residue (preferably small)- A - positively charged residue - A - positively charged residue.
Thus the present invention has shown that it is possible to synthesise a polypeptide based on the sequence of the Glu318 to Lys322 sequence which can be used directly in, vivo to compete with the binding of Clq. This ability would be expected to have potential as an anti-infammatory drug.
Referring now to Figure 2 of the accompanying drawings; there is shown graphically the inhibition of complement lysis by synthetic peptides of this invention. In Figure 2, the circles represent lysis for the peptide Acetyl-Ala-Glu-Ala-Lys-Ala-Lys-Ala-NH- and squares indicate that same for a control ppeptide of sequence Ser-Asp-Glu-Lys-Ala-Ser-Pro-Asp-Lys-Tyr, which both contain acidic and basic residues.
The method employed in the tests illustrated by
Figure 2 was as follows: Peptides were purified by reverse-phase HPLC and the composition checked by amino acid analysis. Freeze dried peptide was weighed and dissolved in CFD (Complement Fixation Diluent - Oxoid) to a concentration of 4mM and serial dilutions of the peptide made into 200 microlitre NIP-derivatized red cells (5 x 7 10 cells/ml), guinea pig serum (1/40 dilution) and antibody (7 microgram/ml), and incubated at 37°C for 30 minutes and then scanned using a Titertek Multiscan (Trade
Mark) . The results were converted to % lysis using a standard curve for red cell lysis, and plotted against peptide concentration. An apparent Iςo value of 170 micromolar compares with an Ic_ value of 75 micromolar
(or 150 micromolar per CH2 domain) which has been reported for monomeric IgG.
Claims
1. A polypeptide, having the ability to inhibit complement mediated lysis, consisting of or containing the amino acid sequence I;
-X-A-Y-A-Z- (I)
in which: X is a polar amino acid;
A is any amino acid;
Y is a basic amino acid; and,
Z is a basic amino acid
2. A polypeptide, having the ability to inhibit complement mediated lysis, having the general formula II:
Head-X-A-Y-A-Z-Tail (II)
in which; X is Asn, Glu, Thr or Gin
Y and Z are, independently, Lys or Arg ; 'Head' is a hydrogen atom or a sequence of amino acid residues attached to the amino group of the adjacent ;amino acid X; 'Tail' is a hydrogen atom or a sequence of amino acid residues attached to the carboxyl group of the adjacent amino acid Y; and, each of the groups represented by A, which may be the same or different, is an amino acid residue.
3. A polypeptide as claimed in claim 2 in which the group X is Glu or Thr, and Y and Z are both Lys or Arg.
4. A polypeptide as claimed in claim 2 or 3, in which each A is a non-ionic amino acid residue.
5. A polypeptide as claimed in claim 2 or 3 or 4, in which the groups represented by 'Head' and 'Tail' are joined by a peptide bridge to form a cyclic polypeptide or an. analogue.
6. A pentapeptide, having the ability to inhibit complement mediated lysis, having the general formula III:
X-A-Y-A-Z (III)
in which; X is Asp, Glu, Thr or Gin;
Y and Z are, independently, Lys or Arg; and, each of the groups represented by A, which may be the same or different, is an amino acid residue.
7. A polypeptide as claimed in claim 2 in which 'Head' and 'Tail' each represents a sequence of amino acids mimicing the natural sequence of a complete or incomplete CH2 domain of an Ig.
8. A polypeptide as claimed in claim 2, in which 'Head' and 'Tail' represent identical sequences of amino acids.
9. A the polypeptide of the invention, having the ability to inhibit complement mediated lysis, havin the formula IV:
Acetyl-Ala-Glu-Ala-Lys-Ala-Lys-Ala-Amide (IV)
10. A carrier sheet having atteched thereto a polypeptide as claimed in any of the preceding claims.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878706425A GB8706425D0 (en) | 1987-03-18 | 1987-03-18 | Altering complement activity of antibodies |
| GB8706425 | 1987-03-18 | ||
| GB878718897A GB8718897D0 (en) | 1987-08-10 | 1987-08-10 | Altering complement binding activity of antibodies |
| GB8718897 | 1987-08-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1988007054A1 true WO1988007054A1 (en) | 1988-09-22 |
Family
ID=26292028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1988/000213 WO1988007054A1 (en) | 1987-03-18 | 1988-03-18 | Complement-binding peptide |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0351410A1 (en) |
| WO (1) | WO1988007054A1 (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7053202B2 (en) | 2001-10-19 | 2006-05-30 | Millennium Pharmaceuticals, Inc. | Immunoglobulin DNA cassette molecules, monobody constructs, methods of production, and methods of use therefor |
| WO2012142515A2 (en) | 2011-04-13 | 2012-10-18 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
| WO2014126884A1 (en) | 2013-02-12 | 2014-08-21 | Bristol-Myers Squibb Company | High ph protein refolding methods |
| WO2014126871A1 (en) | 2013-02-12 | 2014-08-21 | Bristol-Myers Squibb Company | Tangential flow filtration based protein refolding methods |
| WO2014144791A2 (en) | 2013-03-15 | 2014-09-18 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
| WO2015085210A1 (en) | 2013-12-06 | 2015-06-11 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
| US9932380B2 (en) | 2013-03-14 | 2018-04-03 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| US10279021B2 (en) | 2014-03-14 | 2019-05-07 | Dana-Faber Cancer Institute, Inc. | Vaccine compositions and methods for restoring NKG2D pathway function against cancers |
| US10793633B2 (en) | 2011-09-30 | 2020-10-06 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
| US10851144B2 (en) | 2015-04-10 | 2020-12-01 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| US11634495B2 (en) | 2017-04-07 | 2023-04-25 | Miltenyi Biotec B.V. & Co. KG | Methods of activating CD32b/c comprising administering an antibody that binds BDCA-2 (CD303) |
-
1988
- 1988-03-18 WO PCT/GB1988/000213 patent/WO1988007054A1/en not_active Application Discontinuation
- 1988-03-18 EP EP19880902527 patent/EP0351410A1/en not_active Withdrawn
Non-Patent Citations (2)
| Title |
|---|
| Biochemistry, volume 20, 27 October 1981, American Chemical Society M.B. Prystowsky et al.: "Inhibition of the classical complement pathway by synthetic peptides from the second constant domain of the heavy chain of human immunoglobin G", pages 6349-6356 * |
| Nature, volume 282, 13 December 1979, Macmillan Journals Ltd R.J. Boackle et al.: "An IgG primary sequence exposure theory for complement activation using synthetic peptides", pages 742-743 * |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7053202B2 (en) | 2001-10-19 | 2006-05-30 | Millennium Pharmaceuticals, Inc. | Immunoglobulin DNA cassette molecules, monobody constructs, methods of production, and methods of use therefor |
| EP3415528A2 (en) | 2011-04-13 | 2018-12-19 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
| WO2012142515A2 (en) | 2011-04-13 | 2012-10-18 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
| US10214579B2 (en) | 2011-04-13 | 2019-02-26 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
| EP3896083A1 (en) | 2011-04-13 | 2021-10-20 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
| US9469676B2 (en) | 2011-04-13 | 2016-10-18 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
| EP3144320A1 (en) | 2011-04-13 | 2017-03-22 | Bristol-Myers Squibb Company | Fc fusion proteins comprising novel linkers or arrangements |
| US10793633B2 (en) | 2011-09-30 | 2020-10-06 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
| WO2014126871A1 (en) | 2013-02-12 | 2014-08-21 | Bristol-Myers Squibb Company | Tangential flow filtration based protein refolding methods |
| EP3299378A1 (en) | 2013-02-12 | 2018-03-28 | Bristol-Myers Squibb Company | High ph protein refolding methods |
| WO2014126884A1 (en) | 2013-02-12 | 2014-08-21 | Bristol-Myers Squibb Company | High ph protein refolding methods |
| EP3617220A1 (en) | 2013-02-12 | 2020-03-04 | Bristol-Myers Squibb Company | High ph protein refolding methods |
| EP3744728A1 (en) | 2013-02-12 | 2020-12-02 | Bristol-Myers Squibb Company | Tangential flow filtration based protein refolding methods |
| US10829535B2 (en) | 2013-03-14 | 2020-11-10 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| US10093711B2 (en) | 2013-03-14 | 2018-10-09 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| US10562950B2 (en) | 2013-03-14 | 2020-02-18 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| US9932380B2 (en) | 2013-03-14 | 2018-04-03 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| US11976102B2 (en) | 2013-03-14 | 2024-05-07 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| WO2014144791A2 (en) | 2013-03-15 | 2014-09-18 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
| US10745483B2 (en) | 2013-03-15 | 2020-08-18 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
| EP3666886A1 (en) | 2013-03-15 | 2020-06-17 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
| WO2015085210A1 (en) | 2013-12-06 | 2015-06-11 | Dana-Farber Cancer Institute, Inc. | Therapeutic peptides |
| US10106611B2 (en) | 2013-12-06 | 2018-10-23 | Dana-Farber Cancer Institute, Inc. | Antibodies that bind to MHC class I polypeptide-related sequence A |
| US10279021B2 (en) | 2014-03-14 | 2019-05-07 | Dana-Faber Cancer Institute, Inc. | Vaccine compositions and methods for restoring NKG2D pathway function against cancers |
| US11976103B2 (en) | 2015-04-10 | 2024-05-07 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| US10851144B2 (en) | 2015-04-10 | 2020-12-01 | Amgen Inc. | Interleukin-2 muteins for the expansion of T-regulatory cells |
| US11634495B2 (en) | 2017-04-07 | 2023-04-25 | Miltenyi Biotec B.V. & Co. KG | Methods of activating CD32b/c comprising administering an antibody that binds BDCA-2 (CD303) |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0351410A1 (en) | 1990-01-24 |
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