WO1995019374A1 - Bacterial receptor structures - Google Patents
Bacterial receptor structures Download PDFInfo
- Publication number
- WO1995019374A1 WO1995019374A1 PCT/SE1995/000034 SE9500034W WO9519374A1 WO 1995019374 A1 WO1995019374 A1 WO 1995019374A1 SE 9500034 W SE9500034 W SE 9500034W WO 9519374 A1 WO9519374 A1 WO 9519374A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- proteins
- protein
- receptor
- bacterial
- receptors
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/1034—Isolating an individual clone by screening libraries
- C12N15/1037—Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/305—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Micrococcaceae (F)
- C07K14/31—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Micrococcaceae (F) from Staphylococcus (G)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/315—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/822—Microorganisms using bacteria or actinomycetales
- Y10S435/882—Staphylococcus
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/822—Microorganisms using bacteria or actinomycetales
- Y10S435/882—Staphylococcus
- Y10S435/883—Staphylococcus aureus
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/82—Proteins from microorganisms
- Y10S530/825—Bacteria
Definitions
- Fc receptors Several bacteria known to invade mammals have evolved surface proteins capable of binding to a variety of sub ⁇ stances including host specific carbohydrates and prote ⁇ ins. Several such receptors from Gram-positive bacterial pathogens have been isolated and characterized in detail as will be shown below. Most well-characterized are the Fc receptors, named after the capability of binding to the constant Fc part of IgG. Based on binding experiments to IgG from various mammalian sources, and subclasses there- of, Fc receptors have been divided into six types I-VI.
- SPA protein A
- the structure for a complex between human Fc [IgGl] and a single domain [B] of SPA has been determined by X- ray crystallography at a resolution of 2.8 A [Deisenhofer, J. et al 1981 Biochemistry 20:2361-2370]. Based on this structure and additional information from NMR experiments, the B domain can be viewed as a compact structure consis- ting of three anti-parallel -helices connected with loops. In the Fc binding, which is of both electrostatic and hydrophobic nature, only side chains of residues from helices 1 and 2 are involved, whilst the third helix is not participating in the binding. Based on this domain B, a synthetic IgG-binding domain [Z] [Nilsson, B.
- Streptococcal strains of serological groups C and G display a binding repertoire for mammalian IgGs, including human IgG3, which is even broader than for the type I re ⁇ ceptor.
- the name protein G was suggested for this type III receptor from group G streptococci.
- Olsson and co- workers reported on the cloning and sequencing of the gene from the serological group G streptococci [G148] [Guss, B. et al, 1987 EMBO J. 5:1567-1575; Olsson, A. et al, 1987 Eur.J.Biochem. 168:319-324].
- SPG In analogy with SPA is SPG a repetitively arranged molecule, comprising an IgG-binding region of three homologous domains [C1,C2,C3], spaced by smaller D-regions (Fig. 2A). Compared to SPA, SPG displays a different binding spectra for imrnunoglobulins from dif ⁇ ferent species and subclasses thereof.
- the IgG binding domains of protein G are now widely used as an immuno- logical tool, i.e. in the affinity purification of mono ⁇ clonal antibodies. Production of subfragments constructed by DNA-technology, have shown that an individual C-region is sufficient for full IgG-binding.
- SPG serum albumin binding strength
- the binding strength is species depen- dent, and among the tested samples, SPG binds strongest to serum albumin from rat, man and mouse.
- Production and bin ⁇ ding studies of subfragments of SPG shows that the two binding activities are structurally separated and that the serum albumin binding function is located at the repeti- tive A-B region [Nygren et al 1990 Eur.J.Biochem. 193:143- 148] . This region has been used for several biotechnolo- gical purposes. Recombinant proteins have been produced as fusions to the region which enables the purification by affinity chroma ography, where human serum albumin most frequently has been used as immobilized ligand.
- Proteins found to be proteolytically sensitive have been produced as "dual affinity fusions" in which they are flanked by two different affinity tails derived from SPA and SPG, respectively. Purification schemes employing both the N- and C-terminal are thus possible which ensures the recove ⁇ ry of an intact target protein [Hammarberg et al 1989 Proc.Natl.Acad.Sciences USA 86:4367-4371], The strong and specific binding to serum albumin has also been used for the In vivo stabilization of therapeutic proteins.
- the receptor is carried in the circulation (macaque apes) with a half-life which is close to the half-life for serum albumin itself.
- mice with the for HIV/AIDS therapy interesting, but rapidly cleared T-cell receptor CD4 showed that it was substantially sta ⁇ bilized when fused to the serum albumin binding region, when compared with an unfused control protein [Nygren et al 1991 Vaccines 91 Cold Spring Harbor Press 363-368] .
- the slow clearance can probably be explained by the complex formation with serum albumin which circumvents elimination by the liver and excretion in the kidney.
- SPG is regarded to be trivalent with regard to binding to serum albumin. Similar to the monovalent IgG-binding domains Z and Cl B2A3 is relatively small and shows high solubility and stability and is therefore a suitable candidate for modification.
- the present invention has for its main purpose to provide new bacterial receptor structures by modifying natural bacterial receptors in regard to their original interaction functions to result in new structures having modified interaction functions.
- Another object of the invention is to provide arti ⁇ ficial bacterial receptor structures which are stable and more resistant to various conditions, such as increased temperatures.
- Yet another object of the invention is to provide artificial bacterial receptor structures, the interaction functions of which have been modified to direct same to other desired interaction partners.
- novel proteins obtainable by mutagenesis of surface- exposed amino acids of domains of natural bacterial re- ceptors said proteins being obtained without substantial loss of basic structure and stability of said natural bacterial receptors.
- Said proteins have preferably been selected from a protein library embodying a repertoire of said novel proteins.
- at least one amino acid residue involved in the interaction fuction of the or._jinal bacterial receptor has been made subject to substitution by another amino acid residue so as to result in substantial loss of the original interaction capacity with a modified interaction capacity being created, said substitution being made with ⁇ out substantial loss of basic structure and stability of the original bacterial receptor.
- said bacterial structures origi ⁇ nate from Gram-positive bacteria there may be mentioned Staphylococcu ⁇ aureus .
- Streptococcus pyogenes [group A] Streptococcus group C,G,L, bovine group G streptococci, Streptococcus zooepidemicus [group C] , Streptococcus zooepidemicu ⁇ S212, Streptococcus pyogenes [group A] , streptococci groups A,C,G, Peptostreptococcus magnus, Streptococcus agalactiae [group B] .
- thermophilic bacteria evolved to persist in environments of elevated temperatures.
- Re ⁇ ceptors from species like e.g. Bacillus ⁇ tearother ⁇ o- philu ⁇ , Ther u ⁇ aquaticu ⁇ , Theirmococcu ⁇ litoralis and Pyrococcus have the potential of being naturally excep ⁇ tionally stable, thus suitable for providing structural frameworks for protein engineering according to the in ⁇ vention.
- bac ⁇ terial receptors originating from Fc[IgG]receptor type I, type II, type III, type IV, type V and type VI, fibronec- tin receptor, M protein, plasmin receptor, collagen re ⁇ ceptor, fibrinogen receptor or protein L [K light chains], protein H [human IgG], protein B [human IgA,Al], protein Arp [human IgA] .
- Particularly preferred bacterial receptors originate from the Fc[IgG]receptor type I of staphylococcal protein A or the serum albumin receptor of streptococcal protein G.
- the substi ⁇ tution involving amino acid residues taking part in the interaction function of the original bacterial receptor does not involve more than about 50% of the amino acid residues of the original bacterial receptor. It is parti- cularly preferred that not more than about 25% of the amino acid residues of the original bacterial receptor are made subject to substitution.
- substitution thereof involves not more than substantially all of the amino acid residues taking part in the interaction function of the original bacterial receptor.
- the bacterial receptor according to the pre ⁇ sent invention is comprised of not more than about 100 amino acid residues. It is known from scientific reports that proteins of a relatively small size are fairly resis ⁇ tant to increased temperatures and also to low pH and cer- tain chemicals. For details concerning temperature resis ⁇ tance c.f. the article by Alexander et al. in Biochemistry 1992, 31, pp 3597-3603.
- interaction part ⁇ ners are IGF-I, IGF-II, hGH, Factor VIII, insulin and apolipoprotein and their respective receptors as interac ⁇ tion partners. Furthermore, by selecting new receptor variants with specificity for different folding forms of proteins, affinity resins or analytical tools to facili ⁇ tate the isolation of correctly folded molecules can be produced. Further examples are viral coat proteins, bac ⁇ terial antigens, biotin and cell markers, such as CD 34 and CD 4.
- the present invention is applicable to a variety of natural bacterial receptors the following illustration of the invention more in detail will be directed to the use of the IgG-binding domains Z, Cl and B2A3.
- the concept of the present invention residing in the use of artificial bacterial receptors based on the natural structures of naturally occurring bacterial receptors is associated with several advantages.
- the invention makes it possible to use robust and stable, highly soluble and secretion competent receptors. This is in contrast to previous techniques based on the use of polyclonals and monoclonals, such as for diagnostic purposes, which are not very stable in connection with storage, varying condi ⁇ tions, such as varying temperatures etc.
- the invention makes it possible to modify natural bacterial receptors to obtain desired interaction capacities for specific purposes.
- phage display technique can be used for selection of both small peptides as well as more complicated proteins such as antibodies, receptors and hormones.
- intra- cellular systems have been developed in which the library of proteins are fused to a repressor protein with affinity for a specific plasmid-borne operator region resulting in a coupling between the specific protein variant and the plasmid that encoded it.
- An alternative to the phages as bearer of protein libraries would be to use bacterial cells.
- bacterial recep ⁇ tors as structural frameworks are several. They have evol ⁇ ved to express a binding function without disturbing the overall structure. They are naturally highly soluble, robust to unphysiological conditions, such as pH and heat, folding efficient and are in addition secretion competent. The invention finds use in several different areas.
- the introductory part of the above-identified patent specification WO92/20791 gives an excellent survey on an ⁇ tibodies and their structure. Reference is particularly made to page 1 thereof.
- the bacterial receptors SPA and SPG have been widely used in antibody technology for detection and purification of antibodies from e.g. hybridom supernatants and ascites fluids. However, not all antibodies are recognized by these receptors, depending on species and subclass. For the smaller subfragments of antibodies (Fig. 4), SPA and SPG show a limited binding, and efficient tools for gene- ral purification schemes are lacking. However, from a repertoire of mutant receptors including SPA and SPG, forms displaying a broader affinity for antibodies and subfragments thereof can potentially be selected.
- the complex structural organization of antibodies has a number of consequences for their use in different appli ⁇ cations as well for the production of recombinant deriva ⁇ tives.
- the arrangement of sub- units connected by disulphide bonds can lead to a leakage of released heavy and light chains from columns.
- the re ⁇ quirement of successful docking of the two subunits con ⁇ tributing to the antigen binding site makes the production in bacteria of small subfragments with a low association difficult.
- the folding of the antibody is dependent on the formation of intra- and inter chain disulphidebonds, which are not able to form in the intracellular environment of bacterial cells.
- High-level intracellular expression sys ⁇ tems for recombinant antibodies leads to the formation of inclusion bodies, which have to be renatured to obtain biological activity.
- the CDR regions forming the antigen bidning part of an antibody forms a total surface available for the anti ⁇ gen of approximately 800 A 2 , with typical 10-20 residues from the antibody involved in the binding.
- the binding surface of about 600 A 2 is of the same order of magnitude as between an antibody and its antigen.
- Immunoglobulins are substantially tetramers built up from so called ⁇ -sheet structures which stabilize the orientation of the antigen- binding loops which in turn consist of continuous peptide sequences.
- the purification of the product is frequently a major problem.
- the hybrid product can effectively and selec ⁇ tively be recovered from the cell lysate or in certain cases from the culture medium by passage through a column containing an immobilized ligand.
- gene fusion systems have been described which are based on the inter- action of a certain protein with a ligand. For industrial applications it is often desirable to clean effectively the columns between the runs to satisfy purity require ⁇ ments by authorities.
- the relatively harsh conditions NaOH, acids, heat
- organic or physical matrises for example in ion exchange chromatography and gel filtration
- the use of new ligands based on stable structures originating from bacterial receptors are of great importance.
- the Z domain from SPA is an excellent example since said domain can be subjected to such difficult conditions as a pH of 1 or heating to 80°C without denaturating non-reversibly (see Example 2 below).
- Z variants inte ⁇ resting protein products can be selected for use immobi ⁇ lized on a solid phase for affinity chromatography.
- the high solubility of the said domain enables the use of in ⁇ creased solubility of proteins in either refolding from inclusion bodies or in so called reshuffling of disulphide bridges.
- new forms can be selected having improved properties to facilitate and even make refolding of recombinant proteins possible (cis-acting chaperones) .
- Recently a new unit operation for the purification of recombinant proteins based on ion exchange chromatography in so called expanded bed has been described [Hansson, M. et al 1994 Bio/Technol. in press].
- the present invention provides means for producing and selecting proteins with novel functions. According to the invention this is achieved by extensive mutation of defined residues of stable domains of bacterial receptors. Due to the novel functions of the artificial bacterial re ⁇ ceptors, these can be used as specific binders for thera ⁇ Illustrated, diagnostic, biotechnology or in research. 17 Figure 9. Phagemid vector pKNl .
- the library PCR products encoding the variegated helices 1 and 2 was subclo- ned into the phagemid vector, pKNl, containing the gene for residues 44-58 of the wild type Z domain (essentially helix 3), followed by the gene for a 46 residues serum albumin binding region (ABP) derived from streptococcal protein G linked in frame with a truncated version of the M13 phage coat protein 3 gene.
- the phagemid contains the origin of replication derived from plasmid pBR322 as well as the intergenic region ( f1 ori ) required for packing into the phage particles.
- FIG. 10 SDS-PAGE. HSA-affinity purified proteins from the periplasm of E ⁇ cherichia coli cells produ ⁇ cing the wild type Z domain and two different acid Z-variants as ABP fusion proteins encoded from their respective phagemid vectors were analyzed by SDS/PAGE.
- M molecular weight mar ⁇ ker; lane 1, wild type Z domain; lane 2, clone 10; lane 3, clone 12.
- FIG. 11 CD-data. Overlay plot of CD spectra obtained for the wild type Z domain and two variants of the Z-protein library. The signals of the pro ⁇ teins were obtained after subtraction of the CD signal contribution of the ABP tail, present during the analysis.
- FIG. 12 Ion exchange chromatography.
- the two acid Z- variant proteins no. 10 and no. 12 together with the wild type Z-domain (produced as ABP fusion proteins) were each subjected to analy ⁇ sis at pH 5.5, employing an anion exchange chromatography column. Elution of the proteins 18 from the column was obtained by a NaCl gradi ⁇ ent.
- FIG. 13 Z-domain structure.
- the structure of helices one and two are from the co-crystal structure be ⁇ tween domain B of SPA and Fc (Deisenhofer, (1981) Biochemistry, 20, 2361-2370).
- the third helix was built based on the secondary structu ⁇ re assignments from NMR spectroscopy (Gouda et al., (1992) Biochemistry, 31, 9665-9672).
- Non- hydrogen atoms of side-chains of residues that were mutated in the construction of the combi ⁇ natorial library are displayed as ball-and- stick models.
- the display was generated by the program MOLSCRIPT (Kraulis (1991) J.Appl.
- Figure 14 Amino acid sequences. Result from DNA-sequen- cing of 31 randomly chosen Z-variants from the library. The residues subjected to the mutage ⁇ nesis are boxed. Horisontal lines indicate nu- cleotide identity with the wild type Z sequence listed at the top. Indicated are the clones that were expressed and characterized as fusion proteins to the ABP-tail.
- Figure 15 Aminoacid distribution. Result from the statis ⁇ tical analysis of the deduced amino acids at the mutated positions. In total, 13 residues from 31 clones (403 codons) were included in the calculation. The ratios between observed and expected frequencies are shown for all 20 Figure 9 Phagemid vector pKNl .
- the library PCR products encoding the variegated helices 1 and 2 was subclo- ned into the phagemid vector, pKNl, containing the gene for residues 44-58 of the wild type Z domain (essentially helix 3), followed by the gene for a 46 residues serum albumin binding region (ABP) derived from streptococcal protein G linked in frame with a truncated version of the M13 phage coat protein 3 gene.
- the phagemid contains the origin of replication derived from plasmid pBR322 as well as the intergenic region ( f1 ori ) required for packing into the phage particles.
- FIG. 10 SDS-PAGE. HSA-affinity purified proteins from the periplasm of E ⁇ cherichia coli cells produ ⁇ cing the wild type Z domain and two different acid Z-variants as ABP fusion proteins encoded from their respective phagemid vectors were analyzed by SDS/PAGE.
- M molecular weight mar ⁇ ker; lane 1, wild type Z domain; lane 2, clone 10; lane 3, clone 12.
- FIG. 11 CD-data. Overlay plot of CD spectra obtained for the wild type Z domain and two variants of the Z-protein library. The signals of the pro ⁇ teins were obtained after subtraction of the CD signal contribution of the ABP tail, present during the analysis.
- FIG 12 Ion exchange chromatography.
- the two acid Z- variant proteins no. 10 and no. 12 together with the wild type Z-domain (produced as ABP fusion proteins) were each subjected to analy ⁇ sis at pH 5.5, employing an anion exchange chromatography column. Elution of the proteins from the column was obtained by a NaCl gradi ⁇ ent.
- FIG. 13 Z-domain structure.
- the structure of helices one and two are from the co-crystal structure be ⁇ tween domain B of SPA and Fc (Deisenhofer, (1981) Biochemistry, 20, 2361-2370).
- the third helix was built based on the secondary structu ⁇ re assignments from NMR spectroscopy (Gouda et al., (1992) Biochemistry, 31, 9665-9672).
- Non- hydrogen atoms of side-chains of residues that were mutated in the construction of the combi ⁇ natorial library are displayed as ball-and- stick models.
- the display was generated by the program MOLSCRIPT (Kraulis (1991) J.Appl.
- Figure 14 Amino acid sequences. Result from DNA-sequen- cing of 31 randomly chosen Z-variants from the library. The residues subjected to the mutage ⁇ nesis are boxed. Horisontal lines indicate nu- cleotide identity with the wild type Z sequence listed at the top. Indicated are the clones that were expressed and characterized as fusion proteins to the ABP-tail.
- Figure 15 Aminoacid distribution. Result from the statis ⁇ tical analysis of the deduced amino acids at the mutated positions. In total, 13 residues from 31 clones (403 codons) were included in the calculation. The ratios between observed and expected frequencies are shown for all 20 amino acids as well for the only termination signal (TAG) included in the NNG/T degeneracy profile.
- TAG termination signal
- FIG. 16 SDS-PAGE analysis. HSA-affinity purified pro ⁇ teins from the periplasm of E.coli cells produ ⁇ cing the wild type Z domain and four different Z-variants as ABP fusion proteins encoded from their respective phagemid vectors were analyzed by SDS/PAGE. Lanes 1-5: Reduced conditions.
- Lanes 6 and 7 Non-reduced conditions. Lane 1, wild type Z domain; lane 2, clone 16; lane 3, clone 21; lane 4, clone 22; lane 5, clone 24; M, molecular weight marker; lane 6, clone 16 and lane 7, clone 22.
- Figure 17 CD-data. Overlay plot of CD spectra obtained for the wild type Z domain and four variants of the ⁇ -helical protein surface library. The sig- nals of the variants were obtained after sub ⁇ traction of the CD signal contribution of the ABP tail, present during the analysis.
- FIG. 18 Biosensor assay. An overlay plot of sensorgrams obtained from the BIA-coreTM analysis of the wild type Z domain and four different variants (no. 16,21,22,24; Figure 4) fused to the ABP tail. The IgG-binding activities of the diffe ⁇ rent proteins were analyzed using a sensor chip coated with approx. 5000 RU human polyclonal
- oligonucleotides (Fig. 6) were purchased from Scandinavian Gene Synthesis (Sweden), and phosphorylated where indicated according to [Maniatis et al (1988) Mole ⁇ cular cloning. A laboratory manual. Cold Spring Harbor Laboratory Press].
- ZLIB-1 was biotinylated in the 5 ' -end enabling immobilization on paramagnetic beads M-280 Strep- tavidin purchased from Dynal A/S (Norway). Washing/binding buffer was 1 M NaCl, 10 mM Tris-HCl, pH 7.5, 1 mM EDTA (ethylenediamine tetraacetic acid).
- the annealing/ligation buffer was 30 mM Tris-HCl, pH 7.5, 10 mM MgCl 2 , 0.2 mM ATP, 1 mM 1.4 dithiothreitol (DTT).
- DNA ligase were from Boehringer Mannheim, Germany.
- 10 x PCR buffer contained 20 rnM MgCl 2 , 2 mM dNTPs, 100 mM Tris-HCl, pH 8.3, 50 mM KC1, 1% Tween 20.
- Tag DNA polymerase was from Cetus Inc., USA.
- the thermal cycler was a Perkin-Elmer 9600.
- the synthetic 58 residue SPA analogue Z [Nilsson et al, Prot.Eng] was subjected to a mutagenesis approach to construct new variants with an altered pi, in order to produce fusion partners for recombinant proteins to be pu- rified by ion-exchange chromatography.
- the PCR mix (50 ⁇ l ) contained one pmole each of PCR primers ZLIB-3 and ZLIB-5, 5 ⁇ l each of the ligation mix, 10 x PCR buffer and 10 x CHASE, 1 unit of Tag polymerase and sterile water to 50 ⁇ l.
- the temperature cycling programme was: 96°C, 1 min, 60°C, 1 min and 72°C, 2 min, repeated for 35 cycles.
- Ana ⁇ lysis by 1% agarose gel electrophoresis showed a band of the expected size of 179 bp, showing the feasibility of the assembly concept.
- the 179 bp band from the PCR of the Z(Acid)-library was cut out from the gel and purified (GenecleanTM, Bio 101, Inc.
- the temperature stability of the Z conformation was determined by following the ellipticity at 222 run by cir ⁇ cular dichroism (CD) spectroscopy through a temperature scan. This wavelength is used to monitor the presence of ⁇ -helicity of Z [Cedergren et al. 1993 Prot. Eng. 6:441- 448] .
- the experiment was performed at a rather low pH (approximately 2.9) in order to destabilize the molecule since the mid-point of temperature denaturation (Tm) is ⁇ 95°C at neutral pH (data not shown), which is outside the range that can be determined by a complete scan through the transition under normal atmospheric pressure.
- the experiment shows (Fig. 4) that the Tm (as defined by the inflexion point of the temperature scan) of the Z domain is as high as 71°C at pH 2.9. This demonstrates the ex- treme temperature stability of the ⁇ -helices of the Z molecule.
- the experiment was performed in a J-720 spectro- polarimeter (JASCO, Japan) and the temperature was con ⁇ trolled by circulating water through the cuvette holder from a NESLAB water bath. The temperature was monitored in the cuvette through a micro sensor device (JASCO, Japan).
- the buffer was 50 mM acetic acid, pH 2.9.
- the protein was domain Z [Cedergren et al 1993 Prot. Eng. 6:441-448] at a protein concentration of 50 ⁇ g/mL and the cuvette cell path length was 1 cm.
- the temperature scan speed in the experiment was 50°C/h. 23
- Example 3 Characterization of proteins derived from the acid Z-library.
- the restricted fragments (approximately 5 ⁇ g) were purified by phenol/chloroform/isoamylaJcohol extraction followed by additional washing with chloroform and later ethanol precipitated before ligation at 15 C C over night to Mlu I-Nhe I cleaved pKNl vector (1 ⁇ g) (see below) using 13.5 Weiss units of T4 DNA ligase.
- the ligation mixture was heat-treated at 70°C for 20 min, extracted with phenol/chloroform/isoamylalcohol followed by washing with chloroform, ethanol precipitated and redissolved in 20 ⁇ l of sterile water.
- the phagemid vector pK l (figure 9) was constructed in several steps as follows.
- a double stranded linker encoding the invariant residues 44-58 of the Z-domain was formed from oligonucleotides ZLIB-6 and ZLIB-7 and cloned as a Mlu l-Xho I fragment into phagemid pKP9S6 (A kind gift from Dr. Lars Abrahmsen. Pharmacia BioScience Center, Sweden),- resulting in pK .
- Plasmid pKP9S6 encodes the E. coli Omp A leader peptide followed by residues 249-406 of fd filamentous phage coat protein ' 3 (Lowman et al.
- a gene fragment encoding a monovalent serum albumin binding region derived from streptococcal protein G was amplified by PCR from the plasmid pB2T (Eliasson et al, Molecular Immunol, 28, 1055- 1061), using primers ABP- 1 and ABP-2 (which contain Xn' o I and Sal I recognition sites, respectively) and cloned into Xho I restricted plasmid pKN, yielding pKNl.
- This phagemid vector thus encodes for the Omp A signal peptide, the third helix of the wild type Z domain followed by a 46 residue albumin binding protein (ABP) linked to residues 249-406 of fd phage protein III and is adapted for inse ⁇ ion of ⁇ sp 3l/Nhe I-digested PCR products encoding variegated helices one and two of the Z domain.
- ABC albumin binding protein
- the solid-phase DNA sequencing of the PCR products was performed employing the FITC labeled sequencing primers NOKA-3 (for the immobilized strand) and ABP-2 (for the eluted strand) on a robotic workstation (BiomekTM 1000, Beckman Instruments, Fullerton, CA) and an Automated Laser Fluorescent (A.L.F.) DNA SequencerTM (Pharmacia Biotech, Sweden) as described by Hultman and coworkers (Hultman et al, ( 19S9) Nucleic acids Research, 17, 4937-4946).
- the periplasmic content from the cells was subjected to affinity chromatography on HSA-Sepharose as described by Nygren and coworkers (Nygren et al, (1988) J. Mol. Recognit., 1, 69-74) and analyzed by SDS/PAGE on a homogeneous 12% slab gel (BioRad Inc., USA), which was stained with Coomassie Brilliant Blue R-250.
- SDS- PAGE analysis Figure 10 of purified proteins suggest that the acid Z variants analyzed are stably expressed in E. coli.
- the proteins Z(wild 5 type) and the acid variants no. 10 and no. 12 were each (5 ⁇ g) dissolved in 300 ⁇ l of 20 mM Piperazine buffer (pH 5.5) and separately applied at 100 ⁇ l/min on a MonoQ. PC 1.6/5 column (Pharmacia, Sweden). Elution of the proteins were performed by applying a NaCl gradient in Piperazine buffer (pH 5.5) (Sigma, USA) ranging from 0-50 % NaCl in 20 min.
- the series of experiments performed on the two acid Z-variant proteins shows that the expression behaviour, proteolytic stability and secondary structure content of the variants were unchanged when compared to the native Z-domain. Furthermore, a novel functions were introduced into the two Z-variants by the substitution of surface located positions with acid amino acids.
- the two acid variants can be used e.g. as 0 fusion partners to facilitate purification of recombinant proteins by ion exchange chromatography at low pH. Thus, it is showed that among the members of the acid Z- library, variants with novel functions can be isolated.
- a library of Z-variants was assembled using a solid-phase gene assembly strategy (see example 1). Most of the amino acid residues suggested to take part in the binding Q to Fc (Deisenhofer, (1981) Biochemistry, 20. 2361-2370) were found to be on the molecule surface (Q9, Q10, Ni l, F13, Y14, L17, N28, Q32 and K35), and therefore included in the mutagenesis. In addition, based on their surfacial location, other residues (H18, E24, E25 and R27) were also decided to be included. In total, 13 residues in the Z scaffold where thus chosen for simultaneous and random 5 mutagenesis.
- a set of oligonucleotides ( Figure 6) were synthesized for construction of the library of surface mutants of the 58-residues monovalent IgG-binding domain denoted Z.
- the chosen NNK degeneracy includes 32 codons covering all 20 amino acids, including the TAG (amber) termination signal.
- Oligonucleotide ZLIB- 1 was synthesized with a 5' biotin group to enable robust anchoring onto streptavidin-coated paramagnetic beads used as solid support during the gene assembly.
- This ZLIB- 1 oligonucleotide, together with its complementary sequence (ZLIB-2) encodes residues 1-8 of the Z domain, preceeded by the first six residues of region E of protein A which were included to facilitate the E. coli secretion of the Z variants (Abrahmsen et al, (1986) EMBO J., 4, 3901-3906).
- the oligonucleotides DEGEN- 1 and DEGEN-2 (Table I) encode the two mutated helices of the Z domain, respectively, normally involved in Fc-binding. Theoretically, full and simultaneous NNK degeneracy at the 13 selected positions would yield a combinatorial library of appr. 8* 10 ⁇ protein variants encoded by 3.7* 10 ⁇ different DNA sequences. However, here the assembly of the library was initiated by the immobilization of appr. 15 pmole of prehybridized oligonucleotides ZLIB-1 and ZLIB-2 ( Figure 6), which limits the theoretical size of the Z-library to appr. 0.9* 10 1 - 5 different DNA sequences encoding appr. 2* 10 ⁇ Z variants.
- oligonucleotides ZLIB-3 and ZLIB-5 containing the recognition sequences for the endonucleases Esp 3 I and Nhe I respectively, were used as primers for PCR amplification of the assembled constructs using one tenth of t he bead-immobilized ssDNA as template (theoretically corresponding to 2* 10 ⁇ protein variants).
- oligonucleotides ZLIB-2, BRIDGE and ZLIB-5 were first eluted with alkali. The resulting PCR product was analysed by agarose gel electrophoresis and found to be homogenous and of the expected size. 179 bp.
- the PCR product was subcloned into the pK l phagemid vector containing the gene for residues 44-58 of the wild type Z domain in frame with a truncated version of the fd phage coat protein 3 gene for surface display on phage particles upon helper phage s perinfection of phagemid transformed E. coli cells (Lowman et al, ( 1991) Biochemistry, 30, 10S32-10S44) ( Figure 9).
- the phagemid vector contains an interspaced in-frame cassette encoding a 5 kDa (46 aa) serum albumin binding region (denoted .ABP) derived from streptococcal protein G (Nygren et al, (1988) J.
- the serum albumin binding activity can potentially be used for pre-selection of phage panicles earning recombinant molecules, prior to the panning for Z variants with new binding functions, to decrease the background originating from unspecifically bound non-recombinant phage particles.
- PCR screening using the oligonucleotides PJT-27 and NOKA- 2 of 25 clones showed that over 959c (24/25) of the clones contained an insert of the expected length, suggesting that the gene assembly procedure was carried out with high efficiency.
- Fo ⁇ yfive transformants were randomly selected and subjected to direct solid phase DNA sequencing (see Example 3) in order to further analyze the quality and heterogeneity of the library. Approximately 699 of the clones were correct, containing wild type and degenerate codons at expected positions. The remaining clones had spurious discrepancies which in part can be attributed to the oligonucleotide synthesis or errors introduced during PCR.
- Soluble proteins from the periplasm of IPTG-induced cultures were subjected to HSA-affmity chromatography employing the .ABP-tail for general and efficient recovery (Nygren et al, (19SS) J. Mol. Recognit., 1, 69-74). For all proteins appr. 1.5-2.5 mg/L culture could be recovered, indicating similar production and secretion efficiencies for the variants and the wild type domain.
- the results from a SDS-PAGE analysis ( Figure 16) of purified proteins suggest that the four Z variants analyzed are stably expressed in E. coli.
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95907175A EP0739353B1 (en) | 1994-01-14 | 1995-01-16 | Bacterial receptor structures |
JP51898495A JP4089920B2 (en) | 1994-01-14 | 1995-01-16 | Bacterial receptor structure |
DE69533644T DE69533644T2 (en) | 1994-01-14 | 1995-01-16 | RECEPTOR STRUCTURES FROM BACTERIA |
AU15487/95A AU696186B2 (en) | 1994-01-14 | 1995-01-16 | Bacterial receptor structures |
CA002181042A CA2181042C (en) | 1994-01-14 | 1995-01-16 | Bacterial receptor structures |
DK95907175T DK0739353T3 (en) | 1995-01-16 | 1995-01-16 | Bacterial Receptor Structures |
AT95907175T ATE279439T1 (en) | 1994-01-14 | 1995-01-16 | RECEPTOR STRUCTURES FROM BACTERIA |
US08/669,360 US5831012A (en) | 1994-01-14 | 1995-01-16 | Bacterial receptor structures |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9400088A SE9400088D0 (en) | 1994-01-14 | 1994-01-14 | Bacterial receptor structures |
SE9400088-2 | 1994-01-14 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/082,468 Continuation US6534628B1 (en) | 1994-01-14 | 1998-05-21 | Bacterial receptor structures |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1995019374A1 true WO1995019374A1 (en) | 1995-07-20 |
WO1995019374A9 WO1995019374A9 (en) | 2006-04-13 |
Family
ID=20392561
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1995/000034 WO1995019374A1 (en) | 1994-01-14 | 1995-01-16 | Bacterial receptor structures |
Country Status (12)
Country | Link |
---|---|
US (2) | US5831012A (en) |
EP (1) | EP0739353B1 (en) |
JP (3) | JP4089920B2 (en) |
AT (1) | ATE279439T1 (en) |
AU (1) | AU696186B2 (en) |
CA (1) | CA2181042C (en) |
DE (1) | DE69533644T2 (en) |
ES (1) | ES2225838T3 (en) |
NZ (1) | NZ278991A (en) |
PT (1) | PT739353E (en) |
SE (1) | SE9400088D0 (en) |
WO (1) | WO1995019374A1 (en) |
Cited By (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997024130A1 (en) * | 1995-12-27 | 1997-07-10 | Ngk Insulators, Ltd. | CANCEROUS METASTASIS INHIBITOR COMPRISING SURFACE POLYSACCHARIDE OF STREPTOCOCCUS AGALACTIAE Ia TYPE OR Ib TYPE AS PRINCIPAL COMPONENT |
WO2000063243A1 (en) | 1999-04-19 | 2000-10-26 | Biovitrum Ab | Derivatives of the b or z domain from staphylococcal protein a (spa) interacting with at least one domain of human factor viii |
WO2002008263A3 (en) * | 2000-07-19 | 2002-06-13 | Got A Gene Ab | Modified virus having an altered tropism |
US6602977B1 (en) | 1999-04-19 | 2003-08-05 | Biovitrum Ab | Receptor structures |
US6740734B1 (en) * | 1994-01-14 | 2004-05-25 | Biovitrum Ab | Bacterial receptor structures |
US6831161B1 (en) | 1998-10-21 | 2004-12-14 | Affibody Ab | Method of affinity separation and ligands for use therein |
EP1600459A3 (en) * | 2002-06-28 | 2005-12-07 | Domantis Limited | Ligand |
WO2007065635A1 (en) * | 2005-12-05 | 2007-06-14 | Affibody Ab | Polypeptides |
EP1826270A1 (en) * | 1999-07-20 | 2007-08-29 | Affibody AB | Method and library for in vitro selection |
EP2014359A1 (en) | 2007-07-10 | 2009-01-14 | Millipore Corporation | Media for affinity chromatography |
WO2009019117A1 (en) * | 2007-08-03 | 2009-02-12 | Affibody Ab | Igf-1r binding polypeptides and their use |
WO2009080811A1 (en) * | 2007-12-21 | 2009-07-02 | Affibody Ab | Polypeptide libraries with a predetermined scaffold |
AU2003217119B2 (en) * | 2002-03-25 | 2010-02-18 | Cytiva Bioprocess R&D Ab | A mutated immunoglobulin-binding protein |
US7993650B2 (en) | 2003-07-04 | 2011-08-09 | Affibody Ab | Polypeptides having binding affinity for HER2 |
WO2012083425A1 (en) * | 2010-12-21 | 2012-06-28 | The University Of Western Ontario | Novel alkali-resistant variants of protein a and their use in affinity chromatography |
WO2013022091A1 (en) | 2011-08-11 | 2013-02-14 | 小野薬品工業株式会社 | Therapeutic agent for autoimmune diseases comprising pd-1 agonist |
EP2559702A1 (en) | 2007-02-08 | 2013-02-20 | Domantis Limited | Antibody single variable domains against serum albumin |
US8388979B2 (en) | 2006-01-31 | 2013-03-05 | Ishihara Sangyo Kaisha, Ltd. | Polypeptide having affinity for envelope virus constituent and use thereof in transferring substance into cell |
US8501909B2 (en) | 2007-12-21 | 2013-08-06 | Affibody Ab | Polypeptides having affinity for HER2 |
WO2013143890A1 (en) | 2012-03-28 | 2013-10-03 | Affibody Ab | Oral administration |
WO2014013016A1 (en) | 2012-07-20 | 2014-01-23 | Affibody Ab | Method for determining the her2 status of a malignancy |
WO2014076179A1 (en) | 2012-11-14 | 2014-05-22 | Affibody Ab | New polypeptide |
US8754196B2 (en) | 2011-06-08 | 2014-06-17 | Emd Millipore Corporation | Chromatography matrices including novel Staphylococcus aureus protein A based ligands |
WO2014103203A1 (en) | 2012-12-27 | 2014-07-03 | 独立行政法人産業技術総合研究所 | Molecule library constructed on the basis of backbone structure of microprotein |
US9040661B2 (en) | 2010-12-21 | 2015-05-26 | Jsr Corporation | Support for affinity chromatography and method for isolating immunoglobulin |
US9187535B2 (en) | 2007-12-19 | 2015-11-17 | Affibody Ab | Polypeptide derived from protein A and able to bind PDGF |
US9546198B2 (en) | 2007-10-12 | 2017-01-17 | Cancer Research Technology Limited | Cyclic peptides as ADAM protease inhibitors |
US9920112B2 (en) | 2008-08-11 | 2018-03-20 | Emd Millipore Corporation | Immunoglobulin-binding proteins with improved specificity |
US10072050B2 (en) | 2008-12-24 | 2018-09-11 | Emd Millipore Corporation | Caustic stable chromatography ligands |
WO2018194376A1 (en) | 2017-04-18 | 2018-10-25 | 앱클론(주) | Polypeptide improved in protein purity and affinity for antigen, conjugate thereof with antibody or antigen-binding fragment, and preparation method therefor |
US10155792B2 (en) | 2012-09-25 | 2018-12-18 | Affibody Ab | Albumin binding polypeptide |
US10167322B2 (en) | 2013-12-20 | 2019-01-01 | Affibody Ab | Engineered albumin binding polypeptide |
US10329331B2 (en) | 2010-07-09 | 2019-06-25 | Affibody Ab | Polypeptides |
WO2019203600A1 (en) | 2018-04-18 | 2019-10-24 | 앱클론(주) | Switch molecule and switchable chimeric antigen receptor |
WO2021006199A1 (en) | 2019-07-05 | 2021-01-14 | 小野薬品工業株式会社 | Treatment of hematologic cancer with pd-1/cd3 dual specificity protein |
US10894097B2 (en) | 2008-12-22 | 2021-01-19 | General Electric Company | HER2 binders |
WO2021025140A1 (en) | 2019-08-08 | 2021-02-11 | 小野薬品工業株式会社 | Dual-specific protein |
WO2021210939A1 (en) | 2020-04-17 | 2021-10-21 | 앱클론(주) | Anti-her2 affibody, and switchable chimeric antigen receptor using same as switch molecule |
WO2022080851A1 (en) | 2020-10-13 | 2022-04-21 | 인센 주식회사 | Testosterone-specific affibody and uses thereof |
Families Citing this family (297)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9400088D0 (en) * | 1994-01-14 | 1994-01-14 | Kabi Pharmacia Ab | Bacterial receptor structures |
GB9722131D0 (en) * | 1997-10-20 | 1997-12-17 | Medical Res Council | Method |
SE9704141D0 (en) * | 1997-11-12 | 1997-11-12 | Sbl Vaccin Ab | New protein and nucleotide sequence, encoding said protein |
EP1181052A4 (en) * | 1999-05-15 | 2004-08-11 | Univ California San Diego | Protein a based binding domains with desirable activities |
US7163686B1 (en) | 1999-05-15 | 2007-01-16 | The Regents Of The University Of California | Protein A based binding domains with desirable activities |
CA2390691C (en) * | 1999-12-24 | 2016-05-10 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
US20040077017A1 (en) * | 2001-01-12 | 2004-04-22 | Amelie Karlstrom | Detection methods |
JP2005504261A (en) * | 2001-01-12 | 2005-02-10 | アフィボディ・アーベー | Detection method |
US20030157561A1 (en) * | 2001-11-19 | 2003-08-21 | Kolkman Joost A. | Combinatorial libraries of monomer domains |
AU2002256371B2 (en) * | 2001-04-26 | 2008-01-10 | Amgen Mountain View Inc. | Combinatorial libraries of monomer domains |
US20050048512A1 (en) * | 2001-04-26 | 2005-03-03 | Avidia Research Institute | Combinatorial libraries of monomer domains |
US20040175756A1 (en) * | 2001-04-26 | 2004-09-09 | Avidia Research Institute | Methods for using combinatorial libraries of monomer domains |
US20050053973A1 (en) * | 2001-04-26 | 2005-03-10 | Avidia Research Institute | Novel proteins with targeted binding |
US20050089932A1 (en) * | 2001-04-26 | 2005-04-28 | Avidia Research Institute | Novel proteins with targeted binding |
US7981863B2 (en) | 2001-09-19 | 2011-07-19 | Neuronova Ab | Treatment of Parkinson's disease with PDGF |
FI115343B (en) * | 2001-10-22 | 2005-04-15 | Filtronic Lk Oy | Internal multi-band antenna |
EP2075256A2 (en) | 2002-01-14 | 2009-07-01 | William Herman | Multispecific binding molecules |
EP1474161A4 (en) * | 2002-01-16 | 2005-06-29 | Zyomyx Inc | Engineered binding proteins |
US20060002935A1 (en) | 2002-06-28 | 2006-01-05 | Domantis Limited | Tumor Necrosis Factor Receptor 1 antagonists and methods of use therefor |
US20050074865A1 (en) | 2002-08-27 | 2005-04-07 | Compound Therapeutics, Inc. | Adzymes and uses thereof |
US20060211044A1 (en) * | 2003-02-24 | 2006-09-21 | Green Lawrence R | Translucent solid matrix assay device dor microarray analysis |
US6861251B2 (en) | 2003-02-24 | 2005-03-01 | Pritest, Inc. | Translucent solid matrix assay device for microarray analysis |
WO2004097368A2 (en) * | 2003-04-28 | 2004-11-11 | Ciphergen Biosystems, Inc. | Improved immunoassays |
ES2639301T3 (en) | 2003-04-30 | 2017-10-26 | Universität Zürich | Cancer treatment procedures using an immunotoxin |
IL157086A0 (en) * | 2003-07-24 | 2004-02-08 | Guy Patchornik | Multivalent ligand complexes |
US7956165B2 (en) | 2003-07-24 | 2011-06-07 | Affisink Biotechnology Ltd. | Compositions and methods for purifying and crystallizing molecules of interest |
US20050181398A1 (en) * | 2004-01-16 | 2005-08-18 | Fung Eric T. | Specific detection of host response protein clusters |
EP1732613A2 (en) | 2004-04-06 | 2006-12-20 | Affibody AB | Use of serum albumin binding peptides conjugates for the preparation of a medicament |
US8092549B2 (en) | 2004-09-24 | 2012-01-10 | The Invention Science Fund I, Llc | Ciliated stent-like-system |
US9011329B2 (en) | 2004-04-19 | 2015-04-21 | Searete Llc | Lumenally-active device |
US8361013B2 (en) | 2004-04-19 | 2013-01-29 | The Invention Science Fund I, Llc | Telescoping perfusion management system |
US8353896B2 (en) | 2004-04-19 | 2013-01-15 | The Invention Science Fund I, Llc | Controllable release nasal system |
US7998060B2 (en) | 2004-04-19 | 2011-08-16 | The Invention Science Fund I, Llc | Lumen-traveling delivery device |
US8019413B2 (en) | 2007-03-19 | 2011-09-13 | The Invention Science Fund I, Llc | Lumen-traveling biological interface device and method of use |
US7850676B2 (en) | 2004-04-19 | 2010-12-14 | The Invention Science Fund I, Llc | System with a reservoir for perfusion management |
US8337482B2 (en) | 2004-04-19 | 2012-12-25 | The Invention Science Fund I, Llc | System for perfusion management |
US7857767B2 (en) | 2004-04-19 | 2010-12-28 | Invention Science Fund I, Llc | Lumen-traveling device |
US9801527B2 (en) | 2004-04-19 | 2017-10-31 | Gearbox, Llc | Lumen-traveling biological interface device |
US8921528B2 (en) * | 2004-06-01 | 2014-12-30 | Domantis Limited | Bispecific fusion antibodies with enhanced serum half-life |
US20060045877A1 (en) * | 2004-08-30 | 2006-03-02 | Goldmakher Viktor S | Immunoconjugates targeting syndecan-1 expressing cells and use thereof |
US7563443B2 (en) * | 2004-09-17 | 2009-07-21 | Domantis Limited | Monovalent anti-CD40L antibody polypeptides and compositions thereof |
KR20070084069A (en) | 2004-10-08 | 2007-08-24 | 도만티스 리미티드 | Single domain antibodies against tnfr1 and methods of use therefor |
NZ555464A (en) | 2004-12-02 | 2010-03-26 | Domantis Ltd | Bispecific domain antibodies targeting serum albumin and glp-1 or pyy |
US7741275B2 (en) * | 2004-12-22 | 2010-06-22 | Lipopeptide Ab | Agents and use thereof |
US20070003528A1 (en) | 2005-06-29 | 2007-01-04 | Paul Consigny | Intracoronary device and method of use thereof |
CA2628238A1 (en) | 2005-11-07 | 2007-05-18 | The Scripps Research Institute | Compositions and methods for controlling tissue factor signaling specificity |
US20110183319A1 (en) * | 2010-01-22 | 2011-07-28 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Compositions and methods for therapeutic delivery with microorganisms |
US8682619B2 (en) | 2005-12-14 | 2014-03-25 | The Invention Science Fund I, Llc | Device including altered microorganisms, and methods and systems of use |
US20110172826A1 (en) * | 2005-12-14 | 2011-07-14 | Amodei Dario G | Device including altered microorganisms, and methods and systems of use |
US8734823B2 (en) | 2005-12-14 | 2014-05-27 | The Invention Science Fund I, Llc | Device including altered microorganisms, and methods and systems of use |
US8278094B2 (en) | 2005-12-14 | 2012-10-02 | The Invention Science Fund I, Llc | Bone semi-permeable device |
US9220917B2 (en) | 2006-04-12 | 2015-12-29 | The Invention Science Fund I, Llc | Systems for autofluorescent imaging and target ablation |
US20120035438A1 (en) | 2006-04-12 | 2012-02-09 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Path selection by a lumen traveling device in a body tub tree based on previous path |
AU2007268364B8 (en) * | 2006-05-26 | 2013-05-16 | Obodies Limited | OB fold domains |
GB0611116D0 (en) | 2006-06-06 | 2006-07-19 | Oxford Genome Sciences Uk Ltd | Proteins |
CN101627055A (en) | 2006-09-05 | 2010-01-13 | 梅达雷克斯公司 | The antibody of bone morphogenetic protein and acceptor thereof and their using method |
SI2066351T1 (en) | 2006-10-02 | 2016-02-29 | E.R. Squibb & Sons, L.L.C. | Human antibodies that bind cxcr4 and uses thereof |
US20080096233A1 (en) * | 2006-10-20 | 2008-04-24 | Robotti Karla M | Isolation Of Immune Complexes |
GB0621513D0 (en) | 2006-10-30 | 2006-12-06 | Domantis Ltd | Novel polypeptides and uses thereof |
KR20150067395A (en) | 2006-12-01 | 2015-06-17 | 메다렉스, 엘.엘.시. | Human antibodies that bind cd22 and uses thereof |
US7981691B2 (en) * | 2006-12-08 | 2011-07-19 | General Electric Company | Two helix binders |
US7977118B2 (en) * | 2006-12-08 | 2011-07-12 | General Electric Company | Two helix binders |
US8198043B2 (en) * | 2006-12-08 | 2012-06-12 | General Electric Company | Two helix binders |
US7989216B2 (en) * | 2006-12-08 | 2011-08-02 | General Electric Company | Two helix binders |
CL2007003622A1 (en) | 2006-12-13 | 2009-08-07 | Medarex Inc | Human anti-cd19 monoclonal antibody; composition comprising it; and tumor cell growth inhibition method. |
NZ578354A (en) | 2006-12-14 | 2012-01-12 | Medarex Inc | Antibody-partner molecule conjugates that bind cd70 and uses thereof |
EP2121745A2 (en) | 2007-02-26 | 2009-11-25 | Oxford Genome Sciences (UK) Limited | Proteins |
WO2008104803A2 (en) | 2007-02-26 | 2008-09-04 | Oxford Genome Sciences (Uk) Limited | Proteins |
US8303960B2 (en) * | 2007-02-27 | 2012-11-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Radiolabeled affibody molecules |
WO2008124639A2 (en) * | 2007-04-04 | 2008-10-16 | Massachusetts Institute Of Technology | Poly (amino acid) targeting moieties |
GB0708376D0 (en) | 2007-05-01 | 2007-06-06 | Alligator Bioscience Ab | Novel polypeptides and uses thereof |
BRPI0812400A2 (en) | 2007-06-05 | 2014-10-29 | Univ Yale | UNIT, HYBRIDOMA, PHARMACEUTICAL COMPOSITION, METHOD FOR IDENTIFYING A UNIT, ANTIBODY ISOLATED TO A SAME ANTIGEN CONNECTION UNIT, PEPTIDES MOLECULE, AND UNIT USE. |
WO2009039192A2 (en) | 2007-09-17 | 2009-03-26 | The Regents Of The University Of Californina | Internalizing human monoclonal antibodies targeting prostate cancer cells in situ |
EP2853267B1 (en) | 2007-09-21 | 2016-12-07 | The Regents of the University of California | Targeted interferon demonstrates potent apoptotic and anti-tumor activities |
AR068767A1 (en) | 2007-10-12 | 2009-12-02 | Novartis Ag | ANTIBODIES AGAINST SCLEROSTIN, COMPOSITIONS AND METHODS OF USE OF THESE ANTIBODIES TO TREAT A PATHOLOGICAL DISORDER MEDIATIONED BY SCLEROSTIN |
WO2009070350A1 (en) | 2007-11-30 | 2009-06-04 | Siemens Healthcare Diagnostics Inc. | Adiponectin receptor fragments and methods of use |
RU2537265C2 (en) * | 2007-12-26 | 2014-12-27 | Биотест Аг | Cd138-targeted cell agents and using them |
US9011864B2 (en) * | 2007-12-26 | 2015-04-21 | Biotest Ag | Method of decreasing cytotoxic side-effects and improving efficacy of immunoconjugates |
HUE024291T2 (en) * | 2007-12-26 | 2016-01-28 | Biotest Ag | Immunoconjugates targeting cd138 and uses thereof |
ES2543201T3 (en) * | 2007-12-26 | 2015-08-17 | Biotest Ag | Methods and agents that improve the direction to tumor cells expressing CD138 |
WO2009146099A2 (en) | 2008-04-02 | 2009-12-03 | Georgia State University Research Foundation, Inc. | Contrast agents, methods for preparing contrast agents, and methods of imaging |
DK2700651T3 (en) | 2008-07-18 | 2019-07-22 | Bristol Myers Squibb Co | MONOVALENT COMPOSITIONS FOR CD28 BINDING AND METHODS FOR USING IT |
US20100022494A1 (en) * | 2008-07-24 | 2010-01-28 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Method, device, and kit for maintaining physiological levels of steroid hormone in a subject |
US20100022497A1 (en) * | 2008-07-24 | 2010-01-28 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Method for treating or preventing a cardiovascular disease or condition utilizing estrogen receptor modulators based on APOE allelic profile of a mammalian subject |
US20100061976A1 (en) * | 2008-07-24 | 2010-03-11 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Method for treating or preventing osteoporosis by reducing follicle stimulating hormone to cyclic physiological levels in a mammalian subject |
US20100022991A1 (en) * | 2008-07-24 | 2010-01-28 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | System and device for maintaining physiological levels of steroid hormone in a subject |
ES2752025T3 (en) | 2008-07-25 | 2020-04-02 | Wagner Richard W | Protein screening methods |
SG10201405377XA (en) | 2008-08-05 | 2014-12-30 | Novartis Ag | Compositions and methods for antibodies targeting complement protein c5 |
US9187330B2 (en) | 2008-09-15 | 2015-11-17 | The Invention Science Fund I, Llc | Tubular nanostructure targeted to cell membrane |
US20100137787A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Delivery devices for modulating inflammation |
US20100135983A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100136097A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100136095A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100136096A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100137246A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100136094A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20110295090A1 (en) | 2008-12-04 | 2011-12-01 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems, devices, and methods including implantable devices with anti-microbial properties |
CN102245771B (en) | 2008-12-16 | 2013-04-10 | 诺瓦提斯公司 | Yeast display systems |
CA2750581A1 (en) | 2009-01-21 | 2010-07-29 | Oxford Biotherapeutics Ltd. | Pta089 protein |
US8317737B2 (en) * | 2009-02-25 | 2012-11-27 | The Invention Science Fund I, Llc | Device for actively removing a target component from blood or lymph of a vertebrate subject |
US8758324B2 (en) | 2010-03-05 | 2014-06-24 | The Invention Science Fund I, Llc | Device for actively removing a target cell from blood or lymph of a vertebrate subject |
US8246565B2 (en) * | 2009-02-25 | 2012-08-21 | The Invention Science Fund I, Llc | Device for passively removing a target component from blood or lymph of a vertebrate subject |
US8454547B2 (en) | 2009-02-25 | 2013-06-04 | The Invention Science Fund I, Llc | Device, system, and method for controllably reducing inflammatory mediators in a subject |
PT2403878T (en) | 2009-03-05 | 2017-09-01 | Squibb & Sons Llc | Fully human antibodies specific to cadm1 |
GB0904355D0 (en) | 2009-03-13 | 2009-04-29 | Imp Innovations Ltd | Biological materials and uses thereof |
US9834815B2 (en) | 2009-03-25 | 2017-12-05 | Life Technologies Corporation | Discriminatory positive/extraction control DNA |
US8728479B2 (en) | 2009-03-31 | 2014-05-20 | The Trustees Of The University Of Pennsylvania | Antigen-binding proteins comprising recombinant protein scaffolds |
KR20120057563A (en) | 2009-03-31 | 2012-06-05 | 노파르티스 아게 | Composition and methods of use for therapeutic antibodies specific for the il-12 receptore betal subunit |
EP2414391B1 (en) | 2009-04-02 | 2018-11-28 | Roche Glycart AG | Multispecific antibodies comprising full length antibodies and single chain fab fragments |
NZ595792A (en) | 2009-04-20 | 2014-01-31 | Oxford Biotherapeutics Ltd | Antibodies specific to cadherin-17 |
ES2693165T3 (en) | 2009-04-23 | 2018-12-07 | Siemens Healthcare Diagnostics Inc. | Monomeric and dimeric forms of adiponectin receptor fragments and methods of use |
HUE035240T2 (en) | 2009-04-27 | 2018-05-02 | Novartis Ag | Compositions and methods for increasing muscle growth |
US8154285B1 (en) | 2009-05-29 | 2012-04-10 | The Invention Science Fund I, Llc | Non-external static magnetic field imaging systems, devices, methods, and compositions |
US8063636B2 (en) * | 2009-05-29 | 2011-11-22 | The Invention Science Fund I, Llc | Systems, devices, methods, and compositions including targeted ferromagnetic structures |
US8058872B2 (en) | 2009-05-29 | 2011-11-15 | The Invention Science Fund I, Llc | Systems, devices, methods, and compositions including functionalized ferromagnetic structures |
US8106655B2 (en) * | 2009-05-29 | 2012-01-31 | The Invention Science Fund I, Llc | Multiplex imaging systems, devices, methods, and compositions including ferromagnetic structures |
US20100303733A1 (en) * | 2009-05-29 | 2010-12-02 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems, devices, methods, and compositions including ferromagnetic structures |
IE20090514A1 (en) | 2009-07-06 | 2011-02-16 | Opsona Therapeutics Ltd | Humanised antibodies and uses therof |
DK2464657T3 (en) | 2009-08-10 | 2015-06-29 | Morphosys Ag | New screening strategies for the identification of antibodies or fragments thereof which bind an antigen with enzymatic activity |
US9024766B2 (en) * | 2009-08-28 | 2015-05-05 | The Invention Science Fund, Llc | Beverage containers with detection capability |
US8810417B2 (en) * | 2009-08-28 | 2014-08-19 | The Invention Science Fund I, Llc | Beverage immersate with detection capability |
WO2011029823A1 (en) | 2009-09-09 | 2011-03-17 | Novartis Ag | Monoclonal antibody reactive with cd63 when expressed at the surface of degranulated mast cells |
RU2573915C2 (en) | 2009-09-16 | 2016-01-27 | Дженентек, Инк. | Protein complexes containing superhelix and/or banding, and their use |
JP5954876B2 (en) | 2009-10-13 | 2016-07-20 | ナノストリング テクノロジーズ, インコーポレイテッド | Protein detection by nanoreporter |
EP2470569A1 (en) | 2009-10-13 | 2012-07-04 | Oxford Biotherapeutics Ltd. | Antibodies against epha10 |
WO2011054007A1 (en) | 2009-11-02 | 2011-05-05 | Oxford Biotherapeutics Ltd. | Ror1 as therapeutic and diagnostic target |
EP2496944A2 (en) | 2009-11-05 | 2012-09-12 | Novartis AG | Biomarkers predictive of progression of fibrosis |
WO2011080050A2 (en) | 2009-12-11 | 2011-07-07 | Novartis Ag | Binding molecules |
EP2518078B1 (en) * | 2009-12-15 | 2020-05-20 | Choe, Muhyeon | Method for manufacturing dimers and multimers by increasing the production of bond bridges in a complex of multiple monomers and repeating chains of an affinity domain of a type specifically binding to protein monomers |
CN102770767A (en) | 2010-02-10 | 2012-11-07 | 诺瓦提斯公司 | Methods and compounds for muscle growth |
AR080793A1 (en) | 2010-03-26 | 2012-05-09 | Roche Glycart Ag | BISPECIFIC ANTIBODIES |
MX346731B (en) | 2010-04-23 | 2017-03-30 | Genentech Inc * | Production of heteromultimeric proteins. |
AU2011249782B2 (en) | 2010-05-06 | 2014-10-02 | Novartis Ag | Compositions and methods of use for therapeutic low density lipoprotein - related protein 6 (LRP6) multivalent antibodies |
ES2659406T3 (en) | 2010-05-06 | 2018-03-15 | Novartis Ag | Compositions and methods of use for therapeutic antibodies against protein 6 related to low density lipoproteins (LRP6) |
US20120100166A1 (en) | 2010-07-15 | 2012-04-26 | Zyngenia, Inc. | Ang-2 Binding Complexes and Uses Thereof |
CA2808185A1 (en) | 2010-08-13 | 2012-02-16 | Genentech, Inc. | Antibodies to il-1.beta. and il-18, for treatment of disease |
CN103080134B (en) | 2010-08-20 | 2015-11-25 | 诺华股份有限公司 | The antibody of EGF-R ELISA 3 (HER3) |
WO2012025530A1 (en) | 2010-08-24 | 2012-03-01 | F. Hoffmann-La Roche Ag | Bispecific antibodies comprising a disulfide stabilized - fv fragment |
ES2678145T3 (en) | 2010-08-24 | 2018-08-09 | Abbott Laboratories | Specific antibodies against HIV core protein and their uses |
SG188666A1 (en) | 2010-09-30 | 2013-05-31 | Agency Science Tech & Res | Methods and reagents for detection and treatment of esophageal metaplasia |
EP2625203A1 (en) | 2010-10-05 | 2013-08-14 | Novartis AG | Anti-il12rbeta1 antibodies and their use in treating autoimmune and inflammatory disorders |
WO2012085111A1 (en) | 2010-12-23 | 2012-06-28 | F. Hoffmann-La Roche Ag | Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery |
US10144950B2 (en) | 2011-01-31 | 2018-12-04 | Roche Sequencing Solutions, Inc. | Methods of identifying multiple epitopes in cells |
WO2016100976A2 (en) | 2014-12-19 | 2016-06-23 | Apprise Bio, Inc. | Methods for identifying multiple epitopes in selected sub-populations of cells |
RU2018108836A (en) | 2011-02-04 | 2019-03-14 | Дженентек, Инк. | Fc OPTIONS AND METHODS FOR PRODUCING THEM |
US10689447B2 (en) | 2011-02-04 | 2020-06-23 | Genentech, Inc. | Fc variants and methods for their production |
WO2012109624A2 (en) | 2011-02-11 | 2012-08-16 | Zyngenia, Inc. | Monovalent and multivalent multispecific complexes and uses thereof |
GB201114858D0 (en) | 2011-08-29 | 2011-10-12 | Nvip Pty Ltd | Anti-nerve growth factor antibodies and methods of using the same |
EP4026845A1 (en) | 2011-05-06 | 2022-07-13 | Zoetis Services LLC | Anti-nerve growth factor antibodies and methods of preparing and using the same |
CA2834983C (en) | 2011-05-06 | 2020-11-17 | Nvip Pty Ltd | Anti-nerve growth factor antibodies and methods of preparing and using the same |
JP6258194B2 (en) | 2011-05-06 | 2018-01-10 | ネックスヴェット オーストラリア プロプライエタリー リミテッド | Anti-nerve growth factor antibodies and methods of making and using them |
ES2704038T3 (en) | 2011-05-24 | 2019-03-13 | Zyngenia Inc | Multivalent and monovalent multispecific complexes and their uses |
WO2012172495A1 (en) | 2011-06-14 | 2012-12-20 | Novartis Ag | Compositions and methods for antibodies targeting tem8 |
SI2726094T1 (en) | 2011-06-28 | 2017-04-26 | Oxford Biotherapeutics Ltd | Therapeutic and diagnostic target |
CA2840537C (en) | 2011-06-28 | 2021-12-14 | Oxford Biotherapeutics Ltd. | Antibodies to adp-ribosyl cyclase 2 |
SI2726099T1 (en) | 2011-07-01 | 2018-11-30 | Novartis Ag | Method for treating metabolic disorders |
JP2014526886A (en) | 2011-07-15 | 2014-10-09 | モルフォシス・アー・ゲー | Antibodies cross-reactive with macrophage migration inhibitory factor (MIF) and D-dopachrome tomerase (D-DT) |
CN107266577B (en) | 2011-10-11 | 2022-09-13 | 弗·哈夫曼-拉罗切有限公司 | Improved assembly of bispecific antibodies |
CN104080471B (en) | 2011-10-14 | 2018-08-10 | 诺华股份有限公司 | Antibody and method for Wnt approach relevant diseases |
EP2784159B1 (en) | 2011-11-25 | 2018-05-09 | SNU R&DB Foundation | Hepatitis b virus-derived cis-regulatory element and use thereof |
JP6243345B2 (en) | 2011-12-05 | 2017-12-06 | ノバルティス アーゲー | Antibody to epidermal growth factor receptor 3 (HER3) |
KR20140103135A (en) | 2011-12-05 | 2014-08-25 | 노파르티스 아게 | Antibodies for epidermal growth factor receptor 3 (her3) directed to domain ii of her3 |
US10117932B2 (en) | 2011-12-08 | 2018-11-06 | Biotest Ag | Uses of immunoconjugates targeting CD138 |
CN106831985A (en) | 2011-12-21 | 2017-06-13 | 诺华股份有限公司 | The composition and method of the P factors are targeted for antibody |
BR112014019579A2 (en) | 2012-02-10 | 2019-10-15 | Genentech, Inc | SINGLE CHAIN ANTIBODY, POLYNUCLEOTIDE, VECTOR, HOST CELL, METHOD OF PRODUCTION OF A SINGLE CHAIN ANTIBODY, HETEROMULTYMER AND METHOD OF PRODUCTION |
NZ628625A (en) | 2012-02-20 | 2016-03-31 | Swedish Orphan Biovitrum Ab Publ | Polypeptides binding to human complement c5 |
AU2013222334A1 (en) | 2012-02-23 | 2014-09-11 | President And Fellows Of Harvard College | Modified microbial toxin receptor for delivering agents into cells |
CA2871882A1 (en) | 2012-06-27 | 2014-01-03 | F. Hoffmann-La Roche Ag | Method for making antibody fc-region conjugates comprising at least one binding entity that specifically binds to a target and uses thereof |
BR112014032193A2 (en) | 2012-06-27 | 2017-06-27 | Hoffmann La Roche | bispecific antibody production and combination determination methods, bispecific antibody, formulation and use of bispecific antibody |
GB201213652D0 (en) | 2012-08-01 | 2012-09-12 | Oxford Biotherapeutics Ltd | Therapeutic and diagnostic target |
WO2014026032A2 (en) | 2012-08-08 | 2014-02-13 | Apprise Bio, Inc. | Increasing dynamic range for identifying multiple epitopes in cells |
JOP20200308A1 (en) | 2012-09-07 | 2017-06-16 | Novartis Ag | IL-18 binding molecules |
WO2014084859A1 (en) | 2012-11-30 | 2014-06-05 | Novartis Ag | Molecules and methods for modulating tmem16a activities |
CN104968678B (en) | 2012-12-05 | 2018-12-11 | 诺华股份有限公司 | Target the composition and method of the antibody of EPO |
WO2014093417A1 (en) | 2012-12-12 | 2014-06-19 | University Of Virginia Patent Foundation | Compositions and methods for regulating erythropoiesis |
WO2014120916A1 (en) | 2013-02-01 | 2014-08-07 | Bristol-Myers Squibb Company | Pegylated domain antibodies monovalent for cd28 binding and methods of use |
WO2015198217A2 (en) | 2013-02-08 | 2015-12-30 | Novartis Ag | Compositions and methods for long-acting antibodies targeting il-17 |
PL2953969T3 (en) | 2013-02-08 | 2020-02-28 | Novartis Ag | Anti-il-17a antibodies and their use in treating autoimmune and inflammatory disorders |
GB201302447D0 (en) | 2013-02-12 | 2013-03-27 | Oxford Biotherapeutics Ltd | Therapeutic and diagnostic target |
DK2962100T3 (en) | 2013-02-28 | 2021-11-01 | Caprion Proteomics Inc | TUBERCULOSEBIOMARKEARS AND USES THEREOF |
WO2014141064A1 (en) | 2013-03-13 | 2014-09-18 | Novartis Ag | Notch2 binding molecules for treating respiratory diseases |
EP2970479B1 (en) | 2013-03-14 | 2019-04-24 | Novartis AG | Antibodies against notch 3 |
BR112015023752B1 (en) | 2013-03-15 | 2023-11-14 | Zyngenia, Inc. | MODULAR RECOGNITION DOMAIN (MRD), COMPLEX COMPRISING MRD AND CETUXIMAB, USES OF THE COMPLEX TO INHIBIT ANGIOGENESIS AND TREAT CANCER AND PHARMACEUTICAL COMPOSITION COMPRISING SAID COMPLEX |
WO2014145252A2 (en) | 2013-03-15 | 2014-09-18 | Milone Michael C | Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy |
GB201311031D0 (en) * | 2013-06-20 | 2013-08-07 | Queen Mary & Westfield College | Method |
AR096601A1 (en) | 2013-06-21 | 2016-01-20 | Novartis Ag | ANTIBODIES OF LEXINED OXIDATED LDL RECEIVER 1 AND METHODS OF USE |
US9562101B2 (en) | 2013-06-21 | 2017-02-07 | Novartis Ag | Lectin-like oxidized LDL receptor 1 antibodies and methods of use |
US10208125B2 (en) | 2013-07-15 | 2019-02-19 | University of Pittsburgh—of the Commonwealth System of Higher Education | Anti-mucin 1 binding agents and uses thereof |
MX371455B (en) | 2013-08-02 | 2020-01-28 | Pfizer | Anti-cxcr4 antibodies and antibody-drug conjugates. |
TW201536318A (en) | 2013-08-14 | 2015-10-01 | Novartis Ag | Methods of treating sporadic inclusion body myositis |
US10203327B2 (en) | 2013-11-05 | 2019-02-12 | Novartis Ag | Organic compounds |
EP3087101A4 (en) | 2013-12-20 | 2017-12-06 | Novartis AG | Regulatable chimeric antigen receptor |
EP3811970A1 (en) | 2014-03-15 | 2021-04-28 | Novartis AG | Regulatable chimeric antigen receptor |
TW201622746A (en) | 2014-04-24 | 2016-07-01 | 諾華公司 | Methods of improving or accelerating physical recovery after surgery for hip fracture |
KR20230164192A (en) | 2014-05-06 | 2023-12-01 | 제넨테크, 인크. | Production of heteromultimeric proteins using mammalian cells |
WO2016014553A1 (en) | 2014-07-21 | 2016-01-28 | Novartis Ag | Sortase synthesized chimeric antigen receptors |
EP3660042B1 (en) | 2014-07-31 | 2023-01-11 | Novartis AG | Subset-optimized chimeric antigen receptor-containing t-cells |
JP6649358B2 (en) | 2014-08-07 | 2020-02-19 | ノバルティス アーゲー | Angiopoietin-like 4 antibodies and methods of use |
US9988443B2 (en) | 2014-08-07 | 2018-06-05 | Novartis Ag | Angiopoetin-like 4 (ANGPTL4) antibodies and methods of use |
ES2891332T3 (en) | 2014-09-17 | 2022-01-27 | Novartis Ag | Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy |
MA41044A (en) | 2014-10-08 | 2017-08-15 | Novartis Ag | COMPOSITIONS AND METHODS OF USE FOR INCREASED IMMUNE RESPONSE AND CANCER TREATMENT |
US11566082B2 (en) | 2014-11-17 | 2023-01-31 | Cytiva Bioprocess R&D Ab | Mutated immunoglobulin-binding polypeptides |
WO2016087416A1 (en) | 2014-12-03 | 2016-06-09 | F. Hoffmann-La Roche Ag | Multispecific antibodies |
UY36449A (en) | 2014-12-19 | 2016-07-29 | Novartis Ag | COMPOSITIONS AND METHODS FOR ANTIBODIES DIRECTED TO BMP6 |
AU2015371265B2 (en) | 2014-12-24 | 2021-06-03 | Neximmune, Inc | Nanoparticle compositions and methods for immunotherapy |
EP3280432B8 (en) | 2015-04-06 | 2021-04-14 | Subdomain, LLC | De novo binding domain containing polypeptides and uses thereof |
HUE059218T2 (en) | 2015-04-08 | 2022-11-28 | Novartis Ag | Cd20 therapies, cd22 therapies, and combination therapies with a cd19 chimeric antigen receptor (car) - expressing cell |
AU2016273028B2 (en) | 2015-06-05 | 2019-02-14 | Novartis Ag | Antibodies targeting bone morphogenetic protein 9 (BMP9) and methods therefor |
JOP20200312A1 (en) | 2015-06-26 | 2017-06-16 | Novartis Ag | Factor xi antibodies and methods of use |
CA2993009A1 (en) | 2015-07-31 | 2017-02-09 | Research Institute At Nationwide Children's Hospital | Peptides and antibodies for the removal of biofilms |
US11236159B2 (en) | 2015-08-03 | 2022-02-01 | Novartis Ag | Methods of treating FGF21-associated disorders |
US10000561B2 (en) | 2015-09-09 | 2018-06-19 | Novartis Ag | Thymic stromal lymphopoietin (TSLP)-binding molecules and methods of using the molecules |
CA2996635A1 (en) | 2015-09-09 | 2017-03-16 | Novartis Ag | Thymic stromal lymphopoietin (tslp)-binding molecules and methods of using the molecules |
WO2017066719A2 (en) | 2015-10-14 | 2017-04-20 | Research Institute At Nationwide Children's Hospital | Hu specific interfering agents |
CA3003969A1 (en) | 2015-11-06 | 2017-05-11 | Orionis Biosciences Nv | Bi-functional chimeric proteins and uses thereof |
BR112018010052A2 (en) | 2015-11-19 | 2019-02-05 | Asclepix Therapeutics Llc | peptides with antiangiogenic, anti-lymphogenic and antiedemic properties and nanoparticle formulations |
US10946106B2 (en) | 2015-11-30 | 2021-03-16 | The Regents Of The University Of California | Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen |
JP2019506844A (en) | 2015-12-18 | 2019-03-14 | ノバルティス アーゲー | Antibodies targeting CD32b and methods of use thereof |
LT3402880T (en) | 2016-01-15 | 2024-03-12 | Thermo Fisher Scientific Baltics Uab | Thermophilic dna polymerase mutants |
JP6991979B2 (en) | 2016-02-05 | 2022-03-04 | オリオニス バイオサイエンシズ ビーブイ | CD8 binding substance |
US11248057B2 (en) | 2016-03-07 | 2022-02-15 | Vib Vzw | CD20 binding single domain antibodies |
KR20170108203A (en) | 2016-03-16 | 2017-09-27 | 주식회사 피플바이오 | Method for Detecting Aggregate Form of Aggregate-Forming Polypeptides |
CN109071647B (en) | 2016-04-27 | 2022-11-22 | 诺华股份有限公司 | Anti-growth differentiation factor 15 antibody and application thereof |
DK3452591T3 (en) | 2016-05-02 | 2023-09-18 | Encodia Inc | MACROMOLECULAR ANALYSIS USING NUCLEIC ACID CODING |
US10889615B2 (en) | 2016-05-11 | 2021-01-12 | Cytiva Bioprocess R&D Ab | Mutated immunoglobulin-binding polypeptides |
US10654887B2 (en) | 2016-05-11 | 2020-05-19 | Ge Healthcare Bio-Process R&D Ab | Separation matrix |
US10703774B2 (en) | 2016-09-30 | 2020-07-07 | Ge Healthcare Bioprocess R&D Ab | Separation method |
CN109071613A (en) | 2016-05-11 | 2018-12-21 | 通用电气医疗集团生物工艺研发股份公司 | Isolation medium |
JP7106187B2 (en) | 2016-05-11 | 2022-07-26 | サイティバ・バイオプロセス・アールアンドディ・アクチボラグ | How to save the separation matrix |
US10730908B2 (en) | 2016-05-11 | 2020-08-04 | Ge Healthcare Bioprocess R&D Ab | Separation method |
JP6987424B2 (en) | 2016-05-11 | 2022-01-05 | サイティバ・バイオプロセス・アールアンドディ・アクチボラグ | How to clean and / or disinfect the isolation matrix |
CN109563141A (en) | 2016-05-13 | 2019-04-02 | 奥里尼斯生物科学公司 | To the therapeutic targeting of cellular structures |
EP3454887B1 (en) | 2016-05-13 | 2021-01-20 | Orionis Biosciences BV | Targeted mutant interferon-beta and uses thereof |
TW201802121A (en) | 2016-05-25 | 2018-01-16 | 諾華公司 | Reversal binding agents for anti-factor XI/XIa antibodies and uses thereof |
WO2017216724A1 (en) | 2016-06-15 | 2017-12-21 | Novartis Ag | Methods for treating disease using inhibitors of bone morphogenetic protein 6 (bmp6) |
EA201990868A1 (en) | 2016-10-04 | 2019-09-30 | Асклепикс Терапьютикс, Инк. | CONNECTIONS AND METHODS FOR ACTIVATING A Tie2 SIGNAL SYSTEM |
CA3040802A1 (en) | 2016-10-24 | 2018-05-03 | Orionis Biosciences Nv | Targeted mutant interferon-gamma and uses thereof |
US20180163270A1 (en) | 2016-12-12 | 2018-06-14 | Cepheid | Integrated immuno-pcr and nucleic acid analysis in an automated reaction cartridge |
JP7139332B2 (en) | 2016-12-23 | 2022-09-20 | ノバルティス アーゲー | Factor XI Antibodies and Methods of Use |
US11564982B2 (en) | 2017-01-04 | 2023-01-31 | Research Institute At Nationwide Children's Hospital | DNABII vaccines and antibodies with enhanced activity |
WO2018144999A1 (en) | 2017-02-06 | 2018-08-09 | Orionis Biosciences, Inc. | Targeted engineered interferon and uses thereof |
MX2019009255A (en) | 2017-02-06 | 2019-11-05 | Orionis Biosciences Nv | Targeted chimeric proteins and uses thereof. |
US11246911B2 (en) | 2017-02-07 | 2022-02-15 | Vib Vzw | Immune-cell targeted bispecific chimeric proteins and uses thereof |
WO2018146594A1 (en) | 2017-02-08 | 2018-08-16 | Novartis Ag | Fgf21 mimetic antibodies and uses thereof |
CN110392697A (en) | 2017-03-02 | 2019-10-29 | 国家医疗保健研究所 | There is the antibody and application thereof of specificity to NECTIN-4 |
CA3056088A1 (en) | 2017-03-15 | 2018-09-20 | Research Institute At Nationwide Children's Hospital | Composition and methods for disruption of bacterial biofilms without accompanying inflammation |
AU2018240117A1 (en) | 2017-03-24 | 2019-09-19 | Beth Israel Deaconess Medical Center, Inc. | Methods for preventing and treating heart disease |
WO2018229715A1 (en) | 2017-06-16 | 2018-12-20 | Novartis Ag | Compositions comprising anti-cd32b antibodies and methods of use thereof |
EP3645710A1 (en) | 2017-06-26 | 2020-05-06 | Thermo Fisher Scientific Baltics Uab | Thermophilic dna polymerase mutants |
CN110785433A (en) | 2017-06-28 | 2020-02-11 | 诺华股份有限公司 | Method for preventing and treating urinary incontinence |
EP3661536A4 (en) | 2017-08-03 | 2021-07-21 | Asclepix Therapeutics, Inc. | Methods for identifying and preparing pharmaceutical agents for activating tie2 receptor |
US20210040205A1 (en) | 2017-10-25 | 2021-02-11 | Novartis Ag | Antibodies targeting cd32b and methods of use thereof |
SG11202003924YA (en) | 2017-10-31 | 2020-05-28 | Encodia Inc | Kits for analysis using nucleic acid encoding and/or label |
US11464803B2 (en) | 2017-11-14 | 2022-10-11 | Arcellx, Inc. | D-domain containing polypeptides and uses thereof |
AU2018369639A1 (en) | 2017-11-14 | 2020-04-23 | Arcellx, Inc. | D-domain containing polypeptides and uses thereof |
CA3082410A1 (en) | 2017-11-14 | 2019-05-23 | Arcellx, Inc. | Multifunctional immune cell therapies |
EP3713965A1 (en) | 2017-11-22 | 2020-09-30 | Novartis AG | Reversal binding agents for anti-factor xi/xia antibodies and uses thereof |
CN111556900A (en) | 2017-12-22 | 2020-08-18 | 赛默飞世尔科技波罗的海封闭股份公司 | Polymerase chain reaction compositions comprising amines |
EP3749295A4 (en) | 2018-02-05 | 2022-04-27 | Orionis Biosciences, Inc. | Fibroblast binding agents and use thereof |
UY38247A (en) | 2018-05-30 | 2019-12-31 | Novartis Ag | ANTIBODIES AGAINST ENTPD2, COMBINATION THERAPIES AND METHODS OF USE OF ANTIBODIES AND COMBINATION THERAPIES |
DE202019005887U1 (en) | 2018-07-03 | 2023-06-14 | Marengo Therapeutics, Inc. | Anti-TCR antibody molecules and uses thereof |
EP3626265A1 (en) | 2018-09-21 | 2020-03-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anti-human cd45rc antibodies and uses thereof |
US20210347851A1 (en) | 2018-09-28 | 2021-11-11 | Novartis Ag | Cd19 chimeric antigen receptor (car) and cd22 car combination therapies |
EP3856779A1 (en) | 2018-09-28 | 2021-08-04 | Novartis AG | Cd22 chimeric antigen receptor (car) therapies |
EP3861021A4 (en) | 2018-10-05 | 2022-06-22 | Research Institute at Nationwide Children's Hospital | Compositions and methods for enzymatic disruption of bacterial biofilms |
AR117343A1 (en) | 2018-12-18 | 2021-07-28 | Novartis Ag | REVERSIBLE BINDING AGENTS FOR ANTI-FACTOR XI / XIa ANTIBODIES AND USES OF THEM |
AU2020223293A1 (en) | 2019-02-15 | 2021-08-19 | Integral Molecular, Inc. | Claudin 6 antibodies and uses thereof |
WO2020168024A1 (en) | 2019-02-15 | 2020-08-20 | Integral Molecular, Inc. | Antibodies comprising a common light chain and uses thereof |
AU2020235455A1 (en) | 2019-03-08 | 2021-10-28 | Oxford Genetics Limited | Method of selecting for antibodies |
GB201903233D0 (en) | 2019-03-08 | 2019-04-24 | Oxford Genetics Ltd | Method of selecting for antibodies |
EP3941580A1 (en) | 2019-03-22 | 2022-01-26 | Reflexion Pharmaceuticals, Inc. | D-peptidic compounds for vegf |
EP3941581A2 (en) | 2019-03-22 | 2022-01-26 | Reflexion Pharmaceuticals, Inc. | Multivalent d-peptidic compounds for target proteins |
CA3138367A1 (en) | 2019-04-30 | 2020-11-05 | Encodia, Inc. | Methods for preparing analytes and related kits |
US20220251232A1 (en) | 2019-05-20 | 2022-08-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Novel anti-cd25 antibodies |
CA3145385A1 (en) | 2019-07-08 | 2021-01-14 | Steven D. Goodman | Antibody compositions for disrupting biofilms |
TW202124446A (en) | 2019-09-18 | 2021-07-01 | 瑞士商諾華公司 | Combination therapies with entpd2 antibodies |
JP2022548881A (en) | 2019-09-18 | 2022-11-22 | ノバルティス アーゲー | ENTPD2 Antibodies, Combination Therapy and Methods of Using Antibodies and Combination Therapy |
CA3155930A1 (en) | 2019-09-27 | 2021-04-01 | Starkage Therapeutics | Senescent cell-associated antigen-binding domains, antibodies and chimeric antigen receptors comprising the same, and uses thereof |
WO2021116119A1 (en) | 2019-12-09 | 2021-06-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antibodies having specificity to her4 and uses thereof |
KR20230004510A (en) | 2020-03-20 | 2023-01-06 | 인썸(인스티튜트 내셔날 드 라 싼테 에 드 라 리셰르셰메디칼르) | Chimeric antigen receptor specific for human CD45RC and uses thereof |
GB202004514D0 (en) | 2020-03-27 | 2020-05-13 | Inst De Medicina Molecular Joaeo Lobo Antunes | Treatment of Immunosuppressive Cancer |
JP2023525053A (en) | 2020-05-12 | 2023-06-14 | インサーム(インスティテュ ナシオナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシェ メディカル) | A new method to treat cutaneous T-cell lymphoma and TFH-derived lymphoma |
CN116419747A (en) | 2020-08-07 | 2023-07-11 | 福蒂斯治疗公司 | CD46 targeting immunoconjugates and methods of use thereof |
JP2023551353A (en) | 2020-10-13 | 2023-12-08 | アヴィタイド エルエルシー | Three-helix bundle protein affinity ligand library and its use |
JP2023550446A (en) | 2020-11-20 | 2023-12-01 | インセルム(インスティチュート ナショナル デ ラ サンテ エ デ ラ リシェルシェ メディカル) | Anti-CD25 antibody |
JP2024504547A (en) | 2020-11-20 | 2024-02-01 | インセルム(インスティチュート ナショナル デ ラ サンテ エ デ ラ リシェルシェ メディカル) | Anti-CD25 antibody |
WO2022130300A1 (en) | 2020-12-16 | 2022-06-23 | Molecular Partners Ag | Novel slow-release prodrugs |
EP4294542A1 (en) | 2021-02-19 | 2023-12-27 | Avitide LLC | Aav2 affinity agents |
JP2024509890A (en) | 2021-03-09 | 2024-03-05 | モレキュラー パートナーズ アクチェンゲゼルシャフト | Protease cleavable prodrugs |
AU2022231913A1 (en) | 2021-03-09 | 2023-09-28 | Molecular Partners Ag | Novel darpin based cd33 engagers |
CA3211368A1 (en) | 2021-03-09 | 2022-09-15 | Molecular Partners Ag | Novel darpin based cd123 engagers |
WO2022216993A2 (en) | 2021-04-08 | 2022-10-13 | Marengo Therapeutics, Inc. | Multifuntional molecules binding to tcr and uses thereof |
WO2023170296A1 (en) | 2022-03-11 | 2023-09-14 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Nucleic acid system to specifically reprogram b and t cells and uses thereof |
WO2024003380A1 (en) | 2022-06-30 | 2024-01-04 | Icm (Institut Du Cerveau Et De La Moelle Épinière) | Vascular endothelial growth factor receptor-1 (vegfr-1) inhibitors for promoting myelination and neuroprotection |
WO2024008755A1 (en) | 2022-07-04 | 2024-01-11 | Vib Vzw | Blood-cerebrospinal fluid barrier crossing antibodies |
WO2024052503A1 (en) | 2022-09-08 | 2024-03-14 | Institut National de la Santé et de la Recherche Médicale | Antibodies having specificity to ltbp2 and uses thereof |
WO2024077118A2 (en) | 2022-10-06 | 2024-04-11 | Bicara Therapeutics Inc. | Multispecific proteins and related methods |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4954618A (en) * | 1986-02-14 | 1990-09-04 | Genex Corporation | Cloned streptococcal genes encoding protein G and their use to construct recombinant microorganisms to produce protein G |
US5084559A (en) * | 1987-03-27 | 1992-01-28 | Repligen Corporation | Protein a domain mutants |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5312901A (en) * | 1986-02-14 | 1994-05-17 | Pharmacia Lkb Biotechnology Ab | Cloned streptococcal genes encoding protein G and their use to construct recombinant microorganisms to produce protein G |
US5229492A (en) * | 1986-02-14 | 1993-07-20 | Pharmacia Lkb Biotechnology Ab | Cloned streptococcal genes encoding protein G and their use to construct recombinant microorganisms to produce protein G |
US4879213A (en) * | 1986-12-05 | 1989-11-07 | Scripps Clinic And Research Foundation | Synthetic polypeptides and antibodies related to Epstein-Barr virus early antigen-diffuse |
US5783415A (en) * | 1991-03-29 | 1998-07-21 | Genentech, Inc. | Method of producing an IL-8 receptor polypeptide |
SE9400088D0 (en) * | 1994-01-14 | 1994-01-14 | Kabi Pharmacia Ab | Bacterial receptor structures |
US5877016A (en) * | 1994-03-18 | 1999-03-02 | Genentech, Inc. | Human trk receptors and neurotrophic factor inhibitors |
-
1994
- 1994-01-14 SE SE9400088A patent/SE9400088D0/en unknown
-
1995
- 1995-01-16 US US08/669,360 patent/US5831012A/en not_active Expired - Lifetime
- 1995-01-16 AU AU15487/95A patent/AU696186B2/en not_active Expired
- 1995-01-16 CA CA002181042A patent/CA2181042C/en not_active Expired - Lifetime
- 1995-01-16 PT PT95907175T patent/PT739353E/en unknown
- 1995-01-16 NZ NZ278991A patent/NZ278991A/en not_active IP Right Cessation
- 1995-01-16 JP JP51898495A patent/JP4089920B2/en not_active Expired - Lifetime
- 1995-01-16 EP EP95907175A patent/EP0739353B1/en not_active Expired - Lifetime
- 1995-01-16 AT AT95907175T patent/ATE279439T1/en active
- 1995-01-16 ES ES95907175T patent/ES2225838T3/en not_active Expired - Lifetime
- 1995-01-16 WO PCT/SE1995/000034 patent/WO1995019374A1/en active IP Right Grant
- 1995-01-16 DE DE69533644T patent/DE69533644T2/en not_active Expired - Lifetime
-
1998
- 1998-05-21 US US09/082,468 patent/US6534628B1/en not_active Expired - Lifetime
-
2005
- 2005-05-11 JP JP2005138021A patent/JP2005263810A/en active Pending
-
2007
- 2007-07-27 JP JP2007195296A patent/JP4373461B2/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4954618A (en) * | 1986-02-14 | 1990-09-04 | Genex Corporation | Cloned streptococcal genes encoding protein G and their use to construct recombinant microorganisms to produce protein G |
US5084559A (en) * | 1987-03-27 | 1992-01-28 | Repligen Corporation | Protein a domain mutants |
Non-Patent Citations (2)
Title |
---|
PROTEIN ENGINEERING, Volume 6, No. 4, 1993, LENA CEDERGREN et al., "Mutational Analysis of the Interaction Between Staphylococcal Protein A and Human IgG1", page 441 - page 448. * |
THE JOURNAL OF BIOLOGICAL CHEMISTRY, Volume 263, No. 9, March 1988, MARGARETA ELIASSON et al., "Chimeric IgG-Binding Receptors Engineered from Staphylococcal Protein A and Streptococcal Protein G", page 4323 - page 4327. * |
Cited By (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6740734B1 (en) * | 1994-01-14 | 2004-05-25 | Biovitrum Ab | Bacterial receptor structures |
US5939404A (en) * | 1995-12-27 | 1999-08-17 | Ngk Insulators, Ltd. | Cancer metastasis inhibitor containing a streptococcus agalactiae Ia type or Ib type surface polysaccharide as a main ingredient |
WO1997024130A1 (en) * | 1995-12-27 | 1997-07-10 | Ngk Insulators, Ltd. | CANCEROUS METASTASIS INHIBITOR COMPRISING SURFACE POLYSACCHARIDE OF STREPTOCOCCUS AGALACTIAE Ia TYPE OR Ib TYPE AS PRINCIPAL COMPONENT |
US6831161B1 (en) | 1998-10-21 | 2004-12-14 | Affibody Ab | Method of affinity separation and ligands for use therein |
WO2000063243A1 (en) | 1999-04-19 | 2000-10-26 | Biovitrum Ab | Derivatives of the b or z domain from staphylococcal protein a (spa) interacting with at least one domain of human factor viii |
US6602977B1 (en) | 1999-04-19 | 2003-08-05 | Biovitrum Ab | Receptor structures |
EP1826270A1 (en) * | 1999-07-20 | 2007-08-29 | Affibody AB | Method and library for in vitro selection |
US7456008B2 (en) | 2000-07-19 | 2008-11-25 | Got-A-Gene Ab | Modified virus comprising one or more non-native polypeptides |
WO2002008263A3 (en) * | 2000-07-19 | 2002-06-13 | Got A Gene Ab | Modified virus having an altered tropism |
AU2003217119B2 (en) * | 2002-03-25 | 2010-02-18 | Cytiva Bioprocess R&D Ab | A mutated immunoglobulin-binding protein |
EP1600459A3 (en) * | 2002-06-28 | 2005-12-07 | Domantis Limited | Ligand |
US7993650B2 (en) | 2003-07-04 | 2011-08-09 | Affibody Ab | Polypeptides having binding affinity for HER2 |
US9107965B2 (en) | 2005-12-05 | 2015-08-18 | Affibody Ab | Polypeptides |
US8598113B2 (en) | 2005-12-05 | 2013-12-03 | Affibody Ab | Polypeptides |
US8247375B2 (en) | 2005-12-05 | 2012-08-21 | Affibody Ab | Polypeptides |
WO2007065635A1 (en) * | 2005-12-05 | 2007-06-14 | Affibody Ab | Polypeptides |
EP2431383A1 (en) * | 2005-12-05 | 2012-03-21 | Affibody AB | Polypeptides |
US8388979B2 (en) | 2006-01-31 | 2013-03-05 | Ishihara Sangyo Kaisha, Ltd. | Polypeptide having affinity for envelope virus constituent and use thereof in transferring substance into cell |
EP2559702A1 (en) | 2007-02-08 | 2013-02-20 | Domantis Limited | Antibody single variable domains against serum albumin |
EP2559704A1 (en) | 2007-02-08 | 2013-02-20 | Domantis Limited | Antibody single variable domains against serum albumin |
EP2559703A1 (en) | 2007-02-08 | 2013-02-20 | Domantis Limited | Antibody single variable domains against serum albumin |
US9587009B2 (en) | 2007-07-10 | 2017-03-07 | Emd Millipore Corporation | Media for affinity chromatography |
US8772018B2 (en) | 2007-07-10 | 2014-07-08 | Emd Millipore Corporation | Media for affinity chromatography |
EP2014359A1 (en) | 2007-07-10 | 2009-01-14 | Millipore Corporation | Media for affinity chromatography |
WO2009019117A1 (en) * | 2007-08-03 | 2009-02-12 | Affibody Ab | Igf-1r binding polypeptides and their use |
US8426557B2 (en) | 2007-08-03 | 2013-04-23 | Affibody Ab | IGF-1R binding polypeptides and their use |
US9546198B2 (en) | 2007-10-12 | 2017-01-17 | Cancer Research Technology Limited | Cyclic peptides as ADAM protease inhibitors |
US10472393B2 (en) | 2007-10-12 | 2019-11-12 | Cancer Research Technology Limited | Method for inhibiting ADAM proteases with cyclic peptides |
US9187535B2 (en) | 2007-12-19 | 2015-11-17 | Affibody Ab | Polypeptide derived from protein A and able to bind PDGF |
CN101983204A (en) * | 2007-12-21 | 2011-03-02 | 阿菲博迪公司 | Polypeptide libraries with a predetermined scaffold |
US8501909B2 (en) | 2007-12-21 | 2013-08-06 | Affibody Ab | Polypeptides having affinity for HER2 |
US10556933B2 (en) | 2007-12-21 | 2020-02-11 | Affibody Ab | Polypeptide libraries with a predetermined scaffold |
JP2011509073A (en) * | 2007-12-21 | 2011-03-24 | アフィボディ・アーベー | Polypeptide library having a predetermined scaffold |
US9469670B2 (en) | 2007-12-21 | 2016-10-18 | Affibody Ab | Polypeptide libraries with a predetermined scaffold |
EP2077272A1 (en) | 2007-12-21 | 2009-07-08 | Affibody AB | Polypeptide libraries with a predetermined scaffold |
US8883120B2 (en) | 2007-12-21 | 2014-11-11 | Affibody Ab | Polypeptides having affinity for HER2 |
WO2009080811A1 (en) * | 2007-12-21 | 2009-07-02 | Affibody Ab | Polypeptide libraries with a predetermined scaffold |
CN101983204B (en) * | 2007-12-21 | 2015-06-03 | 阿菲博迪公司 | Polypeptide libraries with a predetermined scaffold |
US9920112B2 (en) | 2008-08-11 | 2018-03-20 | Emd Millipore Corporation | Immunoglobulin-binding proteins with improved specificity |
US10894097B2 (en) | 2008-12-22 | 2021-01-19 | General Electric Company | HER2 binders |
US10072050B2 (en) | 2008-12-24 | 2018-09-11 | Emd Millipore Corporation | Caustic stable chromatography ligands |
US11084851B2 (en) | 2008-12-24 | 2021-08-10 | Emd Millipore Corporation | Caustic stable chromatography ligands |
US10329331B2 (en) | 2010-07-09 | 2019-06-25 | Affibody Ab | Polypeptides |
US9040661B2 (en) | 2010-12-21 | 2015-05-26 | Jsr Corporation | Support for affinity chromatography and method for isolating immunoglobulin |
US9051375B2 (en) | 2010-12-21 | 2015-06-09 | The University Of Western Ontario | Alkali-resistant variants of protein A and their use in affinity chromatography |
WO2012083425A1 (en) * | 2010-12-21 | 2012-06-28 | The University Of Western Ontario | Novel alkali-resistant variants of protein a and their use in affinity chromatography |
CN103403020A (en) * | 2010-12-21 | 2013-11-20 | Jsr株式会社 | Novel alkali-resistant variants of protein a and their use in affinity chromatography |
US11633507B2 (en) | 2010-12-22 | 2023-04-25 | General Electric Company | HER2 binders |
US8754196B2 (en) | 2011-06-08 | 2014-06-17 | Emd Millipore Corporation | Chromatography matrices including novel Staphylococcus aureus protein A based ligands |
US9376474B1 (en) | 2011-06-08 | 2016-06-28 | Emd Millipore Corporation | Chromatography matrices including novel Staphylococcus aureus protein a based ligands |
US9018305B2 (en) | 2011-06-08 | 2015-04-28 | Emd Millipore Corporation | Chromatography matrices including novel Staphylococcus aureus protein a based ligands |
US8895706B2 (en) | 2011-06-08 | 2014-11-25 | Emd Millipore Corporation | Chromatography matrices including novel Staphylococcus aureus protein A based ligands |
US9234010B2 (en) | 2011-06-08 | 2016-01-12 | Emd Millipore Corporation | Chromatography matrices including novel Staphylococcus aureus protein A based ligands |
EP3939613A1 (en) | 2011-08-11 | 2022-01-19 | ONO Pharmaceutical Co., Ltd. | Therapeutic agent for autoimmune diseases comprising pd-1 agonist |
WO2013022091A1 (en) | 2011-08-11 | 2013-02-14 | 小野薬品工業株式会社 | Therapeutic agent for autoimmune diseases comprising pd-1 agonist |
WO2013143890A1 (en) | 2012-03-28 | 2013-10-03 | Affibody Ab | Oral administration |
WO2014013016A1 (en) | 2012-07-20 | 2014-01-23 | Affibody Ab | Method for determining the her2 status of a malignancy |
US10155792B2 (en) | 2012-09-25 | 2018-12-18 | Affibody Ab | Albumin binding polypeptide |
WO2014076179A1 (en) | 2012-11-14 | 2014-05-22 | Affibody Ab | New polypeptide |
WO2014103203A1 (en) | 2012-12-27 | 2014-07-03 | 独立行政法人産業技術総合研究所 | Molecule library constructed on the basis of backbone structure of microprotein |
US9897611B2 (en) | 2012-12-27 | 2018-02-20 | National Institute Of Advanced Industrial Science And Technology | Molecule library constructed on the basis of backbone structure of microprotein |
EP3489396A1 (en) | 2012-12-27 | 2019-05-29 | National Institute of Advanced Industrial Science and Technology | Molecule library constructed on the basis of backbone structure of microprotein |
US10167322B2 (en) | 2013-12-20 | 2019-01-01 | Affibody Ab | Engineered albumin binding polypeptide |
WO2018194376A1 (en) | 2017-04-18 | 2018-10-25 | 앱클론(주) | Polypeptide improved in protein purity and affinity for antigen, conjugate thereof with antibody or antigen-binding fragment, and preparation method therefor |
WO2019203600A1 (en) | 2018-04-18 | 2019-10-24 | 앱클론(주) | Switch molecule and switchable chimeric antigen receptor |
WO2021006199A1 (en) | 2019-07-05 | 2021-01-14 | 小野薬品工業株式会社 | Treatment of hematologic cancer with pd-1/cd3 dual specificity protein |
WO2021025140A1 (en) | 2019-08-08 | 2021-02-11 | 小野薬品工業株式会社 | Dual-specific protein |
WO2021210939A1 (en) | 2020-04-17 | 2021-10-21 | 앱클론(주) | Anti-her2 affibody, and switchable chimeric antigen receptor using same as switch molecule |
WO2022080851A1 (en) | 2020-10-13 | 2022-04-21 | 인센 주식회사 | Testosterone-specific affibody and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
EP0739353B1 (en) | 2004-10-13 |
DE69533644T2 (en) | 2005-02-17 |
CA2181042C (en) | 2008-04-15 |
EP0739353A1 (en) | 1996-10-30 |
US5831012A (en) | 1998-11-03 |
JPH09508016A (en) | 1997-08-19 |
AU1548795A (en) | 1995-08-01 |
ES2225838T3 (en) | 2005-03-16 |
JP2007308509A (en) | 2007-11-29 |
US6534628B1 (en) | 2003-03-18 |
JP2005263810A (en) | 2005-09-29 |
ATE279439T1 (en) | 2004-10-15 |
PT739353E (en) | 2005-01-31 |
JP4089920B2 (en) | 2008-05-28 |
WO1995019374A9 (en) | 2006-04-13 |
AU696186B2 (en) | 1998-09-03 |
JP4373461B2 (en) | 2009-11-25 |
SE9400088D0 (en) | 1994-01-14 |
NZ278991A (en) | 1997-04-24 |
CA2181042A1 (en) | 1995-07-20 |
DE69533644D1 (en) | 2004-11-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0739353B1 (en) | Bacterial receptor structures | |
US6740734B1 (en) | Bacterial receptor structures | |
Nord et al. | A combinatorial library of an α-helical bacterial receptor domain | |
US20210162319A1 (en) | Mutated Immunoglobulin-Binding Polypeptides | |
Gunneriusson et al. | Surface display of a functional single-chain Fv antibody on staphylococci | |
US8883692B2 (en) | Method for cell surface displaying of target proteins using Bacillus anthracis exosporium | |
Nord et al. | Ligands selected from combinatorial libraries of protein A for use in affinity capture of apolipoprotein A-1M and taq DNA polymerase | |
Jonsson et al. | A protein G-related cell surface protein in Streptococcus zooepidemicus | |
JP3043407B2 (en) | Complete synthetic affinity reagent | |
Ljungquist et al. | Thiol‐directed immobilization of recombinant IgG‐binding receptors | |
AU729449B2 (en) | Materials and methods relating to the attachment and display of substances on cell surfaces | |
CA2258518A1 (en) | Recognition molecules interacting specifically with the active site or cleft of a target molecule | |
US9238810B2 (en) | Polypeptide | |
Gräslund et al. | A novel affinity gene fusion system allowing protein A-based recovery of non-immunoglobulin gene products | |
US5411732A (en) | Preparation of fused proteins, antibodies and processes therefore | |
WO2004106361A2 (en) | Peptides for metal ion affinity chromatogrpahy | |
Derouiche et al. | Binding of colicins A and E1 to purified ToIA domains | |
US5801037A (en) | Expression of signal-peptide-free staphylokinases | |
Jansson et al. | A dual-affinity gene fusion system to express small recombinant proteins in a soluble form: expression and characterization of protein A deletion mutants | |
Ståhl et al. | Strategies for gene fusions | |
JP2584697B2 (en) | Recombinant protein A for IgG purification | |
CN107043421B (en) | Single-domain heavy-chain antibody of anti-c-Myc label | |
CN106831991B (en) | Nano antibody of anti-c-Myc label | |
CN106946990B (en) | Nano antibody aiming at c-Myc label | |
CN106831990B (en) | Nano antibody capable of specifically binding c-Myc label |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1995907175 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 278991 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2181042 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08669360 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1995907175 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWG | Wipo information: grant in national office |
Ref document number: 1995907175 Country of ref document: EP |
|
COP | Corrected version of pamphlet |
Free format text: PAGES 15-16, DESCRIPTION, ADDED |