WO2004081051A1 - Anticorps specifiques - Google Patents

Anticorps specifiques Download PDF

Info

Publication number
WO2004081051A1
WO2004081051A1 PCT/GB2004/001026 GB2004001026W WO2004081051A1 WO 2004081051 A1 WO2004081051 A1 WO 2004081051A1 GB 2004001026 W GB2004001026 W GB 2004001026W WO 2004081051 A1 WO2004081051 A1 WO 2004081051A1
Authority
WO
WIPO (PCT)
Prior art keywords
bispecific antibody
antibodies
antibody
cells
cell
Prior art date
Application number
PCT/GB2004/001026
Other languages
English (en)
Inventor
Stephen Peter Young
Original Assignee
The University Of Birmingham
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of Birmingham filed Critical The University Of Birmingham
Publication of WO2004081051A1 publication Critical patent/WO2004081051A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A61K47/6897—Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1084—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody the antibody being a hybrid immunoglobulin
    • A61K51/109—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody the antibody being a hybrid immunoglobulin immunoglobulins having two or more different antigen-binding sites or multifunctional antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to the production of bispecific antibodies providing increased specificity toward target tissues over non-target tissues.
  • the production of antibodies having improved specificity for target tissues and cells and with reduced cross-reactivity to non-target tissues has long been recognised as desirable by the medical profession.
  • a monoclonal antibody has specificity for a single epitope of an antigen, but is normally bivalent (i.e. has two binding interactions) for this epitope providing improved binding characteristics.
  • bispecific antibodies have been developed in which two monoclonal antibodies having specificities for different antigens are coupled together (EP 0468637A). It has been suggested that these bispecific antibodies may be useful in increasing the relative amount of antibody-linked agent delivered to target tissues in vivo compared to the amount of such agent delivered to non-target tissues (EP 0331034B).
  • the individual monoclonal antibodies having differing specificities are generally chosen because of their strong binding affinity for their respective epitopes and are cross-linked to each other to produce the bispecific antibody.
  • the bispecific antibody provides some selectivity, binding more strongly to cells where both epitopes are expressed compared to those where only one is expressed, and may even have reduced affinity for cells expressing a single epitope when compared to the monoclonal antibody (EP 0468637). However, these bispecific antibodies still bind to cells expressing only one of the epitopes, resulting in cross-reactivity to non-target cells.
  • a bispecific antibody comprising two antibodies, each of said antibodies having a binding specificity to a different epitope situated on the surface of a target structure, wherein each of said antibodies has a relatively low binding affinity for its respective epitope.
  • EP 0468637 discloses a method of in vivo targeting specific cells using high affinity commercially available or hybridoma produced monoclonal antibodies to produce bifunctional antibodies. These bifunctional antibodies provide some selectivity for target cells by providing greater avidity to target cells than cross-reactive non-target cells leading, due to the dynamism of the system, to more bispecific antibody being bound to the target than non-target at equilibrium.
  • the BAb disclosed in EP 0468637 still has a relatively high affinity for cross-reactive non- target tissue.
  • the BAbs produced according to the present invention have much lower affinity for cross-reactive non-target tissue due to the lower affinity of the MAbs used to produce them. These BAbs still provide high avidity for target tissue due to the cumulative nature of the binding interactions.
  • the binding affinity of the antibodies is measured in terms of the affinity constant, which is the concentration of an antibody required to cause 50% saturation of a specific antigen. The lower the concentration required, the greater the binding affinity.
  • relatively low binding affinity is defined as an affinity constant of at least 10 "8 M.
  • monoclonal antibodies are typically selected with an affinity constant of 10 "11 M or lower.
  • antibody in the context of the antibodies which comprise the BAbs of the present invention includes an intact antibody molecule, an antibody fragment, for example Fab, Fab' or F(ab')2, or functional equivalents of the antibody/antibody fragment whether naturally occurring, genetically engineered or chemically synthesised.
  • the target structure may be a cell, collection of cells, bodily tissue or organ.
  • the bispecific antibody may also comprise a linker and/or spacer to which the antibodies are attached.
  • Said linker/spacer may be a polymer (preferably non-biodegradable under physiological conditions) such as polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the presence of the linker/spacer permits binding of epitopes which may be in different domains on the surface of the target structure.
  • the affinity constant of each of the antibodies comprising the bispecific antibody is at least 10 "7 M, more preferably, from 10 "7 M to 10 "4 M, and most preferably from 10 ⁇ 7 M to 10 "6 M. It will be understood that each of the antibodies comprising the bispecific antibody may have a different affinity constant for its specific epitope.
  • the bispecific antibody may comprise a therapeutic or diagnostic agent which is desirably targeted to said target structure.
  • suitable classes of agents include, drugs (especially cytotoxic drugs), pro-drugs, T- cells or other immune system cells (e.g. an antibodies) or target markers, including fluorescent, luminescent and radioactive markers, liposomes, complement, inhibitory RNA (RNAi) or suitable plasmids encoding for RNAi sequences, and retroviral vectors coding sequences to "knockdown" or "knock-in” genes of the target structure.
  • Specific therapeutic agents which may be used include, but are not limited to, 13l l, 67 Cu, 97 Ru and 188 Re, anti-cancer drugs such as nitrogen mustards, cytotoxic antibiotics such as bleomycin, cis- diaminodichloroplatinum, alkylating agents, antimetabolites such as 5- fluorouracil, toxins, for example mycotoxins such as trichothecenes, ricin or abrin and biological response modifiers, for example interferons, interleukins or TNF.
  • anti-cancer drugs such as nitrogen mustards, cytotoxic antibiotics such as bleomycin, cis- diaminodichloroplatinum, alkylating agents, antimetabolites such as 5- fluorouracil, toxins, for example mycotoxins such as trichothecenes, ricin or abrin and biological response modifiers, for example interferons, interleukins or TNF.
  • Suitable diagnostic agents include, but are not limited to, 76 Br, 18 F or 123 l or NMR imaging contrast agents.
  • the therapeutic or diagnostic agent may be covalently or otherwise linked to the remainder of the bispecific antibody, said linking being at one or both antibodies and/or at the linker/spacer when present.
  • the combination of an antibody with a therapeutic/diagnostic agent is often referred to as an "immuno-conjugate".
  • Methods of producing immuno- conjugates to target pre-selected sites in the body are well known (US 4801688, US 4845200, Ghose et a/, [1983] Methods in Enzymol. 93, 280-333.), Garnett [2001] Advanced Drug Delivery Reviews 53, 1 71-21 6 and Trail and Bianchi [1999] Current Opinion in Immunology 1 1 , 584- 588.
  • the bispecific antibody may comprise a receptor for a therapeutic/diagnostic agent.
  • said receptor may be an Fc antibody fragment .
  • the Fc fragment can serve as a receptor for complement and cells expressing Fc receptors such as neutrophils and macrophages.
  • monoclonal antibodies isolated from cells produced during the primary immune response are used to produce the bispecific antibody.
  • primary immune response it is meant the immune response to an initial exposure of antibody-producing cells to an antigen.
  • antigen it is also contemplated that, depending upon the particular antigen used, it may be necessary to provide a second exposure of the antibody-producing cells to obtain antibodies having an appropriate binding affinity.
  • B-cells activated during the primary immune response caused by the first exposure of the cells to an antigen are isolated and fused with myeloma cells to produce hybridomas.
  • the fusion of somatic cells to produce MAbs was first described by Kohler and Milstein in 1975 and provides a relatively simple method of producing and screening large numbers of MAbs to a single antigen.
  • the hybridomas created by the cell fusion experiment will produce a number of antibody specificities against the same antigen (i.e. antibodies specific to different regions of the same antigen), each antibody having a different affinity.
  • the production of a panel of antibodies is advantageous as some isotypes are better suited to the enzymatic reactions used in the chemical construction of BAbs than others.
  • the isolated antibody producing cells from the primary immune response are B-cells or plasma cells. They are B-cells or plasma cells which are likely to produce IgM or IgG antibodies.
  • IgM antibodies are the first class of antibodies to appear after exposure to an antigen and generally have lower affinity for their specific epitopes than immunoglobulins produced later in the immune response or upon secondary exposure to an antigen.
  • the bispecific antibody may be produced by any known method such as chemical cross-linking, or cross-linking using anti-lgG Fc antibodies followed by covalent cross-linking. They may also be produced biologically by fusing two antibody producing hybridoma cell lines together. In cases where the antibodies are linked to a linker/spacer, the linker/spacer may participate in the cross linking reaction to produce the bispecific antibody.
  • a method of selecting monoclonal antibodies for use in production of a bispecific antibody comprising screening a large number of hybridomas which produce antibodies specific for each epitope of interest by direct measurement of their binding affinity for their specific epitope, for example, by surface plasmon resonance, so allowing antibodies having differing affinities for the specific epitopes of interest to be selected.
  • a method of treating a patient comprising, administering to a patient a therapeutical ly effective amount of a BAb in accordance with the first aspect, said BAb having a receptor for a therapeutic agent, in conjunction with prior, concomitant or subsequent administration of the therapeutic agent.
  • the method may comprise administering to a patient an immu no-conjugate, said immuno-conjugate comprising a BAb which includes a therapeutic agent in accordance with said first aspect.
  • Administration of said therapeutical ly effective amount of a BAb may be by any known route e.g. by intravenous, intramuscular, or subcutaneous injection, topical administration as an ointment, salve, cream or tincture, oral administration as a tablet, capsule, suspension or liquid and nasally as a spray (e.g. aerosol).
  • the preferred route of administration is intravenous injection.
  • said BAb may be in admixture with one or more excipients, carriers, pH regulators, flavourings, colourings, preservatives, or other commonly used additives in the field of pharmaceuticals as appropriate for the mode of administration.
  • a method of diagnosing a disorder comprising, contacting an immuno- conjugate comprising a bispecific antibody and a diagnostic agent according to the first aspect of the present invention with a tissue, or contacting a bispecific antibody having a receptor for the diagnostic agent according to the first aspect of the present invention with a tissue prior to, concomitantly with or subsequently to addition of the diagnostic agent to said tissue.
  • said tissue is an isolated tissue sample.
  • Antigen in the form of 2 x 10 6 to 5 x 10 10 cells or 1 to 50 ⁇ g protein or peptide in normal saline is prepared for each animal to be immunized.
  • the antigen is drawn into a sterile 1- to 2 ml glass syringe with a Luer-Lock tip, which is then connected to a 3-way stopcock.
  • a volume of complete Freund's adjuvant (CFA) (Sigma-Aldrich, Poole, UK) equal to the antigen volume is drawn into another syringe and connected to the antigen- containing syringe.
  • CFA complete Freund's adjuvant
  • Emulsification of the antigen and CFA is achieved by discharging the antigen into. the CFA, then discharging back and forth until a thickened mixture results.
  • a drop is placed in water (a stable emulsion will not disperse).
  • the CFA/antigen emulsion is drawn into one syringe and a sterile 20-G needle attached, the emulsion is then injected intraperitoneally into the animals using ⁇ 0.2 ml per mouse, 0.5 to 1 ml per rat, or 0.2 to 0.4 ml per hamster. After 10 to 14 days the animals are boosted with the same dose of antigen.
  • the boost immunization is done with antigen alone in aqueous solution, or intact cells in suspension.
  • the boost is done with antigen emulsified in incomplete Freund's adjuvant (IFA).
  • the spleens of some animals are removed for generation of hybridomas.
  • the response to a particular antigen may be very poor, and so other animals receive a booster immunisation in incomplete adjuvant and spleens are removed after a further 14 days. It may be necessary to repeat this process, depending on the nature of the antigen.
  • Standard protocols (Kohler and Milstein (1975) Nature 256, 495-497) are used to create the hybridomas from the spleen cells and these are grown in selection medium prior to screening.
  • One week before fusion expansion of the SP2/0-Ag14 myeloma cell line (European Collection of Cell Cultures, Salisbury, UK) (the fusion partner cell line) is begun in complete DMEM/HEPES/ pyruvate in 175cm 3 flasks containing 100 ml of medium.
  • mice spleen 1 x 10 8 cells
  • hamster spleen 2 x 10 8
  • rat spleen 5-10 x 10 8 cells at approximately 0.5 x 10 6 cells per ml.
  • Two mouse or hamster spleens, or one rat spleen provides enough cells for the fusion.
  • reagents and media are prepared, particularly 50% PEG and the SP2/0-Ag14 myeloma cells are split into fresh complete DMEM-10/HEPES/pyruvate medium, so that the cells are growing vigorously to ensure optimal fusions.
  • the boosted animal(s) is/are sacrificed and the spleen(s) aseptically harvested.
  • the spleen(s) is/are transferred into a sterile 100 mm-diameter petri dish filled with 10 ml sterile complete serum-free DMEM, placed in a laminar flow hood, and teased into a single-cell suspension by squeezing with angled forceps or by chopping with fine-tipped dissecting scissors.
  • the spleen cell suspension is transferred to a sterile 50 ml conical centrifuge tube filled with sterile complete serum-free DMEM, centrifuged for 5 min at 1500 rpm (500 x g) at room temperature and the supernatant discarded.
  • the red blood cells (RBC) are lysed by re-suspending the pellet in 5 ml ammonium chloride solution (0.02 M Tris-CI, pH 7.2 0.14 M NH4CI ) and letting them stand for 5 min at room temperature. 45 ml sterile complete serum-free DMEM is added, and cells centrifuged as above.
  • the cells are washed a further two times in 50 ml sterile complete serum-free DMEM. While the spleen cells are being washed, the SP2/0-Ag14 myeloma cells are harvested by centrifuging at 1500 rpm (500 x g) for 5 min at room temperature and washed three times in DMEM. The spleen and myeloma cells are separately re-suspended in 10 ml complete serum-free DMEM and the cells in each cell suspension counted and their viability assessed using a haemocytometer and trypan blue exclusion.
  • the SP2/0-Ag 14 myeloma and spleen cells are mixed at a 1 :1 ratio in a 50 ml conical centrifuge tube which is then filled with complete serum-free DMEM, and the cell mixture centrifuged for 5 min at 500 x g at room temperature. While the cells are in the centrifuge, three 37°C double-beaker water baths are prepared in a laminar flow hood by placing a 400 m l beaker containing 1 00 ml of 37°C water into 600 ml beaker containing 75 to 100 ml of 37°C water. The tubes of pre-warmed 50% PEG solution and complete serum-free DMEM are placed into two of the 37°C water baths in the hood.
  • the supernatant from the mixed-cell pellet is aspirated and discarded and the tube placed in the third double-beaker water bath in the laminar flow hood.
  • 1 ml pipette 1 ml of pre-warmed 50% PEG is added to the mixed-cell pellet drop-by-drop over 1 m in, with stirring after each drop, the m ixture is then stirred for an additional minute.
  • 1 ml of pre-warmed complete serum- free DMEM is added to the cell mixture drop-by-drop over 1 min, stirring after each drop. This is repeated once with an additional 1 ml of pre-warmed complete serum-free DMEM.
  • DMEM/HEPES/ pyruvate/HAT DMEM medium containing 10 mM HEPES , 1 mM pyruvate, and 1 % 1 00x HAT (hypoxanthine/aminopterin/thym idine)
  • DMEM medium containing 10 mM HEPES , 1 mM pyruvate, and 1 % 1 00x HAT hypoxanthine/aminopterin/thym idine
  • hybridoma supernatants are screened for specific antibodies by directly measuring their binding affinity for antigen.
  • Supernatants are removed from the multi-well plates in which the hybridomas are grown, concentrated and injected over a BIAcore chip (BlAcore, Stevenage, U K), which has been coupled with purified antigen.
  • the concentration of the antigen for coupling is adjusted to aim for three different levels of coupling: 1000, 5000 and 10,000 RU (response units).
  • Antigen is immobilized onto the chips by amide coupling. 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.4 M) and N-hydroxysuccinimide (NHS) (0.1 M) solution are mixed at a ratio of 1 :1 and 35 ⁇ l injected over the CM5 chip at a rate of 5 ⁇ l/min to activate the surface.
  • Antigen at 10 ⁇ g/ml in the selected pH coupling buffer is then injected at 2 ⁇ l/min until the required RU coupling is achieved.
  • Supernatants derived from the hybridomas are assayed for Ig content and isotype using a standard ELISA technique. To be able to detect the low affinity antibodies, the supernatants are concentrated to 30 ⁇ g/ml i.e. approximately 200 nM IgG. This concentration is high enough to observe binding, even if it is low affinity, in the ⁇ M range. This is done using 96 well plate format vacuum filter apparatus. Assays are performed with a mobile phase at a flow rate of 10 ⁇ l/min using 20 mM HEPES, 150 mM NaCI, 3.4 mM EDTA, 0.05% v/v surfactant P20 (pH 7.4).
  • Antibody is cleared from the antigen by an injection of low pH buffer (10 mM glycine pH 3.0) for 1 minute, followed by a wash in pH 7.5 Hepes buffer, the next antibody is then injected.
  • An initial estimate of affinity can be made from the on and off kinetics by curve fitting of the data. Those hybridomas having an affinity in a suitable range are selected for expansion into a larger scale culture. After this expansion the affinity is re-assessed using the BIAcore method. A titration of the Ig's at 30, 15, 7.5, 3.75, 1.875, 0.93, 0.47, 0.23, 0.12, 0.06 ⁇ g/ml (200, 100, 50, 25, 12.5, 6.25, 3.1 , 1.5, 0.75, 0.37 nM) is then done to give a better estimate of the binding affinity.
  • purified antigens are not available, then crude preparations, cell membranes or whole cells may be coupled to the BIAcore chip and used in a similar fashion.
  • suitable hybridomas Once suitable hybridomas have been provisionally identified, they are re- cloned to make certain that they are definitely monoclonal.
  • the candidate hybridoma lines are resuspended in their wells and the numbers and viability assessed using a haemocyto meter and Trypan blue.
  • 1 0 m l of cel ls at 50 viable cel ls/m l and 1 0 m l at 5 viable cel ls/m l are prepared in cloning/expansion medium.
  • a 96-well plate is seeded with the cel l suspensions at 200 ⁇ l/well and Incubated for 7 to 10 days in a humidified 37°C, 5% CO, incubator.
  • the optimum dilution for monoclonal growth is identified by determining the number of wells that showed growing hybridomas. Wells are inspected for monoclonality with an inverted microscope by looking for tight single clusters of cells before the cells are fed. The supernatants are re-screened using ELISA and BIAcore as above.
  • a second re-cloning is done, after the desired clone has been expanded as above, at lower cell density by seeding two new 96-well plates at 0.3 cells/well (60 viable cells in 40 ml cloning medium). The screening process is repeated as above and the re-cloned hybridoma expanded.
  • the re-cloned cells are weaned on to complete DMEM-10/HEPES/ pyruvate by splitting the cells 1 :2 every day for 3 days with complete DMEM-IO/HEPES/pyruvate.
  • hybridomas are gradually expanded in DMEM/HEPES/ pyruvate containing fetal bovine serum, which has been passed through a protein A-Sepharose affinity column to clear any residual immunoglobul ins from it.
  • Supernatants from the hybridoma are col lected and Ig purified by passing the medium through a protein G-Sepharose column and eluting the bound antibody with 0.1 M glycine pH 2.0 and rapidly neutralizing with I M Tris pH 8.0.
  • Hetero-bifunctional antibodies are produced by chemical crosslinking or by crosslinking using anti-lgG Fc antibodies, followed by covalent crosslinking. Once the value of a particular coupled pair has been established the hybridomas are used as a source of material for further manipulation such as humanisation or other structural manipulations. Polyethylene glycol (PEG) derivitisation.
  • PEG Polyethylene glycol
  • PEGylation of proteins has been widely reported and can give rise to products with greatly prolonged blood half-lives.
  • Several derivitized PEG preparations are available commercially which can be coupled to proteins using standard mild cross-linking conditions using either amino or sulphydryl groups.
  • Whole antibody molecules or derived Fab or Fab2 fragments can be used for different purposes.
  • Pepsin- Sepharose (2mg enzyme per 100mg of IgG). After mixing and incubation overnight at 37°C, the pepsin-Sepharose is centrifuged out, the supernatant taken to pH 7.4 and passed into a Protein A-Sepharose column. This binds undigested IgG and the Fc fragments released by the digestion. After dialysis against PBS, any remaining unfragmented or small material is removed by chromatography on a Sephacryl S200 gel column. The purity is checked by SDS page analysis and the Fab' fragments can be made by reducing with dithiothreitol (DTT).
  • DTT dithiothreitol
  • the protein is equilibrated with Tris-HCI, degassed and made 20mM with DTT. After an hour, the DTT is rapidly removed by centrifugation on a column of Sephadex G25 and is used immediately to re-form heterodimeric F(ab')2 complexes.
  • the pH of the reaction mixture is adjusted to 8 using 1 M Tris-HC1 , pH 8.0 before reducing with mercaptoethanol at a final concentration of 20 mM for 30 min at 30°C and blocking any free SH groups by alkylating with 25 mM iodoacetamide.
  • the bispecific F(ab')2 is separated using Sephacryl S200 in 0.2 M Tris- HC1 , 10 mM EDTA, pH 8.0.
  • a 4 mg/ml solution of F(ab')2 is equilibrated in 50 mM sodium phosphate buffer (pH 8.0).
  • Five milliliters of the protein solution is mixed with the 3400 kDa- PEG (Shearwater Polymers, Huntsville, AL) reagent:protein at a molar ratio of 3:1 .
  • the reaction is carried out in a 15 ml polypropylene tube (Falcon), and the PEG is added while vortexing the sample at low speed.
  • Branched derivitized PEGs are also available to which individual Fab' fragments can be coupled to yield products with variable spacing between the hetero Fab' fragments, which may have benefits when binding to widely spaced antigens on cells.
  • the Fab' fragments are mixed at a ratio of 1 :1 in phosphate buffer pH 6.5 and the bifunctional maleimide branched PEG mPEG(MAL)2 (Shearwater Polymers, Huntsville, AL) is added.
  • the reactivity with SH groups is greater than that with amino groups at this pH and so should orient the Fab' and leave the antigen recognition site intact.
  • the sample is then incubated at room temperature while shaking on a rotator for 30 min.
  • the extent of modification was evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
  • the complete reaction mixture was passed through an ion exchange column to remove any unreacted PEG and purification of singly or doubly PEGylated species. This will contain a mixture of heterobifunctional and homobifunctional molecules which will be separated using sequential affinity chromatography through columns with each bound antigen. Only the complexes retained by both columns will contain the required heterobifunctional PEG-Ab complexes.
  • oligonucleotide is separated from unreacted crosslinker by gel filtration on a Sephadex G-25 PD10 column (Pharmacia Biotech), equilibrated with 0.1 M phosphate buffer, pH 7.5, containing 10 mM ethylenediamine tetraacetic acid (EDTA).
  • EDTA ethylenediamine tetraacetic acid
  • a 7- fold molar excess of the activated oligonucleotide in 0.1 M phosphate buffer, pH 7.5, 10 mM EDTA is incubated with the Fab' overnight at 4°C.
  • the Fab'-oligonucleotide conjugate is purified by size exclusion chromatography using Sephacryl S200 chromatography.
  • the oligonucleotide-labelled Fab' fragments are then mixed at a ration 1 :1 and left overnight at 4°C for binding to occur. Heterodimers are separated from unbound monomers by gel permeation chromatography on Sephacryl S200 columns.
  • a one-to-one mixture of two low affinity antibodies is made and, if the ⁇ hybridomas are derived from mouse, one half mole equivalent of a rat anti-mouse IgG Fc region is added. After 1 hr incubation on ice the mixture is passed though a sizing column of Sephacryl S-300 equilibrated in 20 mM HEPES 150 mM NaCl to separate full trimeric complexes of rat Ig coupled to two mouse IgG molecules (450,000 mw) which elutes first from the column.
  • Two separate affinity columns are made by coupling the individual antigens recognized by the antibodies to CNBr-Sepharose.
  • the antibody mixture is pumped on to the column containing the first antigen, at 4°C to maximize the binding affinity and washed through with equilibration buffer (20 mM HEPES 0.15M NaCI pH 7.5) until no further buffer is eluted.
  • the antibodies are eluted using 100 mM glycine buffer pH 3.0. This eluate is concentrated on a 30,000MW cutoff Centricon filter, re- equilibrated to pH 7.5 and applied to an affinity column loaded with the second antigen. Antibody binding to this column is collected in the same way. This results in an antibody preparation that will recognize both antigens, and so must contain the required heterobifunctional antibody.
  • binding characteristics are derived using a BIAcore chip to which both antigens have been coupled.
  • an effective binding constant or "avidity" is derived. If antigens are present on cells an estimate of binding can be achieved using flow cytometry by labelling cells with the heterobifunctional complex, followed by a FITC labeled second antibody.
  • a more accurate effective binding constant can be derived by radiolabelling of the antibody with 125 l and performing cell binding and Scatchard analysis of the binding data.
  • the methods described above can also be used to screen for low affinity Fab fragments or components thereof expressed in bacteria by using a phage display approach. Combinations of these low affinity fragments made by coupling, for example, to a larger carrier molecule such as PEG can also be useful.

Abstract

L'invention concerne un anticorps spécifique (Bab) comprenant deux anticorps, dont chacun présente une spécificité de liaison à un épitope différent situé à la surface d'une structure cible. Chaque desdits anticorps présente une affinité de liaison relativement faible à l'épitope respectif. Les Bab produits selon l'invention présentent une affinité nettement moindre à l'égard de tissus cibles, en raison de la nature cumulative des interactions de liaison.
PCT/GB2004/001026 2003-03-12 2004-03-11 Anticorps specifiques WO2004081051A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0305702.3A GB0305702D0 (en) 2003-03-12 2003-03-12 Bispecific antibodies
GB0305702.3 2003-03-12

Publications (1)

Publication Number Publication Date
WO2004081051A1 true WO2004081051A1 (fr) 2004-09-23

Family

ID=9954658

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/001026 WO2004081051A1 (fr) 2003-03-12 2004-03-11 Anticorps specifiques

Country Status (2)

Country Link
GB (1) GB0305702D0 (fr)
WO (1) WO2004081051A1 (fr)

Cited By (108)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2129689A1 (fr) * 2007-03-07 2009-12-09 Next Biomed Technologies NBT Oy Polypeptide de fusion permettant de détecter des épitopes combinatoires ou composites conservés dans des protéines non conservées
WO2012085111A1 (fr) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Complexe polypeptide-polynucléotide et son utilisation dans l'administration d'une fraction effectrice ciblée
WO2012085113A1 (fr) 2010-12-23 2012-06-28 Roche Diagnostics Gmbh Agent de liaison
WO2014001326A1 (fr) 2012-06-27 2014-01-03 F. Hoffmann-La Roche Ag Procédé de sélection et de production de molécules thérapeutiques multi-spécifiques, sélectives et personnalisées comprenant au moins deux entités de ciblage différentes et leurs utilisations
WO2015138920A1 (fr) 2014-03-14 2015-09-17 Novartis Ag Molécules d'anticorps anti-lag-3 et leurs utilisations
WO2015142675A2 (fr) 2014-03-15 2015-09-24 Novartis Ag Traitement du cancer au moyen d'un récepteur antigénique chimérique
WO2015181282A1 (fr) * 2014-05-29 2015-12-03 Ucb Biopharma Sprl Nouveau format bispécifique adapté pour être utilisé dans le criblage à haut débit
WO2016014530A1 (fr) 2014-07-21 2016-01-28 Novartis Ag Combinaisons de faibles doses renforçant l'immunité d'inhibiteurs de mtor et car
WO2016014553A1 (fr) 2014-07-21 2016-01-28 Novartis Ag Récepteurs d'antigènes chimères synthétisés par l'intermédiaire d'une sortase
WO2016014565A2 (fr) 2014-07-21 2016-01-28 Novartis Ag Traitement du cancer au moyen d'un récepteur d'antigène chimérique anti-bcma humanisé
WO2016025880A1 (fr) 2014-08-14 2016-02-18 Novartis Ag Traitement du cancer à l'aide du récepteur d'antigène chimérique gfr alpha-4
WO2016044605A1 (fr) 2014-09-17 2016-03-24 Beatty, Gregory Ciblage de cellules cytotoxiques avec des récepteurs chimériques pour l'immunothérapie adoptive
WO2016061142A1 (fr) 2014-10-14 2016-04-21 Novartis Ag Molécules d'anticorps de pd-l1 et leurs utilisations
WO2016090034A2 (fr) 2014-12-03 2016-06-09 Novartis Ag Méthodes de pré-conditionnement de cellules b dans une thérapie car
WO2016164731A2 (fr) 2015-04-08 2016-10-13 Novartis Ag Thérapies anti-cd20, thérapies anti-cd22, et polythérapies comprenant une cellule exprimant le récepteur antigénique chimérique (car) dirigé contre le cd19
WO2016172583A1 (fr) 2015-04-23 2016-10-27 Novartis Ag Traitement du cancer à l'aide de protéine récepteur antigénique chimérique et un inhibiteur de protéine kinase
WO2017019894A1 (fr) 2015-07-29 2017-02-02 Novartis Ag Polythérapies comprenant des molécules d'anticorps dirigées contre lag-3
WO2017019897A1 (fr) 2015-07-29 2017-02-02 Novartis Ag Polythérapies comprenant des molécules d'anticorps contre tim -3
WO2017106656A1 (fr) 2015-12-17 2017-06-22 Novartis Ag Molécules d'anticorps anti-pd-1 et leurs utilisations
WO2017106810A2 (fr) 2015-12-17 2017-06-22 Novartis Ag Combinaison d'un inhibiteur de c-met avec une molécule d'anticorps dirigée contre pd-1 et ses utilisations
US9688758B2 (en) 2012-02-10 2017-06-27 Genentech, Inc. Single-chain antibodies and other heteromultimers
WO2017125897A1 (fr) 2016-01-21 2017-07-27 Novartis Ag Molécules multispécifiques ciblant cll-1
WO2017149515A1 (fr) 2016-03-04 2017-09-08 Novartis Ag Cellules exprimant de multiples molécules de récepteur d'antigène chimère (car) et leurs utilisations
WO2017165683A1 (fr) 2016-03-23 2017-09-28 Novartis Ag Mini-corps sécrétés par des cellules et leurs usages
WO2017181119A2 (fr) 2016-04-15 2017-10-19 Novartis Ag Compositions et méthodes pour l'expression sélective d'une protéine
WO2017210617A2 (fr) 2016-06-02 2017-12-07 Porter, David, L. Régimes thérapeutiques pour cellules exprimant un récepteur antigénique chimérique (car)
WO2018013918A2 (fr) 2016-07-15 2018-01-18 Novartis Ag Traitement et prévention du syndrome de libération de cytokine à l'aide d'un récepteur d'antigène chimérique en combinaison avec un inhibiteur de kinase
WO2018023025A1 (fr) 2016-07-28 2018-02-01 Novartis Ag Polythérapies de récepteurs d'antigènes chimériques adn inhibiteurs pd -1
WO2018026819A2 (fr) 2016-08-01 2018-02-08 Novartis Ag Traitement du cancer au moyen d'un récepteur d'antigène chimérique en combinaison avec un inhibiteur d'une molécule de macrophage pro-m2
WO2018067992A1 (fr) 2016-10-07 2018-04-12 Novartis Ag Récepteurs antigéniques chimériques pour le traitement du cancer
US9994646B2 (en) 2009-09-16 2018-06-12 Genentech, Inc. Coiled coil and/or tether containing protein complexes and uses thereof
WO2018140725A1 (fr) 2017-01-26 2018-08-02 Novartis Ag Compositions de cd28 et procédés pour une thérapie à base de récepteur antigénique chimérique
WO2018160731A1 (fr) 2017-02-28 2018-09-07 Novartis Ag Compositions d'inhibiteur shp et utilisations pour une thérapie de récepteur d'antigène chimère
US10106600B2 (en) 2010-03-26 2018-10-23 Roche Glycart Ag Bispecific antibodies
US10106612B2 (en) 2012-06-27 2018-10-23 Hoffmann-La Roche Inc. Method for selection and production of tailor-made highly selective and multi-specific targeting entities containing at least two different binding entities and uses thereof
WO2018201051A1 (fr) 2017-04-28 2018-11-01 Novartis Ag Agent ciblant le bcma et polythérapie incluant un inhibiteur de gamma-sécrétase
WO2018201056A1 (fr) 2017-04-28 2018-11-01 Novartis Ag Cellules exprimant un récepteur antigénique chimérique ciblant le bcma, et polythérapie comprenant un inhibiteur de gamma sécrétase
WO2018237157A1 (fr) 2017-06-22 2018-12-27 Novartis Ag Molécules d'anticorps se liant à cd73 et leurs utilisations
WO2019006007A1 (fr) 2017-06-27 2019-01-03 Novartis Ag Régimes posologiques pour anticorps anti-tim3 et leurs utilisations
WO2019018730A1 (fr) 2017-07-20 2019-01-24 Novartis Ag Régimes posologiques pour des anticorps anti-lag3 et leurs utilisations
WO2019089798A1 (fr) 2017-10-31 2019-05-09 Novartis Ag Compositions anti-car et procédés
WO2019099838A1 (fr) 2017-11-16 2019-05-23 Novartis Ag Polythérapies
EP3514179A1 (fr) 2014-01-24 2019-07-24 Dana-Farber Cancer Institute, Inc. Molécules d'anticorps anti-pd-1 et leurs utilisations
US10370447B2 (en) 2014-07-16 2019-08-06 Ucb Biopharma Sprl Molecules with specificity for CD79 and CD22
WO2019152660A1 (fr) 2018-01-31 2019-08-08 Novartis Ag Polythérapie utilisant un récepteur antigénique chimérique
WO2019200229A1 (fr) 2018-04-13 2019-10-17 Novartis Ag Régimes posologiques pour anticorps anti-pd-l1 et utilisations associées
WO2019210153A1 (fr) 2018-04-27 2019-10-31 Novartis Ag Thérapies reposant sur des cellules car-t présentant une efficacité améliorée
WO2019226617A1 (fr) 2018-05-21 2019-11-28 Compass Therapeutics Llc Compositions et procédés pour améliorer la destruction de cellules cibles par des lymphocytes nk
WO2019226658A1 (fr) 2018-05-21 2019-11-28 Compass Therapeutics Llc Compositions multispécifiques de liaison à l'antigène et procédés d'utilisation
WO2019227003A1 (fr) 2018-05-25 2019-11-28 Novartis Ag Polythérapie comprenant des thérapies par récepteur antigénique chimérique (car)
WO2019232244A2 (fr) 2018-05-31 2019-12-05 Novartis Ag Molécules d'anticorps anti-cd73 et leurs utilisations
WO2019241426A1 (fr) 2018-06-13 2019-12-19 Novartis Ag Récepteurs d'antigènes chimériques bcma et leurs utilisations
WO2019246293A2 (fr) 2018-06-19 2019-12-26 Atarga, Llc Molécules d'anticorps se liant au composant du complément 5 et leurs utilisations
WO2020012337A1 (fr) 2018-07-10 2020-01-16 Novartis Ag Dérivés de 3-(5-amino-1-oxoisoindoline-2-yl)pipéridine-2,6-dione et leur utilisation dans le traitement de maladies dépendant des doigts de zinc 2 de la famille ikaros (ikzf2)
WO2020021465A1 (fr) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Procédé de traitement de tumeurs neuroendocrines
US10590197B2 (en) 2015-07-16 2020-03-17 Ucb Biopharma Sprl Antibody molecules which bind CD22
US10618957B2 (en) 2015-07-16 2020-04-14 Ucb Biopharma Sprl Antibody molecules which bind CD79
US10618979B2 (en) 2015-12-03 2020-04-14 Ucb Biopharma Sprl Multispecific antibodies
US10633457B2 (en) 2014-12-03 2020-04-28 Hoffmann-La Roche Inc. Multispecific antibodies
EP3660042A1 (fr) 2014-07-31 2020-06-03 Novartis AG Lymphocytes t contenant des récepteurs d'antigènes chimériques optimisés par sous-ensemble
WO2020128898A1 (fr) 2018-12-20 2020-06-25 Novartis Ag Combinaisons pharmaceutiques
WO2020128972A1 (fr) 2018-12-20 2020-06-25 Novartis Ag Schéma posologique et combinaison pharmaceutique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2020165833A1 (fr) 2019-02-15 2020-08-20 Novartis Ag Dérivés de 3-(1-oxo-5-(pipéridin-4-yl)isoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
WO2020165868A1 (fr) 2019-02-15 2020-08-20 Perkinelmer Cellular Technologies Germany Gmbh Pré-balayage d'objectif de microscope à faible puissance et balayage d'objectif de microscope à haute puissance dans une direction x, y et z pour imager des objets tels que des cellules à l'aide d'un microscope
WO2020165834A1 (fr) 2019-02-15 2020-08-20 Novartis Ag Dérivés de 3-(1-oxoisoindoline-2-yl)pipéridine-2,6-dione substitués et leurs utilisations
WO2020172553A1 (fr) 2019-02-22 2020-08-27 Novartis Ag Polythérapies à base de récepteurs d'antigènes chimériques egfrviii et d'inhibiteurs de pd -1
US10774157B2 (en) 2015-12-03 2020-09-15 UCB Biopharma SRL Multispecific antibodies
US10774152B2 (en) 2014-07-16 2020-09-15 Ucb Biopharma Sprl Molecules with specificity for CD45 and CD79
EP3712171A1 (fr) 2014-08-19 2020-09-23 Novartis AG Traitement du cancer à l'aide d'un récepteur d'antigène chimérique cd123
WO2020205523A1 (fr) 2019-03-29 2020-10-08 Atarga, Llc Anticorps anti-fgf23
EP3722316A1 (fr) 2014-07-21 2020-10-14 Novartis AG Traitement du cancer à l'aide d'un récepteur d'antigène chimérique cd33
US10829566B2 (en) 2015-12-03 2020-11-10 UCB Biopharma SRL Method employing bispecific antibodies
US10954312B2 (en) 2015-12-03 2021-03-23 UCB Biopharma SRL Method employing bispecific protein complex
US10982007B2 (en) 2010-12-23 2021-04-20 Roche Diagnostics Operations, Inc. Detection of a posttranslationally modified polypeptide by a bivalent binding agent
WO2021079195A1 (fr) 2019-10-21 2021-04-29 Novartis Ag Inhibiteurs de tim-3 et leurs utilisations
WO2021079188A1 (fr) 2019-10-21 2021-04-29 Novartis Ag Polythérapies comprenant du vénétoclax et des inhibiteurs de tim-3
WO2021108661A2 (fr) 2019-11-26 2021-06-03 Novartis Ag Récepteurs antigéniques chimériques et leurs utilisations
WO2021123902A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Combinaison d'anticorps anti-tim-3 mbg453 et d'anticorps anti-tgf-bêta nis793, avec ou sans décitabine ou l'anticorps anti pd-1 spartalizumab, pour le traitement de la myélofibrose et du syndrome myélodysplasique
US11046769B2 (en) 2018-11-13 2021-06-29 Compass Therapeutics Llc Multispecific binding constructs against checkpoint molecules and uses thereof
WO2021144657A1 (fr) 2020-01-17 2021-07-22 Novartis Ag Polythérapies comprenant un inhibiteur tim-3 et un agent d'hypométhylation à utiliser dans le traitement du syndrome myélodysplasique ou de la leucémie myélomonocytaire chronique
WO2021146636A1 (fr) 2020-01-17 2021-07-22 Becton, Dickinson And Company Procédés et compositions pour sécrétomique unicellulaire
WO2021173995A2 (fr) 2020-02-27 2021-09-02 Novartis Ag Procédés de production de cellules exprimant un récepteur antigénique chimérique
WO2021260528A1 (fr) 2020-06-23 2021-12-30 Novartis Ag Schéma posologique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2022013787A1 (fr) 2020-07-16 2022-01-20 Novartis Ag Anticorps anti-bêtacelluline, fragments de ceux-ci et molécules de liaison multi-spécifiques
WO2022026592A2 (fr) 2020-07-28 2022-02-03 Celltas Bio, Inc. Molécules d'anticorps contre le coronavirus et leurs utilisations
WO2022029573A1 (fr) 2020-08-03 2022-02-10 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione substitués par hétéroaryle et leurs utilisations
WO2022043557A1 (fr) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Méthode de traitement de cancers exprimant le psma
WO2022043558A1 (fr) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Méthode de traitement de cancers exprimant le psma
US11286312B2 (en) 2015-12-03 2022-03-29 UCB Biopharma SRL Multispecific antibodies
WO2022097065A2 (fr) 2020-11-06 2022-05-12 Novartis Ag Variants fc d'anticorps
WO2022104061A1 (fr) 2020-11-13 2022-05-19 Novartis Ag Polythérapies avec des cellules exprimant un récepteur antigénique chimérique (car)
JP2022528387A (ja) * 2019-03-29 2022-06-10 エフ．ホフマン－ラ ロシュ アーゲー アビド結合多重特異性抗体を作製する方法
WO2022162569A1 (fr) 2021-01-29 2022-08-04 Novartis Ag Régimes posologiques d'anticorps anti-cd73 et anti-entpd2 et leurs utilisations
US11421022B2 (en) 2012-06-27 2022-08-23 Hoffmann-La Roche Inc. Method for making antibody Fc-region conjugates comprising at least one binding entity that specifically binds to a target and uses thereof
RU2780436C2 (ru) * 2014-05-29 2022-09-23 Юсб Биофарма Срл Новый биспецифический формат, подходящий для применения в скрининге с высокой пропускной способностью
WO2022215011A1 (fr) 2021-04-07 2022-10-13 Novartis Ag UTILISATIONS D'ANTICORPS ANTI-TGFβ ET D'AUTRES AGENTS THÉRAPEUTIQUES POUR LE TRAITEMENT DE MALADIES PROLIFÉRATIVES
WO2022243846A1 (fr) 2021-05-18 2022-11-24 Novartis Ag Polythérapies
WO2023044483A2 (fr) 2021-09-20 2023-03-23 Voyager Therapeutics, Inc. Compositions et procédés pour le traitement du cancer positif her2
WO2023092004A1 (fr) 2021-11-17 2023-05-25 Voyager Therapeutics, Inc. Compositions et méthodes pour le traitement de troubles liés à tau
US11692041B2 (en) 2015-07-16 2023-07-04 UCB Biopharma SRL Antibody molecules which bind CD45
US11718679B2 (en) 2017-10-31 2023-08-08 Compass Therapeutics Llc CD137 antibodies and PD-1 antagonists and uses thereof
WO2023150778A1 (fr) 2022-02-07 2023-08-10 Visterra, Inc. Molécules d'anticorps anti-idiotype et leurs utilisations
US11752207B2 (en) 2017-07-11 2023-09-12 Compass Therapeutics Llc Agonist antibodies that bind human CD137 and uses thereof
WO2023209568A1 (fr) 2022-04-26 2023-11-02 Novartis Ag Anticorps multispécifiques ciblant il-13 et il-18
WO2023220695A2 (fr) 2022-05-13 2023-11-16 Voyager Therapeutics, Inc. Compositions et procédés pour le traitement du cancer her2 positif
US11851497B2 (en) 2017-11-20 2023-12-26 Compass Therapeutics Llc CD137 antibodies and tumor antigen-targeting antibodies and uses thereof
WO2024030976A2 (fr) 2022-08-03 2024-02-08 Voyager Therapeutics, Inc. Compositions et procédés permettant le franchissement de la barrière hémato-encéphalique
EP4324518A2 (fr) 2014-01-31 2024-02-21 Novartis AG Molécules d'anticorps anti-tim-3 et leurs utilisations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0336379A2 (fr) * 1988-04-04 1989-10-11 Oncogen Limited Partnership Hétéro-conjugués d'anticorps pour l'utilisation dans la régulation de l'activité de lymphocytes
EP0468637A1 (fr) * 1990-06-22 1992-01-29 Eli Lilly And Company ciblage in vivo à l'aide d'anticorps bifonctionnels
US6197298B1 (en) * 1991-04-19 2001-03-06 Tanox, Inc. Modified binding molecules specific for T lymphocytes and their use as in vivo immune modulators in animals
US6468530B1 (en) * 1994-08-05 2002-10-22 Immunomedics, Inc. Polyspecific immunoconjugates and antibody composites for targeting the multidrug resistant phenotype
WO2003002144A1 (fr) * 2001-06-26 2003-01-09 Imclone Systems Incorporated Anticorps bispecifiques se liant aux recepteurs vegf

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0336379A2 (fr) * 1988-04-04 1989-10-11 Oncogen Limited Partnership Hétéro-conjugués d'anticorps pour l'utilisation dans la régulation de l'activité de lymphocytes
EP0468637A1 (fr) * 1990-06-22 1992-01-29 Eli Lilly And Company ciblage in vivo à l'aide d'anticorps bifonctionnels
US6197298B1 (en) * 1991-04-19 2001-03-06 Tanox, Inc. Modified binding molecules specific for T lymphocytes and their use as in vivo immune modulators in animals
US6468530B1 (en) * 1994-08-05 2002-10-22 Immunomedics, Inc. Polyspecific immunoconjugates and antibody composites for targeting the multidrug resistant phenotype
WO2003002144A1 (fr) * 2001-06-26 2003-01-09 Imclone Systems Incorporated Anticorps bispecifiques se liant aux recepteurs vegf

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JAMES ND, ATHERTON PJ, JONES J, HOWIE AJ, TCHEKMEDYIAN S & CURNOW RT: "A Phase II Study of the Bispecific Antobody MDX-H210 (Anti-HER2 x CD64) with GM-CSF in HER2+ Advanced Prostate Cancer", BRITISH JOURNAL OF CANCER, vol. 85, no. 2, 20 July 2001 (2001-07-20), pages 152 - 156, XP008031136 *
POLJAK R J: "PRODUCTION AND STRUCTURE OF DIABODIES", 15 December 1994, STRUCTURE, CURRENT BIOLOGY LTD., PHILADELPHIA, PA, US, PAGE(S) 1121-1123, ISSN: 0969-2126, XP000563853 *

Cited By (133)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2129689A4 (fr) * 2007-03-07 2011-11-02 Next Biomed Technologies Nbt Oy Polypeptide de fusion permettant de détecter des épitopes combinatoires ou composites conservés dans des protéines non conservées
EP2129689A1 (fr) * 2007-03-07 2009-12-09 Next Biomed Technologies NBT Oy Polypeptide de fusion permettant de détecter des épitopes combinatoires ou composites conservés dans des protéines non conservées
US9994646B2 (en) 2009-09-16 2018-06-12 Genentech, Inc. Coiled coil and/or tether containing protein complexes and uses thereof
US10106600B2 (en) 2010-03-26 2018-10-23 Roche Glycart Ag Bispecific antibodies
US10982007B2 (en) 2010-12-23 2021-04-20 Roche Diagnostics Operations, Inc. Detection of a posttranslationally modified polypeptide by a bivalent binding agent
WO2012085111A1 (fr) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Complexe polypeptide-polynucléotide et son utilisation dans l'administration d'une fraction effectrice ciblée
WO2012085113A1 (fr) 2010-12-23 2012-06-28 Roche Diagnostics Gmbh Agent de liaison
US10633460B2 (en) 2010-12-23 2020-04-28 Roche Diagnostic Operations, Inc. Binding agent
US11618790B2 (en) 2010-12-23 2023-04-04 Hoffmann-La Roche Inc. Polypeptide-polynucleotide-complex and its use in targeted effector moiety delivery
US9688758B2 (en) 2012-02-10 2017-06-27 Genentech, Inc. Single-chain antibodies and other heteromultimers
WO2014001326A1 (fr) 2012-06-27 2014-01-03 F. Hoffmann-La Roche Ag Procédé de sélection et de production de molécules thérapeutiques multi-spécifiques, sélectives et personnalisées comprenant au moins deux entités de ciblage différentes et leurs utilisations
US10106612B2 (en) 2012-06-27 2018-10-23 Hoffmann-La Roche Inc. Method for selection and production of tailor-made highly selective and multi-specific targeting entities containing at least two different binding entities and uses thereof
US11421022B2 (en) 2012-06-27 2022-08-23 Hoffmann-La Roche Inc. Method for making antibody Fc-region conjugates comprising at least one binding entity that specifically binds to a target and uses thereof
US11407836B2 (en) 2012-06-27 2022-08-09 Hoffmann-La Roche Inc. Method for selection and production of tailor-made highly selective and multi-specific targeting entities containing at least two different binding entities and uses thereof
EP3514179A1 (fr) 2014-01-24 2019-07-24 Dana-Farber Cancer Institute, Inc. Molécules d'anticorps anti-pd-1 et leurs utilisations
EP4324518A2 (fr) 2014-01-31 2024-02-21 Novartis AG Molécules d'anticorps anti-tim-3 et leurs utilisations
EP3660050A1 (fr) 2014-03-14 2020-06-03 Novartis AG Molécules d'anticorps anti-lag-3 et leurs utilisations
WO2015138920A1 (fr) 2014-03-14 2015-09-17 Novartis Ag Molécules d'anticorps anti-lag-3 et leurs utilisations
WO2015142675A2 (fr) 2014-03-15 2015-09-24 Novartis Ag Traitement du cancer au moyen d'un récepteur antigénique chimérique
EP3750915A1 (fr) * 2014-05-29 2020-12-16 UCB Biopharma SRL Nouveau format bispécifique approprié pour une utilisation dans le criblage très haut débit
WO2015181282A1 (fr) * 2014-05-29 2015-12-03 Ucb Biopharma Sprl Nouveau format bispécifique adapté pour être utilisé dans le criblage à haut débit
CN106459220A (zh) * 2014-05-29 2017-02-22 Ucb生物制药私人有限公司 适用于高通量筛选的新的双特异性形式
KR20170012309A (ko) * 2014-05-29 2017-02-02 유씨비 바이오파마 에스피알엘 고처리율 스크리닝에서의 사용에 적합한 신규 이중특이적 포맷
RU2780436C2 (ru) * 2014-05-29 2022-09-23 Юсб Биофарма Срл Новый биспецифический формат, подходящий для применения в скрининге с высокой пропускной способностью
US10358493B2 (en) 2014-05-29 2019-07-23 Ucb Biopharma Sprl Bispecific format suitable for use in high-through-put screening
KR102472643B1 (ko) 2014-05-29 2022-11-29 유씨비 바이오파마 에스알엘 고처리율 스크리닝에서의 사용에 적합한 신규 이중특이적 포맷
CN113480663A (zh) * 2014-05-29 2021-10-08 Ucb生物制药有限责任公司 适用于高通量筛选的新的双特异性形式
US10774152B2 (en) 2014-07-16 2020-09-15 Ucb Biopharma Sprl Molecules with specificity for CD45 and CD79
US11261252B2 (en) 2014-07-16 2022-03-01 UCB Biopharma SRL Molecules with specificity for CD79 and CD22
US10370447B2 (en) 2014-07-16 2019-08-06 Ucb Biopharma Sprl Molecules with specificity for CD79 and CD22
WO2016014565A2 (fr) 2014-07-21 2016-01-28 Novartis Ag Traitement du cancer au moyen d'un récepteur d'antigène chimérique anti-bcma humanisé
WO2016014553A1 (fr) 2014-07-21 2016-01-28 Novartis Ag Récepteurs d'antigènes chimères synthétisés par l'intermédiaire d'une sortase
EP3722316A1 (fr) 2014-07-21 2020-10-14 Novartis AG Traitement du cancer à l'aide d'un récepteur d'antigène chimérique cd33
WO2016014530A1 (fr) 2014-07-21 2016-01-28 Novartis Ag Combinaisons de faibles doses renforçant l'immunité d'inhibiteurs de mtor et car
EP3660042A1 (fr) 2014-07-31 2020-06-03 Novartis AG Lymphocytes t contenant des récepteurs d'antigènes chimériques optimisés par sous-ensemble
EP4205749A1 (fr) 2014-07-31 2023-07-05 Novartis AG Cellules contenant un récepteur d'antigène chimérique optimisé en sous-ensemble
WO2016025880A1 (fr) 2014-08-14 2016-02-18 Novartis Ag Traitement du cancer à l'aide du récepteur d'antigène chimérique gfr alpha-4
EP3712171A1 (fr) 2014-08-19 2020-09-23 Novartis AG Traitement du cancer à l'aide d'un récepteur d'antigène chimérique cd123
EP3967709A1 (fr) 2014-09-17 2022-03-16 Novartis AG Ciblage de cellules cytotoxiques avec récepteurs chimériques pour immunothérapie adoptive
WO2016044605A1 (fr) 2014-09-17 2016-03-24 Beatty, Gregory Ciblage de cellules cytotoxiques avec des récepteurs chimériques pour l'immunothérapie adoptive
WO2016061142A1 (fr) 2014-10-14 2016-04-21 Novartis Ag Molécules d'anticorps de pd-l1 et leurs utilisations
EP4245376A2 (fr) 2014-10-14 2023-09-20 Novartis AG Molécules d'anticorps de pd-l1 et leurs utilisations
WO2016090034A2 (fr) 2014-12-03 2016-06-09 Novartis Ag Méthodes de pré-conditionnement de cellules b dans une thérapie car
US10633457B2 (en) 2014-12-03 2020-04-28 Hoffmann-La Roche Inc. Multispecific antibodies
WO2016164731A2 (fr) 2015-04-08 2016-10-13 Novartis Ag Thérapies anti-cd20, thérapies anti-cd22, et polythérapies comprenant une cellule exprimant le récepteur antigénique chimérique (car) dirigé contre le cd19
EP4056588A1 (fr) 2015-04-08 2022-09-14 Novartis AG Thérapies cd20, thérapies cd22 et thérapies combinées avec une cellule exprimant un récepteur d'antigène chimérique cd19 (car)
WO2016172583A1 (fr) 2015-04-23 2016-10-27 Novartis Ag Traitement du cancer à l'aide de protéine récepteur antigénique chimérique et un inhibiteur de protéine kinase
US11692041B2 (en) 2015-07-16 2023-07-04 UCB Biopharma SRL Antibody molecules which bind CD45
US10590197B2 (en) 2015-07-16 2020-03-17 Ucb Biopharma Sprl Antibody molecules which bind CD22
US10618957B2 (en) 2015-07-16 2020-04-14 Ucb Biopharma Sprl Antibody molecules which bind CD79
US11472879B2 (en) 2015-07-16 2022-10-18 UCB Biopharma SRL Antibody molecules which bind CD22
WO2017019897A1 (fr) 2015-07-29 2017-02-02 Novartis Ag Polythérapies comprenant des molécules d'anticorps contre tim -3
EP3878465A1 (fr) 2015-07-29 2021-09-15 Novartis AG Polythérapies comprenant des molécules d'anticorps tim-3
EP3964528A1 (fr) 2015-07-29 2022-03-09 Novartis AG Polythérapies comprenant des molécules d'anticorps dirigées contre lag-3
WO2017019894A1 (fr) 2015-07-29 2017-02-02 Novartis Ag Polythérapies comprenant des molécules d'anticorps dirigées contre lag-3
US10774157B2 (en) 2015-12-03 2020-09-15 UCB Biopharma SRL Multispecific antibodies
US10829566B2 (en) 2015-12-03 2020-11-10 UCB Biopharma SRL Method employing bispecific antibodies
US11286312B2 (en) 2015-12-03 2022-03-29 UCB Biopharma SRL Multispecific antibodies
US10954312B2 (en) 2015-12-03 2021-03-23 UCB Biopharma SRL Method employing bispecific protein complex
US10618979B2 (en) 2015-12-03 2020-04-14 Ucb Biopharma Sprl Multispecific antibodies
WO2017106810A2 (fr) 2015-12-17 2017-06-22 Novartis Ag Combinaison d'un inhibiteur de c-met avec une molécule d'anticorps dirigée contre pd-1 et ses utilisations
WO2017106656A1 (fr) 2015-12-17 2017-06-22 Novartis Ag Molécules d'anticorps anti-pd-1 et leurs utilisations
WO2017125897A1 (fr) 2016-01-21 2017-07-27 Novartis Ag Molécules multispécifiques ciblant cll-1
EP3851457A1 (fr) 2016-01-21 2021-07-21 Novartis AG Molécules multispécifiques ciblant cll-1
WO2017149515A1 (fr) 2016-03-04 2017-09-08 Novartis Ag Cellules exprimant de multiples molécules de récepteur d'antigène chimère (car) et leurs utilisations
WO2017165683A1 (fr) 2016-03-23 2017-09-28 Novartis Ag Mini-corps sécrétés par des cellules et leurs usages
EP4219721A2 (fr) 2016-04-15 2023-08-02 Novartis AG Compositions et procédés pour l'expression sélective de protéines
WO2017181119A2 (fr) 2016-04-15 2017-10-19 Novartis Ag Compositions et méthodes pour l'expression sélective d'une protéine
WO2017210617A2 (fr) 2016-06-02 2017-12-07 Porter, David, L. Régimes thérapeutiques pour cellules exprimant un récepteur antigénique chimérique (car)
WO2018013918A2 (fr) 2016-07-15 2018-01-18 Novartis Ag Traitement et prévention du syndrome de libération de cytokine à l'aide d'un récepteur d'antigène chimérique en combinaison avec un inhibiteur de kinase
WO2018023025A1 (fr) 2016-07-28 2018-02-01 Novartis Ag Polythérapies de récepteurs d'antigènes chimériques adn inhibiteurs pd -1
WO2018026819A2 (fr) 2016-08-01 2018-02-08 Novartis Ag Traitement du cancer au moyen d'un récepteur d'antigène chimérique en combinaison avec un inhibiteur d'une molécule de macrophage pro-m2
WO2018067992A1 (fr) 2016-10-07 2018-04-12 Novartis Ag Récepteurs antigéniques chimériques pour le traitement du cancer
EP4043485A1 (fr) 2017-01-26 2022-08-17 Novartis AG Compositions de cd28 et procédés pour une thérapie à base de récepteur antigénique chimérique
WO2018140725A1 (fr) 2017-01-26 2018-08-02 Novartis Ag Compositions de cd28 et procédés pour une thérapie à base de récepteur antigénique chimérique
WO2018160731A1 (fr) 2017-02-28 2018-09-07 Novartis Ag Compositions d'inhibiteur shp et utilisations pour une thérapie de récepteur d'antigène chimère
WO2018201051A1 (fr) 2017-04-28 2018-11-01 Novartis Ag Agent ciblant le bcma et polythérapie incluant un inhibiteur de gamma-sécrétase
WO2018201056A1 (fr) 2017-04-28 2018-11-01 Novartis Ag Cellules exprimant un récepteur antigénique chimérique ciblant le bcma, et polythérapie comprenant un inhibiteur de gamma sécrétase
WO2018237157A1 (fr) 2017-06-22 2018-12-27 Novartis Ag Molécules d'anticorps se liant à cd73 et leurs utilisations
WO2019006007A1 (fr) 2017-06-27 2019-01-03 Novartis Ag Régimes posologiques pour anticorps anti-tim3 et leurs utilisations
US11752207B2 (en) 2017-07-11 2023-09-12 Compass Therapeutics Llc Agonist antibodies that bind human CD137 and uses thereof
WO2019018730A1 (fr) 2017-07-20 2019-01-24 Novartis Ag Régimes posologiques pour des anticorps anti-lag3 et leurs utilisations
US11718679B2 (en) 2017-10-31 2023-08-08 Compass Therapeutics Llc CD137 antibodies and PD-1 antagonists and uses thereof
WO2019089798A1 (fr) 2017-10-31 2019-05-09 Novartis Ag Compositions anti-car et procédés
WO2019099838A1 (fr) 2017-11-16 2019-05-23 Novartis Ag Polythérapies
US11851497B2 (en) 2017-11-20 2023-12-26 Compass Therapeutics Llc CD137 antibodies and tumor antigen-targeting antibodies and uses thereof
WO2019152660A1 (fr) 2018-01-31 2019-08-08 Novartis Ag Polythérapie utilisant un récepteur antigénique chimérique
WO2019200229A1 (fr) 2018-04-13 2019-10-17 Novartis Ag Régimes posologiques pour anticorps anti-pd-l1 et utilisations associées
WO2019210153A1 (fr) 2018-04-27 2019-10-31 Novartis Ag Thérapies reposant sur des cellules car-t présentant une efficacité améliorée
WO2019226617A1 (fr) 2018-05-21 2019-11-28 Compass Therapeutics Llc Compositions et procédés pour améliorer la destruction de cellules cibles par des lymphocytes nk
WO2019226658A1 (fr) 2018-05-21 2019-11-28 Compass Therapeutics Llc Compositions multispécifiques de liaison à l'antigène et procédés d'utilisation
WO2019227003A1 (fr) 2018-05-25 2019-11-28 Novartis Ag Polythérapie comprenant des thérapies par récepteur antigénique chimérique (car)
WO2019232244A2 (fr) 2018-05-31 2019-12-05 Novartis Ag Molécules d'anticorps anti-cd73 et leurs utilisations
WO2019241426A1 (fr) 2018-06-13 2019-12-19 Novartis Ag Récepteurs d'antigènes chimériques bcma et leurs utilisations
WO2019246293A2 (fr) 2018-06-19 2019-12-26 Atarga, Llc Molécules d'anticorps se liant au composant du complément 5 et leurs utilisations
WO2020012337A1 (fr) 2018-07-10 2020-01-16 Novartis Ag Dérivés de 3-(5-amino-1-oxoisoindoline-2-yl)pipéridine-2,6-dione et leur utilisation dans le traitement de maladies dépendant des doigts de zinc 2 de la famille ikaros (ikzf2)
WO2020021465A1 (fr) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Procédé de traitement de tumeurs neuroendocrines
US11046769B2 (en) 2018-11-13 2021-06-29 Compass Therapeutics Llc Multispecific binding constructs against checkpoint molecules and uses thereof
WO2020128898A1 (fr) 2018-12-20 2020-06-25 Novartis Ag Combinaisons pharmaceutiques
WO2020128972A1 (fr) 2018-12-20 2020-06-25 Novartis Ag Schéma posologique et combinaison pharmaceutique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2020165834A1 (fr) 2019-02-15 2020-08-20 Novartis Ag Dérivés de 3-(1-oxoisoindoline-2-yl)pipéridine-2,6-dione substitués et leurs utilisations
WO2020165833A1 (fr) 2019-02-15 2020-08-20 Novartis Ag Dérivés de 3-(1-oxo-5-(pipéridin-4-yl)isoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
WO2020165868A1 (fr) 2019-02-15 2020-08-20 Perkinelmer Cellular Technologies Germany Gmbh Pré-balayage d'objectif de microscope à faible puissance et balayage d'objectif de microscope à haute puissance dans une direction x, y et z pour imager des objets tels que des cellules à l'aide d'un microscope
WO2020172553A1 (fr) 2019-02-22 2020-08-27 Novartis Ag Polythérapies à base de récepteurs d'antigènes chimériques egfrviii et d'inhibiteurs de pd -1
WO2020205523A1 (fr) 2019-03-29 2020-10-08 Atarga, Llc Anticorps anti-fgf23
JP2022528387A (ja) * 2019-03-29 2022-06-10 エフ．ホフマン－ラ ロシュ アーゲー アビド結合多重特異性抗体を作製する方法
JP7412440B2 (ja) 2019-03-29 2024-01-12 エフ． ホフマン－ラ ロシュ アーゲー アビド結合多重特異性抗体を作製する方法
WO2021079195A1 (fr) 2019-10-21 2021-04-29 Novartis Ag Inhibiteurs de tim-3 et leurs utilisations
WO2021079188A1 (fr) 2019-10-21 2021-04-29 Novartis Ag Polythérapies comprenant du vénétoclax et des inhibiteurs de tim-3
WO2021108661A2 (fr) 2019-11-26 2021-06-03 Novartis Ag Récepteurs antigéniques chimériques et leurs utilisations
WO2021123996A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Utilisations d'anticorps anti-tgf-bêtas et inhibiteurs de point de contrôle pour le traitement des maladies prolifératives
WO2021123902A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Combinaison d'anticorps anti-tim-3 mbg453 et d'anticorps anti-tgf-bêta nis793, avec ou sans décitabine ou l'anticorps anti pd-1 spartalizumab, pour le traitement de la myélofibrose et du syndrome myélodysplasique
WO2021146636A1 (fr) 2020-01-17 2021-07-22 Becton, Dickinson And Company Procédés et compositions pour sécrétomique unicellulaire
WO2021144657A1 (fr) 2020-01-17 2021-07-22 Novartis Ag Polythérapies comprenant un inhibiteur tim-3 et un agent d'hypométhylation à utiliser dans le traitement du syndrome myélodysplasique ou de la leucémie myélomonocytaire chronique
WO2021173995A2 (fr) 2020-02-27 2021-09-02 Novartis Ag Procédés de production de cellules exprimant un récepteur antigénique chimérique
WO2021260528A1 (fr) 2020-06-23 2021-12-30 Novartis Ag Schéma posologique comprenant des dérivés de 3-(1-oxoisoindoline-2-yl) pipéridine-2,6-dione
WO2022013787A1 (fr) 2020-07-16 2022-01-20 Novartis Ag Anticorps anti-bêtacelluline, fragments de ceux-ci et molécules de liaison multi-spécifiques
WO2022026592A2 (fr) 2020-07-28 2022-02-03 Celltas Bio, Inc. Molécules d'anticorps contre le coronavirus et leurs utilisations
WO2022029573A1 (fr) 2020-08-03 2022-02-10 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione substitués par hétéroaryle et leurs utilisations
WO2022043558A1 (fr) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Méthode de traitement de cancers exprimant le psma
WO2022043557A1 (fr) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Méthode de traitement de cancers exprimant le psma
WO2022097065A2 (fr) 2020-11-06 2022-05-12 Novartis Ag Variants fc d'anticorps
WO2022104061A1 (fr) 2020-11-13 2022-05-19 Novartis Ag Polythérapies avec des cellules exprimant un récepteur antigénique chimérique (car)
WO2022162569A1 (fr) 2021-01-29 2022-08-04 Novartis Ag Régimes posologiques d'anticorps anti-cd73 et anti-entpd2 et leurs utilisations
WO2022215011A1 (fr) 2021-04-07 2022-10-13 Novartis Ag UTILISATIONS D'ANTICORPS ANTI-TGFβ ET D'AUTRES AGENTS THÉRAPEUTIQUES POUR LE TRAITEMENT DE MALADIES PROLIFÉRATIVES
WO2022243846A1 (fr) 2021-05-18 2022-11-24 Novartis Ag Polythérapies
US11970538B2 (en) 2021-05-20 2024-04-30 Compass Therapeutics Llc Multispecific binding constructs against checkpoint molecules and uses thereof
WO2023044483A2 (fr) 2021-09-20 2023-03-23 Voyager Therapeutics, Inc. Compositions et procédés pour le traitement du cancer positif her2
WO2023092004A1 (fr) 2021-11-17 2023-05-25 Voyager Therapeutics, Inc. Compositions et méthodes pour le traitement de troubles liés à tau
WO2023150778A1 (fr) 2022-02-07 2023-08-10 Visterra, Inc. Molécules d'anticorps anti-idiotype et leurs utilisations
WO2023209568A1 (fr) 2022-04-26 2023-11-02 Novartis Ag Anticorps multispécifiques ciblant il-13 et il-18
WO2023220695A2 (fr) 2022-05-13 2023-11-16 Voyager Therapeutics, Inc. Compositions et procédés pour le traitement du cancer her2 positif
WO2024030976A2 (fr) 2022-08-03 2024-02-08 Voyager Therapeutics, Inc. Compositions et procédés permettant le franchissement de la barrière hémato-encéphalique

Also Published As

Publication number Publication date
GB0305702D0 (en) 2003-04-16

Similar Documents

Publication Publication Date Title
WO2004081051A1 (fr) Anticorps specifiques
JP2024050548A (ja) Ｃｄ４７に対するヒト化及びキメラモノクローナル抗体
CN109963591B (zh) B7h3抗体-药物偶联物及其医药用途
JP3803790B2 (ja) 新規なダイアボディ型二重特異性抗体
CN109096401B (zh) 抗Her2纳米抗体及其编码序列和用途
AU2012227883A1 (en) Bi- and monospecific, asymmetric antibodies and methods of generating the same
WO2007108152A1 (fr) Anticorps bispecifique hautement fonctionnel
MX2010011955A (es) Inmunoglobulinas de dominio variable doble y usos de las mismas.
US20050123900A1 (en) Identification of novel broadly cross-reactive neutralizing human monoclonal antibodies using sequential antigen panning of phage display libraries
CN112830969B (zh) 一种特异性结合人Claudin18.2的单克隆抗体及包含其的药物和试剂盒
US20230212273A1 (en) Chimeric antibodies for treatment of amyloid deposition diseases
CN114502591A (zh) 靶向bcma的抗体、双特异性抗体及其用途
CN113321734A (zh) 抗cd47/抗pd-l1抗体及其应用
WO2012144692A1 (fr) Anticorps anti-emap ii humanisé et utilisation associée
CN1946425B (zh) B细胞疾病的靶
CN109879966B (zh) 基于鼠源cd19抗体的人源化设计及表达验证
JP2005333993A (ja) 新規なダイアボディ型二重特異性抗体
CN113461821B (zh) 抗cd3人源化抗体
CN115109156B (zh) 一种靶向bcma的纳米抗体及其应用
CN114763383A (zh) 靶向人bcma的单克隆抗体及其应用
CN113321730B (zh) Cldn18.2抗体及其应用
CN117430708B (zh) 一种抗Claudin18.2抗体
CN116003598B (zh) 靶向人gprc5d的重组人源化单克隆抗体及其应用
US20230287143A1 (en) Binding protein in fab-hcab structure
WO2023178645A1 (fr) Anticorps ciblant cd3 et son utilisation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase