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WO2004056873A1 - Accroissement de la reponse immunitaire par des substances qui influencent la fonction de cellules k naturelles - Google Patents

Accroissement de la reponse immunitaire par des substances qui influencent la fonction de cellules k naturelles Download PDF

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Publication number
WO2004056873A1
WO2004056873A1 PCT/DE2003/004268 DE0304268W WO2004056873A1 WO 2004056873 A1 WO2004056873 A1 WO 2004056873A1 DE 0304268 W DE0304268 W DE 0304268W WO 2004056873 A1 WO2004056873 A1 WO 2004056873A1
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Prior art keywords
active ingredient
cells
hla
cell
antibody
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Legal status (The legal status 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 status listed.)
Ceased
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PCT/DE2003/004268
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German (de)
English (en)
Inventor
Markus Jensen
Hans-Harald Sedlacek
Frank Berthold
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Medinnova Gesellschaft fuer Medizinische Innovationen aus Akademischer Forschung mbH,
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Medinnova Gesellschaft fuer Medizinische Innovationen aus Akademischer Forschung mbH,
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Priority to EP03813541A priority Critical patent/EP1590370A1/fr
Priority to AU2003296553A priority patent/AU2003296553A1/en
Publication of WO2004056873A1 publication Critical patent/WO2004056873A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the invention relates to active substances and pharmaceutical compositions which stimulate the immune system.
  • the immune response against infectious agents and tumors can be divided into an innate defense, in which the natural killer cells play a special role, and an acquired antigen-specific defense, in which cytotoxic T-lymphocytes and specific antibodies play a central role.
  • NK cells Natural killer cells
  • TCR T cell receptor
  • the NK1.1 T cells are said to have a regulatory, in some cases inhibitory, effect on cytotoxic T cells, in particular in autoimmune reactions (Zhang et al., J Exp Med 186: 1677-1687, (1997); Ben - lagha et al., Science 296: 481-482, (2002); Shlomai et al., J Path 195: 498-507, (2001)).
  • the human correlate of the NKl .1 T cell is not yet known.
  • NK cells are enriched in the placenta and may appear to play a role in controlling placentation here. However, it is completely unknown how the NK cells could play this role (Mofett-King Nature Reviews Immunology
  • NK cells 15 2/9; 656-663, 2002.
  • those receptors on NK cells have already been analyzed with the aid of which NK cells can interact with ligands on cells of the allogeneic placenta, in particular the extravillous trophoblast cells.
  • ligands include
  • NK cells are able to kill tumor cells.
  • Experiments on mouse tumor models have shown that removal of NK cells leads to an increase in tumor growth (Karre et al., Nature 319: 675-678 (1986); Smyth et al., Nature Immunol. 2: 293 -299 (2001)).
  • the number of CD57 positive lymphocytes (which include NK cells) in the tumor was directly correlated with survival time (Villegas et al., Lung Cancer 35: 23-28, (2002)). The same could be demonstrated for gastric carcinoma (Ishigami et al. F Cancer 20 88: 577-583, (2000)).
  • NK cells play a decisive role in the induction of cytotoxic T cells and in the control of viral infections. So it was
  • NK cells 30 which no NK cells were detectable (Biron et al., N. Engl. J. Med. 320, 1731-1735 (1989).
  • CMV infections are known to cause the expression of MHC class I Down-regulate molecules as well Express substances that are believed to inhibit NK cells. These substances include UL18, UL40 and UL16 (overview from: Cerwenka et al., Nature Reviews Immunology 1: 41-49, (2001)).
  • NK cells are therefore particularly cytotoxically active for those cells which do not expose MHC class I molecules on their cell membrane.
  • the cytotoxicity-inhibiting receptors on the NK cells could be identified in the mouse Ly49 and CD94 / NKG2A and in humans KIR2DL, KIR3DL, CD 159a, CD853 and CD85d (review by: Cerwenka et al., Nature Reviews Immunology 1: 41- 49 (2001)).
  • NK cells are able to kill tumor cells, although they express MHC class I molecules.
  • the cause was identified on the membrane of NK cells, the cytotoxicity-activating receptors, the activation of which clearly dominates the inhibition by the cytotoxicity-inhibiting receptors of NK cells.
  • These cytotoxicity-activating receptors include NKR-P1C, Ly49D, Ly49H in the mouse and CD16, NKp30, NKp46, KIR2DS, CD94 / NKG2C, NKp44, NKG2D, and CD244 in humans (review by: Cerwenka et al., Nature Reviews Immunology 1: 41-49 (2001)).
  • NK cells The activation of NK cells is thought to be caused by the concerted action of these cytotoxicity-activating receptors with cytokm receptors, adhesion molecules and chemokm receptors (Cerwenka et al., Nature Reviews Immunology 1: 41-49 (2001))
  • Human NK cells are known to express the adhesion molecule N-CAM (CD56, Leu-19, NKHl) and additionally CD7, CD38, CDIla, CDllb and CD45RA.
  • CDllc and CD57 is heterogeneous and variable. After activation, the expression of CDIIa, CD38 and HLADR is increased and CD11b and CD45RA are decreased.
  • Chronically activated NK cells additionally express particularly CD2 and CD57 (Lima et al., Blood Cells Mol Dis 28: 181-190, 2002)).
  • N-CAM is not only found on NK cells, but also on T cells, on nerve cells, and especially on tumor cells of the neuroectoderm (CNS tumors, melanomas, small cell bronchial carcinoma).
  • Antibodies against N-CAM can inhibit the growth of neuroblastoma cells and cells
  • Inhibit glioblasto cells (Krushel et al., PN ⁇ S USA, 95: 2592-2596, (1998); Dehal et al., Biochem. Soc. Trans 30/4: 518-520, (2002)) and thus for diagnostics and therapy of these tumors can be used.
  • the invention is based on the technical problem of specifying pharmaceutical compositions for stimulating the immune system.
  • the invention teaches in particular active ingredients and pharmaceutical compositions according to the claims.
  • the invention is based based on the surprising finding that the inhibition of the function of human NK cells by an inhibiting active ingredient leads to an increase in the antigen-specific immune defense.
  • the invention thus also relates to a method for strengthening the immune defense, the function of NK cells being inhibited by at least one active ingredient.
  • Active substance in the sense of the invention is a binding substance which binds to an NK cell and inhibits it, or a substance which, after administration in an organism, causes the formation of a binding substance in this organism which binds to an NK cell and inhibits it.
  • the invention is based on the further surprising finding that the antigen-specific immune defense is particularly enhanced when the binding substance according to this invention is coupled to a molecule which binds to a T lymphocyte.
  • a molecule which binds to a T lymphocyte can be antigens, cytokines, chemokines, growth factors or antibodies, or fragments of antibodies which bind to the T cell receptor, to an adhesion molecule, to a cytokine receptor or to a chemokine receptor Bind T cells.
  • CD2 Molecules which are preferably used on CD2, CD3, CD4, CD44, CD69, CD5, CD6, CD7, CD8, CD9, CD25, CD26, CD27, CD28, CD30, CD31, CD37, CD38, CD45RA, CD45RB, CD49a, CD49d, CD49f, CD50, CD52, CDw60, CD621, CD70, CD73, CD75, CD76, CD83, CD87, CD89, CD90, CD94, CD96, CD97, CD98, CD99, CD101, CD107a, CD107b, CD109, CD121a, CD121b, CD122, CD124, CD127, CDwl28, CD132, CD134, CDwl37, CD148, CD152, CD153, CD154, CD155, CD160, CD161, CD166, CD226, CD245, CD246, CD247, or to a component of the T cell receptor complex tie.
  • the invention is further based on the surprising finding that the strengthening of the antigen-specific immune defense by
  • active substances according to the invention which are binding substances, are ligands which, by binding to inhibiting receptors of NK cells, inhibit their function.
  • the inhibitory receptors on NK cells and the associated ligands include:
  • binding substances are: partial sequences of these ligands and peptidomimetics of these ligands which bind to inhibiting receptors of the NK cells and inhibit their function, antibodies, antibody fragments and fusion proteins containing at least one antibody or an antibody fragment which bind to the inhibiting receptors of NK cells bind and inhibit their function, substances that inhibit their function by binding to activating receptors of the NK cells.
  • Activating receptors on NK cells and the associated ligands include:
  • UL16 Binding Proteins (ULBPl, -2, -3)
  • the binding substances within the meaning of the invention include mutations or cleavage products or peptidomimetics of the ligands for activating receptors on NK cells which bind to activating receptors on NK cells without activating them, antibodies, antibody fragments or fusion proteins containing at least one antibody or an antibody fragment which bind to activating receptors on NK cells without activating them or which ligands bind to activating receptors and inhibit their binding to these receptors, the ULI ⁇ protein of the CMV, which binds to ULBP-1, ULBP-2 and to MICB, homologs of the UL16 protein and peptidomimetics of the ULl ⁇ protein, antibodies, antibody fragments or fusion proteins containing at least one antibody or at least one antibody fragment which bind to an adhesion molecule on NK cells and thereby inhibits the function of the NK cell.
  • Adhesion molecules of this type are, for example, N-CAM (CD56) and CD57.
  • Examples of antibody fragments specific for an adhesion molecule are peptide sequences which bind to N-CAM and are described by Whittington et al., Medical and Pediatric Oncology 36: 243-246 (2001).
  • Examples of active substances in the sense of the invention which can trigger the formation of a binding substance in the sense of this invention in an organism are membrane components of NK cells which, after injection into an organism, lead to a specific immune reaction, in particular to the appearance of antibodies, which bind to inhibiting receptors on NK cells, or to adhesion molecules on NK cells and thereby inhibit the function of NK cells, ligands for activating receptors on NK cells and complexes of at least one ligand and at least one activating receptor, which after injection in an organism lead to a specific immune reaction, in particular to the appearance of antibodies which inhibit the activation of the activating receptors on NK cells.
  • Active substances in the sense of the invention are added to line preparations from the blood, from organs or from body cavities.
  • Such cell preparations are, for example Leukocyte preparations or lymphocyte preparations.
  • the preparation of such cell preparations from the blood, from organs or from body cavities is familiar to the person skilled in the art.
  • the mixture of this cell preparation and the active ingredient is then administered to an organism in order to strengthen its antigen-specific immune response.
  • Active substances in the sense of the invention are also used as medicaments.
  • the active ingredient according to the invention is mixed with a suitable pharmaceutical auxiliary known to the person skilled in the art.
  • Such pharmaceutical auxiliaries can be, for example, physiological aqueous injection solutions.
  • Active ingredients which are injected in order to produce an immune reaction, in particular an antibody reaction are preferably treated with an ad uvans.
  • adjuvants are aluminum hydroxide or CpG.
  • Medicaments containing an active ingredient according to the invention are administered locally or injected into the bloodstream, into an organ, into a body cavity, into the connective tissue or into the muscles for the prophylaxis or therapy of a disease. Examples of such diseases or therapies are explained below.
  • Active substances according to this invention can be used for T-cell-mediated immunotherapy of malignant tumors.
  • all T cells of the body can be activated; the specificity of the T cell receptor is irrelevant for T cell activation.
  • T cells activated in this way are able to inhibit tumor growth.
  • the inhibition of Tumor growth can be achieved directly by cytotoxically active T cells or indirectly, by activating other components of the immunological network, such as B cells or macrophages.
  • an immunological memory can be built up.
  • T cells In the case of direct antitumor activity of cytotoxic T cells, the tumor cells are attacked by T cells which either use their tumor-specific T Zeil receptor or, regardless of their TcR specificity, use tumor-specific antibodies or tumor and T cell (bi-) specific antibodies or fusion proteins recognize the tumor.
  • Active substances according to the invention can furthermore be used for the therapy of conditions of the T cell deficiency or the T cell underfunction.
  • a decrease in T cell function occurs in various diseases, e.g. as a result of chemotherapy, radio therapy or immunotherapy, under medicinal immunosuppressive therapy, as an accompanying condition of diseases that affect the spleen, lymph nodes or bone marrow, in the case of congenital immune defects or as a concomitant symptom of hematological neoplasia, chronic inflammation reactions or infections.
  • NK cell activity against NK cells in diseases with benign or malignant NK cell proliferation Benign or malignant proliferative diseases of the NK cell system, such as chronic NK cell lymphocytosis, NK cell leukemia or that NK cell lymphoma can preferably be treated with active substances according to the invention which simultaneously have a molecule Bind NK cells as well as a molecule on T cells. These active substances suppress the NK cells, thereby strengthen the T cell activity and target it to NK cells.
  • autoimmune diseases the cause of which is an NK cell hyperfunction
  • Another preferred area of application of an active substance according to the invention is those autoimmune diseases in which overactivity of the NK cells and a consequent malregulation of the T cells occurs.
  • These autoimmune diseases include so-called antibody mediated autoimmune diseases, such as the myasthenia gravis or an allergy.
  • Example 1 Correlation of NK cell depletion to T cell proliferation.
  • PBMCs mononuclear leukocytes
  • Anti-NCAM antibody (clone ERIC-1) were used in a concentration of 1000 ng / ml, as well as anti-CD3 (clone 0KT3) and anti-CD28 antibody (clone 15E8) to specify a T-cell-specific stimulus.
  • the leukocyte subpopulations were determined in the flow cytometer.
  • CD4-FITC, CD8-FITC and CD16-PE conjugated antibodies (Becton Dickmson, Heidelberg, Germany) were used for staining. The measurement was carried out in a FACSCalibur TM flow cytometer (Becton Dickmson) using TruCount TM measuring tubes (Becton Dickmson) to determine the absolute cell numbers.
  • T cells showed a marked increase in their proliferation.
  • the proliferation indices were between 1.14 and 1.73.
  • the correlation value was -0.727.
  • Example 2 Increase in T-cell proliferation by anti-NCAM antibodies which additionally bind to T-lymphocytes.
  • T cell proliferation could be achieved by antibodies that bind to NCAM and CD3 on T cells simultaneously.
  • a bispecific antibody was additionally tested with a specificity against NCAM and against CD3 (clone OE-1). This bispecific antibody was again used in a concentration of 1000 ng / ml together with an anti-CD28 antibody (clone 15E8).
  • the experiments were carried out as described in Example 1, the calculated T cell number being the technical one
  • CD8 + (bright) and CD8 + (dim) population plus the CD4 + cells are based.
  • the mean of the calculated proliferation indices was 2.16.
  • Control examinations with monospecific anti-NCAM antibodies not binding to T cells achieved an average proliferation index of 1.73.
  • AIMV LifeTechnologies. Egganh ⁇ im, Germany, 200 icrollter per nap
  • medium - an antibody against the CD3 ⁇ chain of T-lymphocytes (clone OKT3, 1 ⁇ g / l), the bispecific ⁇ antibody OE-1 (1 ⁇ g / ml ) or a high dose of tetanus toxoid (10 Lf / ml).
  • An anti-CD56 antibody (clone ERIC-1, 1 ⁇ g / ml) or a ⁇ dium control without the addition of antigens or antibodies was used for the negative control INF-y (number of spots) was determined using an IFN- ⁇ ELISPOT kit (Diaclone Research).
  • PBMC from persons vaccinated with tetanus toxoid were exposed for three days in RPMM640 medium (PAA, Linz, Austria) ⁇ 10% fetal calf serum (FCS, Biochrom AG) using the previously determined optimal stimulation conditions (TT 1 Lf / ml + OE- 2 ng / ml; or to control antl-CD5 ⁇ antibody 2 ng ml + TT 1 Lf / ml; or no antibody + TT 1 Lf / ml).
  • RPMM640 medium PAA, Linz, Austria
  • FCS fetal calf serum
  • the cells were washed twice with medium and incubated for 24 hours in an incubator in medium (RPMI1 ⁇ 40 + 10% FCS) without the addition of tetanus toxoid or antibody.
  • medium RPMI1 ⁇ 40 + 10% FCS
  • tetanus toxoid or antibody was followed by an ELISPOT test (3 days incubation period) on human IFN ⁇ y (diaclone re-search) using serum-free AIMV medium and addition (a high dosage) of TT (10 Lf / ml), or omitting TT (medium control) ,
  • the IFN-7 ELISPOT test showed that only the PBMC stimulated with TT + OE-1 were refractory 24 hours after the pre-stimulation against renewed stimulation with TT (10 Lf / ml), ie only very small amounts of IFN- ⁇ were secreted. during controls (PBMC stimulated with TT alone or in Combination with anti-CD56 antibodies) showed a normal TT response. Interestingly, the TT + OE-1 premilled cells were not refractory to non-specific stimulation with, for example, OKT3 antibodies 100 ng / ml.
  • PBMC from persons vaccinated with tetanus toxoid were exposed for three days in RPMI1640 medium + 10% fetal calf serum using the optimal stimulation conditions (TT 1 Lf / ml + OE-1 2 ng / ml; or as a control as a control) -CDS6 antibody 2 ng / ml + TT 1 Lf / m); or no antibody + TT 1 Lf / ml), then letfoch not (as in the previous experiment) incubated for 24 h in medium without TT or antibody, but now for another three days with (an optimal dosage of) 10 Lf / ml TT (in RPM11640 + 10% FCS) incubated to check whether the anergy related to the TT response can be broken.
  • the optimal stimulation conditions TT 1 Lf / ml + OE-1 2 ng / ml; or as a control as a control
  • an active ingredient according to the invention is able to increase the immune response to an antigen and, at the same time, is also able, depending on the use, to trigger an antigen-specific anergy.
  • the triggering of anergy is of particular therapeutic importance in the treatment of autoimmune diseases, allergies and organ rejection.

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  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un principe actif comprenant un premier constituant moléculaire qui se lie à une première molécule sélectionnée dans le groupe constitué de "NCAM, KIR2DL, KIR2DS, KIR3DL, CD94/CD159, CD57, CD85, CD16, NKp30, NKp44, NKp46, NKG2D et CD244", et un deuxième constituant moléculaire qui se lie à une deuxième molécule sélectionnée dans le groupe constitué de "CD2, CD4, CD44, CD69 et du récepteur des cellules T", le premier et le deuxième constituant moléculaire étant liés l'un à l'autre par covalence. L'invention concerne également l'utilisation de ce principe actif pour produire une composition pharmaceutique servant à stimuler le système immunitaire.
PCT/DE2003/004268 2002-12-20 2003-12-19 Accroissement de la reponse immunitaire par des substances qui influencent la fonction de cellules k naturelles Ceased WO2004056873A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP03813541A EP1590370A1 (fr) 2002-12-20 2003-12-19 Accroissement de la reponse immunitaire par des substances qui influencent la fonction de cellules k naturelles
AU2003296553A AU2003296553A1 (en) 2002-12-20 2003-12-19 Increase of the immune response by substances influencing the function of natural killer cells

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10261223.4 2002-12-20
DE10261223A DE10261223A1 (de) 2002-12-20 2002-12-20 Steigerung der Immunantwort durch Substanzen, welche die Funktion von Natürlichen Killerzellen beeinflussen

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WO2004056873A1 true WO2004056873A1 (fr) 2004-07-08

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WO2007048849A1 (fr) * 2005-10-28 2007-05-03 Novo Nordisk A/S Protéines de fusion se liant aux lymphocytes effecteurs et aux cellules cibles
WO2013175237A1 (fr) * 2012-05-24 2013-11-28 Ucl Business Plc Composition comprenant un agent de ligature cd2 et un agent de ligature nkg2d
EP2769993A1 (fr) 2007-12-14 2014-08-27 Novo Nordisk A/S Anticorps contre NKG2D humain et usages correspondants
US9433666B2 (en) 2008-04-17 2016-09-06 IO Bioech ApS Indoleamine 2,3-dioxygenase based immunotherapy
WO2018217947A1 (fr) * 2017-05-23 2018-11-29 Dragonfly Therapeutics, Inc. Protéine se liant au nkg2d, cd16 et antigène associé à une tumeur
US10259882B2 (en) 2015-05-07 2019-04-16 Agenus Inc. Anti-OX40 antibodies
WO2020172605A1 (fr) * 2019-02-21 2020-08-27 Elstar Therapeutics, Inc. Molécules d'anticorps se liant à nkp30 et utilisations associees
WO2020172598A1 (fr) * 2019-02-21 2020-08-27 Elstar Therapeutics, Inc. Molécules multifonctionnelles se liant à des lymphocytes t et leurs utilisations pour traiter des troubles auto-immuns
WO2020172571A1 (fr) * 2019-02-21 2020-08-27 Elstar Therapeutics, Inc. Molécules multifonctionnelles se liant à des cellules cancéreuses associées à des lymphocytes t et leurs utilisations
US10836830B2 (en) 2015-12-02 2020-11-17 Agenus Inc. Antibodies and methods of use thereof
US11359028B2 (en) 2016-11-09 2022-06-14 Agenus Inc. Anti-OX40 antibodies and anti-GITR antibodies
US11834506B2 (en) 2017-02-08 2023-12-05 Dragonfly Therapeutics, Inc. Multi-specific binding proteins that bind NKG2D, CD16, and a tumor-associated antigen for activation of natural killer cells and therapeutic uses thereof to treat cancer
US11845797B2 (en) 2018-07-03 2023-12-19 Marengo Therapeutics, Inc. Anti-TCR antibody molecules and uses thereof
US11884732B2 (en) 2017-02-20 2024-01-30 Dragonfly Therapeutics, Inc. Proteins binding HER2, NKG2D and CD16
US11884733B2 (en) 2018-02-08 2024-01-30 Dragonfly Therapeutics, Inc. Antibody variable domains targeting the NKG2D receptor
EP4139363A4 (fr) * 2020-04-24 2024-09-04 Marengo Therapeutics, Inc. Molécules multifonctionnelles se liant à des cellules cancéreuses associées à des lymphocytes t et leurs utilisations
US12152073B2 (en) 2018-03-14 2024-11-26 Marengo Therapeutics, Inc. Multifunctional molecules that bind to calreticulin and uses thereof
US12157771B2 (en) 2020-05-06 2024-12-03 Dragonfly Therapeutics, Inc. Proteins binding NKG2D, CD16 and CLEC12A
US12215157B2 (en) 2018-02-20 2025-02-04 Dragonfly Therapeutics, Inc. Multi-specific binding proteins that bind CD33, NKG2D, and CD16, and methods of use
US12247060B2 (en) 2018-01-09 2025-03-11 Marengo Therapeutics, Inc. Calreticulin binding constructs and engineered T cells for the treatment of diseases
US12275791B2 (en) 2018-08-08 2025-04-15 Dragonfly Therapeutics, Inc. Multi-specific binding proteins that bind HER2, NKG2D, and CD16, and methods of use
US12378318B2 (en) 2018-08-08 2025-08-05 Dragonfly Therapeutics, Inc. Proteins binding NKG2D, CD16 and a tumor-associated antigen
US12377144B2 (en) 2021-03-03 2025-08-05 Dragonfly Therapeutics, Inc. Methods of treating cancer using multi-specific binding proteins that bind NKG2D, CD16 and a tumor-associated antigen
US12384851B2 (en) 2018-08-08 2025-08-12 Dragonfly Therapeutics, Inc. Multi-specific binding proteins that bind BCMA, NKG2D and CD16, and methods of use
US12384847B2 (en) 2018-02-08 2025-08-12 Dragonfly Therapeutics, Inc. Cancer therapy involving an anti-PD1 antibody and a multi-specific binding protein that binds NKG2D, CD16, and a tumor-associated antigen
US12486326B2 (en) 2020-01-03 2025-12-02 Marengo Therapeutics, Inc. Anti-TCR antibody molecules and uses thereof

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