[go: up one dir, main page]

EP0415929A1 - Anticorps formant des heteroligats et leurs emplois therapeutiques - Google Patents

Anticorps formant des heteroligats et leurs emplois therapeutiques

Info

Publication number
EP0415929A1
EP0415929A1 EP19890901891 EP89901891A EP0415929A1 EP 0415929 A1 EP0415929 A1 EP 0415929A1 EP 19890901891 EP19890901891 EP 19890901891 EP 89901891 A EP89901891 A EP 89901891A EP 0415929 A1 EP0415929 A1 EP 0415929A1
Authority
EP
European Patent Office
Prior art keywords
cells
antibody
group
heteroligating
target ligand
Prior art date
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.)
Withdrawn
Application number
EP19890901891
Other languages
German (de)
English (en)
Inventor
Thomas L. Klug
Yaela Baine
Richard W. Miller
Norman Ledonne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Biotech Inc
Original Assignee
Centocor Inc
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 Centocor Inc filed Critical Centocor Inc
Publication of EP0415929A1 publication Critical patent/EP0415929A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • polydomas herein and in the art. See, for example U.S. Patent No. 4,474,893 (1984); PCT Patent No. WO 83/03679 (1983) which are incorporated by reference.
  • the uses of monoclonal antibodies, chimerics, and the multifunctional antibodies of polydomas are manifold.
  • recombinant monoclonal antibodies are covalently attached to a dye, drug or tracer compound.
  • Polydomas are particularly useful in this regard. For example, a polydoma can be produced containing one binding site specific for the Ricinus communis toxin, and the other site specific for tumor cells.
  • a polydoma can be synthesized containing a tissuespecific antigen in combination with a monoclonal antibody to a fluorescent probe.
  • monoclonal antibodies and bioactive compounds There are, however, drawbacks to the use of both monoclonal antibodies and bioactive compounds in immunotherapy and immunodiagnostics.
  • Use of various lymphokines and monoclonal antibodies to which is bound a plant or bacterial toxin, radiolabel, or a dye cytotoxin have risks associated with injection into a patient. There may be generation of antibody against an injected immunogenic agent, resulting in an anti-idiotypic response in humans and a loss of immunogenic activity. See Talle, M. A. et al. (EPO No. 863,087,854).
  • the present invention discloses a novel approach to the use of polydomas and bioactive compounds in therapy and diagnostics.
  • polydomas in which one antigen binding site is reactive with a target and the other site capable of initiating, directing, or promoting use of at least one endogenous bioactive material
  • this invention discloses a method of augmenting or focussing the organism's normal response to the target by altering the local concentration(s) of the host's existing biomolecules.
  • these multifunctional antibodies, free of toxins, dye, or radiolabels may find clinical utility.
  • the present invention provides a therapeutic procedure employing a multifunctional antibody specifically reactive with a ligand and at least one endogenous biological response modifier.
  • the antibody serves to concentrate endogenous biological modifiers at or near the target ligand to produce a therapeutic effect.
  • the invention provides a therapeutic method which comprises administering a pharmaceutically effective amount of a multifunctional antibody specifically reactive with both a target ligand and an endogenous biological response modifier.
  • Figure 1 schematically illustrates four mechanisms by which tumor cells can be killed by targeted heteroligating monoclonal antibodies.
  • Figure 2 shows results of the chromatographic isolation of 17-1A ⁇ B140 quadroma.
  • Figure 2A illustrates isolation using protein-A sepharose chromatography.
  • Figure 2B illustrates isolation using hydrophobic interaction chromatography (HIC).
  • HIC hydrophobic interaction chromatography
  • Figure 3 shows an SDS:polyacrylamide gel of the 8B4 quadroma illustrating that 8B4 contains a 1:1 ratio of 17-1A and B140 heavy Ig chains.
  • Figure 4 shows an isoelectric focusing gel of 8B4 illustrating that the isoelectric point of 8B4 is the average of its parental antibodies.
  • the invention provides a therapeutic method for concentrating naturally occurring bioactive compounds at or near a specific site or sites within a patient.
  • bioactive compound, “biological response modifier” or “endogenous biological modifier” (EBM)
  • EBM endogenous biological modifier
  • a partial list of endogenous biological modifiers suitable for use in this invention includes the lymphokines, such as B-cell factor, interferons and interleukins; enzymes such as tissue plasminogen activator, hormones, immunoglobins, proteins, cofactors, metabolites, antigenic determinants, salts and ions.
  • the endogenous biological response modifier is a lymphokine or enzyme such as inteferon-gamma or tissue plasminogen activator (TPA), respectively.
  • the invention emcompasses a method of increasing concentration of these bioactive materials at a specific target site or ligand.
  • This "target site” will be located within the body and is an antigen or one or more epitopes on the antigen.
  • antigen is well known in the art and refers to a biological structure or "epitope", usually a protein or carbohydrate, which stimulates within the body the production of an antibody reactive with the antigen.
  • a partial list of pre-selected target sites suitable in this invention includes normal cells such as T-cells, B-cells, endocrine, nerve cells; cancer cells, benign disease cells, vascular occlusions including fibrin and platelets; disease processes such as plaques, amyloid, and arthritic joints; parasites, hormones, bacteria, viruses, immunoglobulins, toxins and/or metabolites.
  • the pre-selected target site or ligand is a cancer cell or a vascular occlusion.
  • the therapeutic method of this invention involves the administration of multifunctional or "heteroligating” antibodies.
  • heteroligating antibody refers to a monoclonal antibody which contains at least two different antigen binding sites on the same molecule.
  • the heteroligating monoclonal antibodies (hereafter HLMAb) of the present invention are useful for binding to, and concentrating these above-mentioned endogenous bioactive molecules at the situs of target sites or ligands.
  • the method of the present invention comprises administering a pharmaceutically effective amount of a HLMAb specifically binding to both a pre-selected target site and a bioactive material.
  • the HLMAb brings the target ligand in close proximity to bioactive components of the host's metabolic and homeostatic system in such a way that the host's endogenous bioactive compounds will respond to, or induce a clinically desirable response to, the target.
  • the present invention is a method of augmenting and/or focussing the patients normal response to the target ligand/antigen by altering the local concentration (s) of the host's endogenous biological response modifiers. It is unimportant whether the HLMAb will bind to the bioactive molecules first and subsequently to target ligands, or vice versa.
  • the mode of action of the invention is defined operationally as either concentrating the endogenous bioactive materials at the target site and/or coating the surface of a target site with HLMAb in order to present an array of receptors for circulating bioactive agents.
  • the invention accomplishes this by virtue of the ability of the HLMAb to bind to two or more agents simultaneously, thus bringing two or more different cell types or two or more different bioactive materials into close proximity. Appropriate dosages of heteroligating antibodies described herein will vary according to the therapeutic effect desired.
  • the HLMAb of the present invention would be formed by joining two (or more) monoclonal antibodies, at least one of which specifically binds to a naturally occuring bioactive molecule and/or to a surface antigen on an endogenous target cell that influences the biologic response of the host to a target ligand.
  • the other part of the HLMAb may consist of a MAb which binds pre-selected target antigen, for example, to a tumor-associated antigen (TAA), a foreign antigen, or a normal cellular antigen or cell product (see attached Table I for list of possible targets and endogenous biological modifiers).
  • TAA tumor-associated antigen
  • foreign antigen a foreign antigen
  • a normal cellular antigen or cell product see attached Table I for list of possible targets and endogenous biological modifiers.
  • the joining of MAbs to form the HLMAb may be achieved by: 1) fusion of two (or more) parental MAb producing cells (hybridomas) into a single cell which will produce the HLMAb as a natural cell product; or 2) by fusion of a MAb producing hybridoma with a lymphocyte producing an antibody having specific binding affinity to another desired antigen.
  • the hybrid hybridoma may be called a
  • triomas a hybridoma and antibody producing lymphocytes.
  • One method for making triomas is disclosed in U.S. Patent 4,474,893, the relevant disclosure of which is incorporated herein by reference. See also Lanzavecchia, A. and D. Scheidegger, Eur. J. Immunol.
  • neoplasia cancer
  • cardiovascular disease autoimmune disease
  • viral, bacterial, and parasitic infections include: neurologic disorders, endocrine and metabolic disorders; diseases of the blood and blood-forming organs; disease of the respiratory system; disease of the skin and subcutaneous tissue; disease of the musculoskeletal and connective tissue; congenital abnormalties; injury and poisoning.
  • heteroligating antibodies are coadministered with exogenous naturally occurring bioactive agents such as IL-2 or interferon-gamma.
  • these are coadministered as an antigen-antibody complex in which the bioactive compound is already bound to the heteroligating antibody, the antibody serving to protect the bound molecule from in vivo degradation until it reaches its target.
  • the heteroligating antibody can also be introduced over a considerable period of time to bind the greatest amount of antibody to the tumor.
  • the target cells then, in effect, carry receptors for the biological response modifiers and can be selectively vulnerable to a brief period of treatment with low levels of the same exogenously administered materials.
  • This invention can also be used to more effectively eliminate, select, or remove tumor cells in vitro. An example of this is in the removal of cancerous cells from autologous bone marrow cells in vitro prior to returning them into irradiation-treated cancer patients.
  • a heteroligating antibody with bispecificity to both a target antigen and endogenous human interferon-gamma can be injected into a patient with a tumor, and this can localize at the tumor site by binding to the tumor surface antigen or epitope.
  • the anti-IFN-gamma portion of the quadroma then binds to and concentrates . endogenous IFN-gamma on the tumor cells.
  • IFN-gamma then mediates killing of the tumor cell by at least three separate independent mechanisms; 1) direct cytotoxicity of IFN-gamma; 2) antibodyindependent, monocyte-mediated cytotoxicity following activation by IFN-gamma; and 3) monocyteindependent, lymphoid-dependent cytotoxicity following IFN-gamma induction of monokines IL-1 and IL-2 to activate LAK and T-cells.
  • a fourth mechanism, ADCC (Antibody Dependent Cellular Cytotoxicity) mediated by monocytes following antibody binding to Fc receptor on the monocyte can be involved.
  • the invention its operation and its effects in concentrating endogenous IFN-gamma are illustrated in Figure 1.
  • IFN-gamma released from the heteroligating MAb, or MAb-bound IFN-gamma pinocytosed by the tumor cell is directly cytotoxic to the cell.
  • released or bound IFN-gamma activates nearby monocytes and these then non-specifically lyse tumor cells upon contact.
  • monocytes are activated as before, but the lymphokines secreted by the activated monocytes (macrophages) amplify the lytic response through activation of adjacent lymphocytes.
  • a fourth mechanism can be invoked if the heteroligating MAb binds specifically to the monocyte's Fc receptor and the bound monocytes are capable of a cytolytic ADCC response.
  • the present invention is not limited to full chain HLMAb's but includes those made from (Fab') or (FAb) 2 fragments. Moreover, this invention is not limited to targeting malignant tumor cells, but may also be used to target any cell population, pathological organisms, or pathological molecule either in vivo or in vitro (See Table I).
  • EBMs Endogenous Biological Modifiers
  • B-cell factors . Interferons B. Normal Cells . IL-2 . T-Cells . B-Cells
  • T-Cell Populations D. Vascular Occlusions . Cytotoxic Cells . Fibrin . Activated T-Cells . Platelets
  • An example for this application is in the delivery of macrophages to gram-negative bacteria with a polydoma composed of anti-lipopolysaccharide and anti-macrophage. Another possibility is treatment of rheumatoid arthritis with a polydoma both to a rheumatoid factor and interferon-gamma.
  • a further example is an HLMAb reagent for use as a thrombolytic and fibrinolytic agent comprising an antiplatelet and an anti-TPA HLMAb.
  • the present invention increases the efficacy of therapy and makes it more economical. This is especially true in embodiments of this invention that use exogenous bioactive agents. In situations where the bioactive agent is bound to the HLMAb prior to administration, less must be injected since they are already targeted to the site.
  • MAb Monoclonal antibodies produced by standard Kohler-Milstein immunization and hybridoma method were identified. Tumor selective MAbs were developed for colorectal, breast, and ovarian carcinomas. Antibodies to interferon-gamma, interleukin-2, tumor necrosis factor (TNF), and T-cells were also developed.. All antibodies were of murine origin and were of the immunoglobulin IgG class. Several of these hybridomas were made drug resistant or drug selectable by DNA transfection with bacterial plasmid vectors using protoplast fusion techniques. See Knight, D.E. and M.C Scrutton, Biochem. J. 234:497, 1986; and Potter, H. et al. Proc. Natl.
  • Bacterial DNA plasmid vectors pSV2-neo (ATCC #37149) and pSV2-gpt (ATCC #37199) were used to introduce the aminoglycoside 3- phosphotransferase (aph) and xanthine-guanine phosphoribosyltransferase (gpt) genes, respectively.
  • the hybridomas secreting MAbs against tumor antigens were transfected with DNA to produce G418 resistance (aph+) and the hybridomas secreting MAbs to the biological response modifiers were transfected to render them resistant to mycophenolic acid (gpt+).
  • Transfectants were cultured in increasing doses of the respective drug until they continued to grow at dose levels of drug that were at least 2-3X the dose that was absolutely lethal to all nontransfected cells (aph-, gpt-). Positive selection for successful hybridoma fusions is obtained by culturing fused hybridomas in the presence of both drugs. A true fusion of hybridomas will be doubly drug selectable (aph+, gpt+).
  • Two heteroligating clones, 8B4 and 1B10 were selected for further recloning. Ascit ⁇ s and hybridoma supernatant were made for both 8B4 and 1B10. These two cells lines were recloned 6 times before a stable clone was eventually found. These were then expanded for use in the production of antibody from supernatants and ascites. Purification protocols for heterobifunctional antibodies were developed using conventional chromatographic techniques for isolating and separating immunoglobulins including protein-A affinity, ionexchange, and hydrophobic interaction chromatography. Immunoglobulins secreted by clone 8B4 have been characterized.
  • Clone 8B4 secretes both 17-1A and B140 parental MAbs as well as the heterobifunctional antibody.
  • the immunoglobulins have been isolated and purified by protein-A chromatography, followed by separation by hydrophobic interaction chromatography (HIC) ( Figure 2A and 2B, respectively). Results indicate that 80% of the antibody produced by clone 8B4 was heteroligating. Ascites yielded as much as 1 mg/ml of the heterobifunctional 17-1A X B140.
  • the behavior of the 8B4 quadroma on SDS:PAGE gels ( Figure 3), and isoelectric focussing (IEF) gels ( Figure 4) gave further evidence that 8B4 is a 1:1 classical combination of the two parental antibodies .
  • 17-lA bivalent There is probably no difference in intrinsic affinity between these, but the multivalent binding of the 17-1A antibody translates into greater enthalpic contribution to the free energy of association and hence greater binding at equivalent antibody concentrations.
  • Human colon HT29 (ATCC No. HTB38) at a concentration of 10 4 cells/well were cultured and labeled with 125 I-uracil deoxyribose (UdR) in the presence of fluorouracil deoxyribose (FUdR) for about 24 hours. Cells were washed, then co-cultured in the presence or absence of human peripheral monocytes for about 72 hours. Monocyte concentrations were 8 or 15 ⁇ 10 4 cells/well. Carcinoma and monocytes were cultured in the presence of recombinant IFN-gamma
  • HLMAb 8B4 HLMAb 8B4 Or an equimolar mixture of 17-1A plus B140 parental antibodies. All antibodies contained negligible amounts of endotoxin, a potent activator of macrophage ( 1 Endotoxin unit of bacterial lipopolysaccharide/mg antibody),
  • Tumor cells were allowed to lyse and the radioactivity (as 125 I-UdR) liberated from 100 ul of supernatant was counted. The percent cytotoxicity was calculated as the fraction of the total number of counts released from cells into the supernatant ⁇ 100 (Table 2).
  • Numbers in parenthesis refer to percentage change in cytotoxicity compared to antibody-free control
  • HLMAb 8B4 Addition of HLMAb 8B4 to tumor cells in the presence of IFN-gamma and monocytes showed a small, but consistent cytotoxic effect over controls with either no antibody or with a mixture of the parental MAbs. This is particularly true at higher effector;target ratios. This was the case in the presence of low levels of IFN-gamma (0 and 0.5 Units/ml). Actually IFN-gamma levels may have been higher since monocytes themselves secrete IFN-gamma. Moreover, present results may actually underestimate the ability of HLMAb 8B4 to potentiate local tumoricidal effects by targeting IFN-gamma since MAb 17-1A by itself is more effective in binding macrophage Fc receptors than is HLMAb 8B4.
  • the present invention discloses the generation of a 17-1A ⁇ B140 (anti-tumor ⁇ anti-interferon gamma) quadroma which is useful in therapeutic procedures since it can be used to concentrate endogenous interferon-gamma at a specific location within the body, i.e., a colorectal tumor.
  • multifunctional antibodies of the type described herein can be valuable as therapeutic reagents in cancer, cardiovascular disease, infectious disease, inflammatory disease, autoimmune disease and others without the need for expensive, time-consuming and possibly toxic, courses of treatment with therapeutic compounds derived from recombinant DNA technology.

Landscapes

  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Est décrit un procédé pour mettre à profit et augmenter les propres composés bioactifs d'origine endogène d'un patient grâce à l'emploi judicieux d'anticorps multifonctionnels de conception spéciale. En particulier, l'invention décrit l'emploi d'anticorps formant des hétéroligats produits par des polydomes dans lesquels un site de liaison d'antigène est réactif avec une cible et l'autre site est susceptible de déclencher, ou de favoriser l'emploi d'au moins un composé bioactif endogène dirigé contre la cible. Un autre mode de réalisation de l'invention décrit des anticorps formant des hétéroligats qui lient un composé bioactif tel qu'une lymphokine ou un métabolite et un ligand cible tel qu'une cellule cancéreuse. Plus précisément, sont décrits des hétéro-anticorps liant l'interféron-gamma et des cellules tumorales. D'autres anticorps lient un activateur de plasminogène tissulaire ainsi que des plaquettes.
EP19890901891 1988-01-15 1989-01-12 Anticorps formant des heteroligats et leurs emplois therapeutiques Withdrawn EP0415929A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14454188A 1988-01-15 1988-01-15
US144541 1988-01-15

Publications (1)

Publication Number Publication Date
EP0415929A1 true EP0415929A1 (fr) 1991-03-13

Family

ID=22509048

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19890901891 Withdrawn EP0415929A1 (fr) 1988-01-15 1989-01-12 Anticorps formant des heteroligats et leurs emplois therapeutiques

Country Status (3)

Country Link
EP (1) EP0415929A1 (fr)
JP (1) JPH03503840A (fr)
WO (1) WO1989006544A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0449879A1 (fr) * 1988-11-25 1991-10-09 Centocor, Inc. Anticorps heterobifonctionnels se liant specifiquement a des plaquettes et a des agents thrombolytiques
EP0608212A1 (fr) * 1990-08-27 1994-08-03 Peptide Technology Ltd Procede de traitement des infections virales
US6248332B1 (en) 1990-10-05 2001-06-19 Medarex, Inc. Targeted immunostimulation with bispecific reagents
US7166423B1 (en) * 1992-10-21 2007-01-23 Miltenyi Biotec Gmbh Direct selection of cells by secretion product
EP3579848B1 (fr) 2017-02-08 2024-10-30 Dragonfly Therapeutics, Inc. Protéines de fixation multi-spécifiques destinées à l'activation de cellules tueuses naturelles et leurs utilisations thérapeutiques pour traiter le cancer
JP7685821B2 (ja) 2017-02-20 2025-05-30 ドラゴンフライ セラピューティクス， インコーポレイテッド Ｈｅｒ２、ＮＫＧ２ＤおよびＣＤ１６に結合するタンパク質
BR112020015994A2 (pt) 2018-02-08 2020-12-15 Dragonfly Therapeutics, Inc. Terapia de combinação do câncer que envolve proteínas de ligação multiespecíficas que ativam células natural killer
MX2020008336A (es) 2018-02-08 2020-09-21 Dragonfly Therapeutics Inc Dominios variables de anticuerpos que se dirigen al receptor nkg2d.
JP7353576B2 (ja) 2018-02-20 2023-10-02 ドラゴンフライ セラピューティクス， インコーポレイテッド Ｃｄ３３、ｎｋｇ２ｄ、及びｃｄ１６に結合する多重特異性結合タンパク質、ならびにその使用方法
SG11202101298XA (en) 2018-08-08 2021-03-30 Dragonfly Therapeutics Inc Proteins binding nkg2d, cd16 and a tumor-associated antigen
EA202091888A1 (ru) 2018-08-08 2020-10-23 Драгонфлай Терапьютикс, Инк. Вариабельные домены антител, нацеленные на рецептор nkg2d
EA202190468A1 (ru) 2018-08-08 2021-07-06 Драгонфлай Терапьютикс, Инк. Мультиспецифические связывающие белки, которые связывают bcma, nkg2d и cd16, и способы их применения
AR122018A1 (es) 2020-05-06 2022-08-03 Dragonfly Therapeutics Inc Proteínas que se unen a nkg2d, cd16 y clec12a
CN117222663A (zh) 2021-03-03 2023-12-12 蜻蜓疗法股份有限公司 使用结合nkg2d、cd16和肿瘤相关抗原的多特异性结合蛋白治疗癌症的方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4613459A (en) * 1982-10-20 1986-09-23 Dana-Farber Cancer Institute Lymphocyte growth factor
GB2148299B (en) * 1983-09-01 1988-01-06 Hybritech Inc Antibody compositions of therapeutic agents having an extended serum half-life
WO1987006240A1 (fr) * 1986-04-14 1987-10-22 The General Hospital Corporation Anticorps heterobifonctionnels et leur procede d'utilisation
US4954617A (en) * 1986-07-07 1990-09-04 Trustees Of Dartmouth College Monoclonal antibodies to FC receptors for immunoglobulin G on human mononuclear phagocytes
ES2073394T3 (es) * 1987-06-10 1995-08-16 Dana Farber Cancer Inst Inc Constructos de anticuerpos bifuncionales y su utilizacion para destruir selectivamente las poblaciones celulares.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8906544A1 *

Also Published As

Publication number Publication date
JPH03503840A (ja) 1991-08-29
WO1989006544A1 (fr) 1989-07-27

Similar Documents

Publication Publication Date Title
US6071517A (en) Bispecific heteroantibodies with dual effector functions
EP0595798B1 (fr) Hetero-anticorps bispecifiques avec fonctions effectrices doubles
RU2129018C1 (ru) Иммуноконьюгат, способ получения иммуноконьюгата и фармацевтическая композиция
US6071515A (en) Dimer and multimer forms of single chain polypeptides
AU2003298187B2 (en) Humanized antibody (H14.18) of the mouse 14.18 antibody binding to GD2 and its fusion with IL-2
EP0496818B1 (fr) ANTICORPS MONOCLONAL SPECIFIQUE POUR LEUR RECEPTEUR IgA
US20030139575A1 (en) Cytokine immunoconjugates
WO1995009917A1 (fr) Anticorps bispecifiques et tetravalents, obtenus par genie genetique
EP0415929A1 (fr) Anticorps formant des heteroligats et leurs emplois therapeutiques
Hornick et al. Chimeric CLL-1 antibody fusion proteins containing granulocyte-macrophage colony-stimulating factor or interleukin-2 with specificity for B-cell malignancies exhibit enhanced effector functions while retaining tumor targeting properties
AU2005220211A1 (en) Immunotherapy of autoimmune disorders using antibodies which target B-cells
JPH01501201A (ja) 抗体
Nitta et al. Induction of cytotoxicity in human T cells coated with anti-glioma× anti-CD3 bispecific antibody against human glioma cells
Vallera et al. Anti-graft-versus-host disease effect of DT390-anti-CD3sFv, a single-chain Fv fusion immunotoxin specifically targeting the CD3 epsilon moiety of the T-cell receptor
Penichet et al. Antibody-IL-2 fusion proteins: a novel strategy for immune potentiation
EP0511308B1 (fr) Immunoglobuline chimerique pour recepteurs de cd4
US5693322A (en) Enhanced intercellular interaction by associational antibody molecules
JP2024505966A (ja) Ｂｃｍａ及びｃｄ３に結合する二重特異性抗体、及びその作製方法並びにその使用
Looney et al. High-level expression and characterization of a mouse-human chimeric CD4 antibody with therapeutic potential
Lefranc et al. Antibody engineering and perspectives in therapy
Kummer et al. Concepts of antibody-mediated cancer therapy
US7037496B2 (en) Chimeric immunoglobulin for CD4 receptors
WO1998017116A1 (fr) Cellules cytotoxiques ciblees
Foon Treatment of Leukemia and Lymphoma with Biological Response Modifiers
JPH013128A (ja) 二官能性抗体構造体及び細胞集団を選択的に破壊する方法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19900418

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19920801