WO1995005468A1 - Molecules de liaison contenant au moins un domaine constant d'immunoglobuline et un determinant allotypique modifie - Google Patents

Molecules de liaison contenant au moins un domaine constant d'immunoglobuline et un determinant allotypique modifie Download PDF

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Publication number
WO1995005468A1
WO1995005468A1 PCT/GB1994/001790 GB9401790W WO9505468A1 WO 1995005468 A1 WO1995005468 A1 WO 1995005468A1 GB 9401790 W GB9401790 W GB 9401790W WO 9505468 A1 WO9505468 A1 WO 9505468A1
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binding molecule
domain
amino acid
heavy chain
molecule according
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PCT/GB1994/001790
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Michael Ronald Clark
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Lynxvale Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/461—Igs containing Ig-regions, -domains or -residues form different species
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5406—IL-4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5409—IL-5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates to binding molecules .
  • antibodies and particularly monoclonal antibodies (Kohler, G. and Milstein C, 1975 Nature 256 :495) represented a significant technical break-through with important consequences scientifically, commercially and therapeutically.
  • Monoclonal antibodies are made by establishing an immortal cell line which is derived from a single immunoglobulin producing cell secreting one form of a biologically functional antibody molecule with a particular specificity. Owing to their specificity, the therapeutic applications of monoclonal antibodies hold great promise for the treatment of a wide range of diseases (Clinical Applications of Monoclonal Antibodies, edited by E. S. Lennox. British Medical Bulletin 1984, publishers Churchill Livingstone) .
  • the simplest antibody comprises four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulphide bonds (see figure 1) .
  • the light chains are of two types, either kappa or lambda.
  • Each of the H and L chains has a region of low sequence variability, the constant region (C) , differences therein giving rise to allotypes and a region of high sequence variability, the variable region (V) differences therein giving rise to idiotypes.
  • the antibody has a tail region (the Fc region) which comprises two or three domains of the C regions of the two H chains. The tail region is responsible for interactions with the effector systems through binding and activation of complement and Fc receptors.
  • the antibody also has two arms (the Fab region) each of which has a V L and a V H region associated with each other and each connected to a C region domain, C L and CH- ⁇ respectively.
  • the C region of an IgG H chain consists of CH X hinge CH 2 and CH 3 . It is this pair of V regions (V L and V H ) that differ from one antibody to another, and which together -are responsible for recognising the antigen.
  • each V region is made up from three complementarity determining regions (CDR) separated by four framework regions (FR) .
  • CDRs are the most variable part of the variable regions, and they perform the critical antigen binding function.
  • the CDR regions are derived from many potential germ line sequences via a complex process involving recombination, mutation and selection. It has been shown that the function of binding antigens can be performed by fragments of a whole antibody and this is well documented in the art.
  • immunoglobulins IgG, IgM, IgA, IgD, IgE known as isotypes. Of these, IgG is most commonly used therapeutically. It exists as isotypic sub-classes IgGl, IgG2, IgG3 and IgG .
  • IgGl immunoglobulin Gl
  • Glm 1, 2, 3 and 17 different allotypes of IgGl
  • Antisera can be raised in other non-human species which can see the alternative isoallotypes provided that the antibody is purified away from the other human isotypes.
  • Such isoallotypes for which such an antisera exists have been called non-allotypes and given the designation for example, nGlm(l) which is.the isoallotype of Glm(l) .
  • nGlm(l) which is.the isoallotype of Glm(l) .
  • IgGl may exist as several allotypes depending on whether aspartic acid or glutamic acid at position 356, or leucine or methionine at position 358 are present .
  • IgGl may exist as either of two allotypes depending on whether glycine or alanine is present at position 431.
  • IgGl may exist as either of two allotypes depending on whether lysine or arginine is present.
  • the allotypes (17) and (3) cannot co-exist as they represent alternative substitutions at the same position.
  • Antibodies are generally raised in animals, particularly rodents for monoclonal antibodies and therefore the immunoglobulins produced, have characteristic features specific to that species. The repeated administration of these foreign rodent proteins for therapeutic purposes to human patients can lead to harmful hypersensitivity reactions. In part, this problem has been overcome in recent years by using the techniques of recombinant DNA technology to 'humanise' non-human antibodies.
  • CMC complement-mediated cytotoxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CMC CMC
  • the first protein component (CI- via Clq) of the complement cascade leading to cleavage of C3
  • activation of the lytic pathway of the complement system and to cytolysis of the foreign cells.
  • the activation of C3 causes platelet aggregation, accumulation of neutrophils, and the formation of an inflammatory exudate.
  • bystander tissue cells can be damaged even though they are not the immediate targets of the antibody recognition.
  • the antibody coated target cells are recognised by cytotoxic cells (eg monocytes and polymorphonuclear cells) having Fc receptors. Binding will occur between the target cells and cytotoxic cells via the antibody-Fc receptor bridge and lysis of the target cells will follow.
  • cytotoxic cells eg monocytes and polymorphonuclear cells
  • Fc receptors Fc receptors
  • FcR Fc receptors
  • FcRs also show specificity of binding eg only a certain group of FcRs bind IgA, another group IgE and another group IgG.
  • FcRs also occur as different classes and subclasses eg Fc ⁇ RI, Fc ⁇ RII and Fc ⁇ lll for those binding IgG (reviewed by van de intel and Capel 1993 Immunol. Today 14, 215-221).
  • IgG4 does not seem to activate complement at all and binds Fc ⁇ RI and Fc ⁇ RII poorly.
  • IgGl and IgG3 are active in both complement activation and in binding to the three classes of receptor Fc ⁇ RI, Fc ⁇ RII and Fc ⁇ RIII.
  • IgG2 can activate complement under some circumstances (eg high antigen density) but does not bind to most Fc ⁇ Rs (Bruggeman et al. , 1987 J. Exp. Med. 166, 1351-1361; Riechmann et al. , 1988 Nature 332, 323-327; Greenwood, Clark and aldmann 1993 Eur. J. Immunol. 23, 1098-1104) .
  • Some receptors exist in a polymorphic form (ie as alleles) and there is an allelic form of the Fc ⁇ RII receptor that can bind IgG2.
  • the subclasses 1-4 of IgG are very homologous in amino acid sequence (>90%) , particularly if the hinge regions (which are not highly conserved) are treated separately. If the constant regions are very similar with only a few amino acid differences, yet the subclasses exhibit different effector functions, some or all of the amino acid differences may be responsible for moderating the observed functions. Experiments have been carried out in which the residues which differ between subclasses are mutated or exchanged to discover which of them are responsible for the observed differences (reviewed in Greenwood and Clark 1993 Protein Engineering of antibody molecules for prophylactic and therapeutic applications in man (ed. Clark, M.) Publ. Academic Titles, UK (1993) p 85-100 Effector functions of matched sets of recombinant IgG subclass antibodies) .
  • the present applicants have now made the surprising discovery that an antibody's allotype can determine its effector function. This enables the design of therapeutic molecules having a binding domain linked to a human immunoglobulin heavy chain constant region having a particularly desired effector function. Prior to the present applicants disclosure this has not been possible.
  • the present invention provides a binding molecule which has a first amino acid sequence comprising a domain with an ability to bind to a target molecule; and a second amino acid sequence substantially homologous to part or all of the constant region of a human immunoglobulin heavy chain, but which differs in an allotypic determinant; wherein the difference in the allotypic determinant results in said binding molecule having an improved effector function as compared to a binding molecule having the first amino acid sequence and part or all of the constant region of the immunoglobulin heavy chain.
  • Also provided is a method for making a binding molecule which has a first amino acid sequence comprising a domain with an ability to bind to a target molecule and a second amino acid sequence comprising part or all of a human immunoglobulin heavy chain having an allotypic determinant of a sequence associated with a desired effector function which method comprises: (a) examining one or more sequences, each comprising part or all of a human immunoglobulin heavy chain and obtaining said second amino acid sequence by either (i) selecting one of said one or more sequences on the basis of it comprising a said allotypic determinant; or (ii) by selecting one of said one or more sequences on the basis of it comprising a sequence suitable for altering to a said allotypic determinant and altering the sequence to make a said second amino acid sequence; (b) obtaining a said first amino acid sequence; (c) creating the binding molecule by either (i) chemically linking said first and second amino acid sequences; or (ii) making a nu
  • the domain with an ability to bind to a target molecule may derive from any molecule with specificity for another molecule.
  • the domain may derive from an enzyme, a hormone, a receptor (cell-bound or circulating) a cytokine or an antigen or antibody.
  • cytokines IL-2,IL-4, IL-5, IL-8, IL-12,IL-13 and IL-15 which are involved in the modulation of the immune response.
  • These interleukins are referenced by Taniguchi et al (1983) Nature 302: 305 (IL- 2), Yokota et al (1986) PNAS 83: 5894 (IL-4) , Campbell et al (1987) PNAS 84: 6629 (IL-5) , Yoshimura et al (1987) PNAS 84: 9233 (IL-8) , Gubler et al (1991) PNAS 88, 4143 (IL-12) , McKenzie et al (1993) PNAS 90: 3735 (IL-13) , Grabstein et al (1994) Science 264: 965 (IL-15) .
  • OX-40 receptor also of interest are the soluble forms of the OX-40 receptor (Latza, U. , et al 1994 Eur. J. Immunol. 24 : 677) and of the OX-40 ligand (Godfrey W.K., et al 1994 J. Exp. Med. 180 : 757) .
  • the human OX-40 receptor is expressed primarily on activated CD4+ T cells.
  • a binding molecule may provide a rodent originating antibody binding domain and a human immunoglobulin heavy chain having a particular allotypic determinant which predisposes the binding molecule to a particular effector function.
  • the above refers to an improved effector function.
  • the binding molecule may have an effector function of a different type to that of a binding molecule having the first amino acid sequence and part or all of the constant region of the immunoglobulin heavy chain.
  • the effector function of the binding molecule may be of the same type as a binding molecule having the first amino acid sequence and part or all of the constant region of the immunoglobulin heavy chain, but the effector function being present to a lesser or greater degree.
  • the improvement is essentially that the effector function is more appropriate to the particular utility of the binding molecule.
  • sequences for human immunoglobulin heavy chains are known and published.
  • sequence information can be obtained from the SwissProt and PIR databases using
  • Lasergene software (DNAStar Limited, London UK) under accession numbers A93433, B90563, A90564, B91668, A91723 and A02146 for human Ig ⁇ -1 chain C region, A93906, A92809, A90752, A93132, A02148 for human Ig ⁇ -2 chain C region, A90933, A90249, A02150 for human Ig ⁇ -4 chain C region, A92249, A91662, A02171 for human Ig ⁇ -1 chain C region, A93828, A93829 and A02172 for human Ig ⁇ -2 chain C region and A23511 for human Ig ⁇ -3 chain C region.
  • the effector functions associated with the various allotypes of the human immunoglobulin heavy chains may be established in accordance with the general teachings herein, as exemplified by the present applicants establishment that it is the arginine at position 214 which is necessary for lysis in the aglycosylated IgGl antibodies and that having in the alternative a lysine or a threonine residue at this position does not give detectable lytic activity.
  • the heavy chain may then be coupled to an amino acid sequence comprising a binding domain at the protein level ie by chemical coupling methods.
  • a variety of methods are available to the skilled person to couple antibody molecules to other moieties such as radio-nucleotides, toxins, enzymes, cytotoxic drugs and other antibody molecules. They include covalent attachment to exposed tyrosine residues, or to the e-amino acid side chains of aspartic and glutamic acids.
  • sulphydryl groups generated by the chemical reduction of cystine residues have- been used to cross-link antibody domains
  • the domain may comprise an antibody binding domain.
  • the antibody binding domain may be non-human.
  • the antibody binding domain may be of rodent origin.
  • the domain may comprise part or all of a cytokine.
  • the cytokine may be selected from IL-2, IL-4, IL-5, IL-8, IL-12, IL-13 and IL-15. In particular the cytokine may be IL-12.
  • the domain may comprise part or all of a soluble form of a cell bound ligand or a cell bound receptor.
  • the cell bound receptor may comprise the OX-40 receptor.
  • the cell bound ligand may comprise-the OX-40 ligand.
  • the human immunoglobulin heavy chain may be of the isotype IgGl.
  • the difference in an allotypic determinant may be in the CH X domain.
  • the difference in an allotypic determinant may comprise the presence or absence of arginine at position 214. Where arginine is absent from position 214, lysine or threonine may instead be present.
  • the difference in an allotypic determinant may be in the CH 2 domain.
  • the difference in an allotypic determinant may comprise the presence or absence of asparagine at position 297. Where asparagine is absent from position 297, alanine may instead be present.
  • the second amino acid sequence may differ from the part or all of the constant region of an immunoglobulin heavy chain in more than one allotypic determinant. The differences may be in both the CH-, and CH 2 domains.
  • An amino acid other than arginine eg lysine or threonine
  • an amino acid other than asparagine eg alanine
  • the present invention also provides a pharmaceutical preparation which comprises a binding molecule as above.
  • the present invention also provides a reagent which comprises a binding molecule as above.
  • the present invention also provides a method of treating a patient which comprises administering a pharmaceutical as above. Also provided is use of a binding molecule as above in the preparation of a pharmaceutical to modify an immune response.
  • Also provided is a packet comprising a pharmaceutical or reagent as provided above along with instructions specifying use thereof.
  • the present invention also provides a recombinant construct which comprises a nucleotide sequence coding for a binding molecule as above. Also provided are cloning and expression vectors which comprise a recombinant construct as above, along with host cells comprising such vectors and transgenic animals carrying such recombinant constructs.
  • Figure 1 illustrates the structure of an IgG antibody (as discussed earlier) .
  • Figure 2 shows the M13TG131 cloning vector containing the human gamma-1 constant region and showing cloning sites and modified polylinker.
  • Figures 3 shows a complement dependent assay for the killing of autologous human peripheral blood lymphocytes with five CAMPATH-1 (CDw52) specific antibody constructs, TF57-19, MTF121, MTF123, MTF133 and MTF13 .
  • the degree of lysis was calculated from the % specific release of the radioisotope 51 Cr.
  • the results for the three allotypes of human ⁇ l agreed with earlier findings, ie there is no significant difference between TF57-19, MTF121 and MTF123 when assayed under conditions for optimal lysis.
  • Aglycosylated mutants of TF57-19 and MTF121 were constructed by mutating the Asn 297->Ala giving rise to MTF133 and MTF134 respectively.
  • construct BTF186 is more closely related to MTF134, than to MTF133, in terms of the lytic function. Referring to Table 1 it can be seen that this ability to give lysis correlates with the Arg 214 in the CH X domain and is independent of the residues found at position 356 and 358 in the CH 3 domain.
  • Figure 5 shows the results of an experiment following on from the observations in Figure 4. The results shown, confirms that it is the Arg at position 214 which is necessary for the observed lysis in the aglycosylated IgGl antibodies and that having the alternative residues of a Lys or a Thr at this position does not give detectable lytic activity.
  • the methods used herein are as described in
  • the data disclosed herein is based on the use of different mutated ⁇ l heavy chain constant regions expressed along with the heavy chain V-region and the light chain for the CAMPATH-1 specificity (against antigen CDw52) .
  • the vectors M13TG131 containing the ⁇ l gene see Fig. 2)
  • the expression vector pSVgpt containing the V H gene methods of mutation and methods of expression are all fully described in W092/16562.
  • the original human IgGl "wild type" construct, Y0 transfectant, clone TF57-19 was of immunoglobulin allotype Glm(1,17).
  • Glm(3) allotype was eliminated by replacing the Arg 214 with a Thr (using oligonucleotide primers M02 and M04 as described in W092/16562) to give the "null" allotype of clone MTF123. Comparison of- these constructs under optimal conditions indicates that they were very similar in their abilities to mediate autologous human complement dependent lysis of human lymphocytes.
  • the major and starting modification is a further mutation in the CH 2 domain encoding intron to alter the conserved site of N- linked glycosylation by mutating the Asn 297 to Ala. This was achieved by site directed mutagenesis (as used previously for the allotype mutants) of the appropriate sequence using an oligonucleotide primer "M03" with the following sequence.
  • PBS phosphate buffered saline
  • BSA Bovine Serum Albumen
  • biotinylated monoclonal antibody (NH3/41.34) specific for human K light chains was added at a concentration of lO ⁇ g/ml as a detection reagent. Bound biotinylated antibody was detected with subsequent steps of streptavidin peroxidase followed by the substrate o-phenylenediamine in citrate- phosphate buffer. The conversion of substrate was determined by measuring the absorbance at 495nm. Results from the three assays were combined in Table 2. '
  • arginine is found in IgG4 and IgG3 whilst threonine is found in IgG2.
  • the amino acid at position 214 depends on the allotype, such that arginine is found in the allotype (Glm(3) and lysine is found in the allotype Glm(17) .
  • the sequence of the allotype G1M(3) is more similar to IgG3 and IgG4 than is the allotype Glm(17) .
  • an IgFc fragment comprising a pair of second amino acid sequences each comprising part or all of a human immunoglobulin heavy chain having an allotypic determinant of a sequence associated with a desired effector function
  • attaching different molecules to the N terminal of an IgFc fragment comprising a pair of second amino acid sequences each comprising part or all of a human immunoglobulin heavy chain having an allotypic determinant of a sequence associated with a desired effector function
  • attachment of a soluble form of a transmembrane receptor, coding for the extracellular portion of that receptor, to the IgFc would produce a molecule capable of binding to a cell expressing a ligand for the receptor (eg binding of soluble CD40.Fc to cells expressing the CD40 ligand, Axmitage et al (1992) , Nature 347: 80-82) .
  • a cytokine to the IgFc fragment and use that hybrid molecule to label cells expressing the receptor for the cytokine (eg binding of IL- 2/IgGl chimeric molecule to cells expressing IL-2 receptors, Landolfi (1991) , J. Immunol. 146: 915-919) .
  • This attachment to IgFc may be by chemical linkage or by recombinant DNA technology to produce a fusion protein.
  • Cells thus labelled could then be destroyed via immune effector activation directed by the IgFc portion of the fusion protein.
  • “Clone Name” gives the name given to the final expressed product in YO cells transfected with a pSVgptV H CAMPATH construct.
  • the "M13 Construct” is the name of the intermediate M13TG131 constru used in derivation of the final antibody. Also given is information on the expressed constant region phenotype and the allotype of the antibodies together with the amino acids found at the relevant positions in the ⁇ l sequence. The final column gives details of the mutagenic oligonucleotides used in for the derivation of the construct.
  • Table 2 Enzyme linked immunoadsorbent assay to detect immunoglobulin allotypes of transfectants Table 2a
  • results of three ELISA assays to detect the allotypes Glm(l) , Glm(3) and Glm(17) are summarise above.
  • results are given as the average of duplicate wells in terms of the measured absorbance at 495nm.
  • results are the normalised in table 2b to a scale of 0 (lowest value) to 1 (highest value) .
  • results are interpreted in terms of a positive result being greater than 0.5 and a negative less than 0.5.
  • the results confirm the expected allotypes predicted from the genetic constructs detailed in Table 1.

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Abstract

Cette demande de brevet concerne une molécule de liaison qui possède une première séquence d'acides aminés comprenant un domaine ayant une capacité à se lier à une molécule cible; et une seconde séquence d'acides aminés sensiblement homologue à une partie ou à toute la région constante d'une chaîne lourde d'immunoglobuline humaine, mais qui diffère d'un déterminant allotypique. La différence intervenant dans le déterminant allotypique se traduit par cette molécule de liaison ayant une fonction d'effecteur améliorée comparée à une molécule de liaison possédant la première séquence d'acides aminés et une partie ou toute la région constante de la chaîne lourde d'immunogloguline. L'invention concerne également un procédé de production d'une molécule de liaison qui possède une première séquence d'acides aminés comprenant un domaine ayant une capacité à se lier à une molécule cible et une séquence d'acides aminés comprenant une partie ou la totalité d'une chaîne lourde d'immunogloguline humaine possédant un déterminant allotypique d'une séquence associée à une fonction d'effecteur désirée.
PCT/GB1994/001790 1993-08-16 1994-08-16 Molecules de liaison contenant au moins un domaine constant d'immunoglobuline et un determinant allotypique modifie WO1995005468A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998053315A1 (fr) * 1997-05-19 1998-11-26 Bayer Corporation Immunodosages utilisant des anticorps monoclonaux anti-allotypiques
WO1999015200A1 (fr) * 1997-09-25 1999-04-01 Mitsui Chemicals, Inc. COMPOSITION MEDICINALE DONT LE PRINCIPE ACTIF EST UN INHIBITEUR DE LIAISON DE gp34
WO1999029732A2 (fr) * 1997-12-08 1999-06-17 Lexigen Pharmaceuticals Corporation Proteines de fusion heterodymeres utiles en therapie immune ciblee et a une stimulation immune generale
WO1999058572A1 (fr) 1998-05-08 1999-11-18 Cambridge University Technical Services Limited Molecules de liaison derivees d'immunoglobulines ne declenchant pas de lyse dependante du complement
US6617135B1 (en) 1999-08-09 2003-09-09 Emd Lexigen Research Center Corp. Multiple cytokine protein complexes
US7098184B2 (en) 1994-02-10 2006-08-29 The Board Of Trustees Of The Leland Stanford Junior University Method of treating rheumatoid arthritis and multiple sclerosis diseases of the human immune system
WO2006029879A3 (fr) * 2004-09-17 2006-09-08 Hoffmann La Roche Anticorps anti-ox40l
US7355008B2 (en) 2003-01-09 2008-04-08 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US7416726B2 (en) 2000-04-13 2008-08-26 The Rockefeller University Enhancement of antibody-mediated immune responses
US7632497B2 (en) 2004-11-10 2009-12-15 Macrogenics, Inc. Engineering Fc Antibody regions to confer effector function
US7662925B2 (en) 2002-03-01 2010-02-16 Xencor, Inc. Optimized Fc variants and methods for their generation
US7740847B2 (en) 2004-08-04 2010-06-22 Applied Molecular Evolution, Inc. Variant Fc regions
US7786270B2 (en) 2006-05-26 2010-08-31 Macrogenics, Inc. Humanized FcγRIIB-specific antibodies and methods of use thereof
US20110071276A1 (en) * 2009-09-24 2011-03-24 Xbiotech, Inc. Method of modifying a monoclonal antibody
US7973136B2 (en) 2005-10-06 2011-07-05 Xencor, Inc. Optimized anti-CD30 antibodies
US8039592B2 (en) 2002-09-27 2011-10-18 Xencor, Inc. Optimized Fc variants and methods for their generation
US8084582B2 (en) 2003-03-03 2011-12-27 Xencor, Inc. Optimized anti-CD20 monoclonal antibodies having Fc variants
US8101720B2 (en) 2004-10-21 2012-01-24 Xencor, Inc. Immunoglobulin insertions, deletions and substitutions
US8124731B2 (en) 2002-03-01 2012-02-28 Xencor, Inc. Optimized Fc variants and methods for their generation
US8133982B2 (en) 2004-05-10 2012-03-13 Macrogenics, Inc. FcγRIIB specific antibodies and methods of use thereof
US8188231B2 (en) 2002-09-27 2012-05-29 Xencor, Inc. Optimized FC variants
US8187593B2 (en) 2002-08-14 2012-05-29 Macrogenics, Inc. FcγRIIB specific antibodies and methods of use thereof
US20120141372A1 (en) * 2002-03-01 2012-06-07 Immunomedics, Inc. RS7 Antibodies
US8318907B2 (en) 2004-11-12 2012-11-27 Xencor, Inc. Fc variants with altered binding to FcRn
US8388955B2 (en) 2003-03-03 2013-03-05 Xencor, Inc. Fc variants
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US8524867B2 (en) 2006-08-14 2013-09-03 Xencor, Inc. Optimized antibodies that target CD19
US8530627B2 (en) 2002-08-14 2013-09-10 Macrogenics, Inc. FcγRIIB specific antibodies and methods of use thereof
US8546543B2 (en) 2004-11-12 2013-10-01 Xencor, Inc. Fc variants that extend antibody half-life
US8658773B2 (en) 2011-05-02 2014-02-25 Immunomedics, Inc. Ultrafiltration concentration of allotype selected antibodies for small-volume administration
US8691952B2 (en) 2005-12-30 2014-04-08 Merck Patent Gmbh Anti-CD19 antibodies with reduced immunogenicity
US8697071B2 (en) 2005-08-10 2014-04-15 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US8795667B2 (en) 2007-12-19 2014-08-05 Macrogenics, Inc. Compositions for the prevention and treatment of smallpox
US8802820B2 (en) 2004-11-12 2014-08-12 Xencor, Inc. Fc variants with altered binding to FcRn
US8835606B2 (en) 2004-01-22 2014-09-16 Merck Patent Gmbh Anti-cancer antibodies with reduced complement fixation
US8907066B2 (en) 2009-04-22 2014-12-09 Merck Patent Gmbh Antibody fusion proteins with a modified FcRn binding site
US20140377287A1 (en) * 2002-03-01 2014-12-25 Immunomedics, Inc. Anti-trop-2 antibody-drug conjugates and uses thereof
US8926973B2 (en) 2001-03-30 2015-01-06 Merck Patent Gmbh Reducing the immunogenicity of fusion proteins
US8946387B2 (en) 2002-08-14 2015-02-03 Macrogenics, Inc. FcγRIIB specific antibodies and methods of use thereof
US8951517B2 (en) 2003-01-09 2015-02-10 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US8968730B2 (en) 2002-08-14 2015-03-03 Macrogenics Inc. FcγRIIB specific antibodies and methods of use thereof
US8993730B2 (en) 2008-04-02 2015-03-31 Macrogenics, Inc. BCR-complex-specific antibodies and methods of using same
US9029330B2 (en) 2005-12-30 2015-05-12 Merck Patent Gmbh Methods of treating cancer using interleukin-12p40 variants having improved stability
US9040041B2 (en) 2005-10-03 2015-05-26 Xencor, Inc. Modified FC molecules
US9051373B2 (en) 2003-05-02 2015-06-09 Xencor, Inc. Optimized Fc variants
US9096877B2 (en) 2009-10-07 2015-08-04 Macrogenics, Inc. Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use
US9150656B2 (en) 2010-03-04 2015-10-06 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
US9200079B2 (en) 2004-11-12 2015-12-01 Xencor, Inc. Fc variants with altered binding to FcRn
US9243069B2 (en) 2008-04-02 2016-01-26 Macrogenics, Inc. HER2/neu-specific antibodies and methods of using the same
US9284375B2 (en) 2005-04-15 2016-03-15 Macrogenics, Inc. Covalent diabodies and uses thereof
US9296816B2 (en) 2005-04-15 2016-03-29 Macrogenics, Inc. Covalent diabodies and uses thereof
US9376495B2 (en) 2011-05-21 2016-06-28 Macrogenics, Inc. Deimmunized serum-binding domains and their use in extending serum half-life
US9441049B2 (en) 2010-03-04 2016-09-13 Macrogenics, Inc. Antibodies reactive with B7-H3 and uses thereof
US9475881B2 (en) 2010-01-19 2016-10-25 Xencor, Inc. Antibody variants with enhanced complement activity
US9487587B2 (en) 2013-03-05 2016-11-08 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells of a companion animal that express an activating receptor and cells that express B7-H3 and uses thereof
US9657106B2 (en) 2003-03-03 2017-05-23 Xencor, Inc. Optimized Fc variants
EP3178493A1 (fr) * 2005-11-14 2017-06-14 Labrys Biologics Inc. Antagonistes d'anticorps dirigés contre un peptide associé au gène de la calcitonine et procédés les utilisant
US9708408B2 (en) 2006-12-08 2017-07-18 Macrogenics, Inc. Methods for the treatment of disease using immunoglobulins having Fc Regions with altered affinities for FcγRactivating and FcγRinhibiting
US9714282B2 (en) 2003-09-26 2017-07-25 Xencor, Inc. Optimized Fc variants and methods for their generation
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US9797907B2 (en) 2015-04-22 2017-10-24 Immunomedics, Inc. Isolation, detection, diagnosis and/or characterization of circulating Trop-2-positive cancer cells
US9822181B2 (en) 2013-08-23 2017-11-21 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding CD123 and CD3, and uses thereof
US9889197B2 (en) 2005-04-15 2018-02-13 Macrogenics, Inc. Covalently-associated diabody complexes that possess charged coil domains and that are capable of enhanced binding to serum albumin
US9896502B2 (en) 2014-03-21 2018-02-20 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
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US10799597B2 (en) 2017-04-03 2020-10-13 Immunomedics, Inc. Subcutaneous administration of antibody-drug conjugates for cancer therapy
US10961311B2 (en) 2016-04-15 2021-03-30 Macrogenics, Inc. B7-H3 binding molecules, antibody drug conjugates thereof and methods of use thereof
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US11254748B2 (en) 2005-04-15 2022-02-22 Macrogenics, Inc. Covalent diabodies and uses thereof
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US11401348B2 (en) 2009-09-02 2022-08-02 Xencor, Inc. Heterodimeric Fc variants
US11820830B2 (en) 2004-07-20 2023-11-21 Xencor, Inc. Optimized Fc variants
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008495A1 (fr) * 1990-11-09 1992-05-29 Abbott Biotech, Inc. Immunoconjugues de cytokine
WO1992016562A1 (fr) * 1991-03-12 1992-10-01 Lynxvale Limited Anticorps humanises ayant des determinants allotypiques modifies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008495A1 (fr) * 1990-11-09 1992-05-29 Abbott Biotech, Inc. Immunoconjugues de cytokine
WO1992016562A1 (fr) * 1991-03-12 1992-10-01 Lynxvale Limited Anticorps humanises ayant des determinants allotypiques modifies

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BIRKELAND, M. ET AL.;: "Cloning and expression of mouse OX-40 the homologue of a rat cell surface protein restricited to CD4-posisitve T blasts", JOURNAL OF CELLULAR BIOCHEMISTRY, vol. 17B, February 1993 (1993-02-01), pages 73 *
JOFFLIFFE, LINDA K.;: "Humanized antibodies : enhancing therapeutic utility through antibody", INTERNATIONAL REVIEW OF IMMUNOLOGY, vol. 10, no. 2-3, 1993, USA, pages 241 - 250 *
OI, V.T.; MORRISON S.L.;: "Chimeric Antibodies", BIOTECHNIQUE, vol. 4, no. 3, 1986, pages 214 - 221 *

Cited By (171)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098184B2 (en) 1994-02-10 2006-08-29 The Board Of Trustees Of The Leland Stanford Junior University Method of treating rheumatoid arthritis and multiple sclerosis diseases of the human immune system
WO1998053315A1 (fr) * 1997-05-19 1998-11-26 Bayer Corporation Immunodosages utilisant des anticorps monoclonaux anti-allotypiques
US6589756B1 (en) 1997-05-19 2003-07-08 Bayer Corporation Immunoassays using anti-allotypic monoclonal antibodies
US6146836A (en) * 1997-05-19 2000-11-14 Bayer Corporation Immunoassays using anti-allotypic monoclonal antibodies
US6333035B1 (en) 1997-09-25 2001-12-25 Mitsui Chemicals, Inc. Medicinal composition containing gp34 binding-inhibitor as the active ingredient
WO1999015200A1 (fr) * 1997-09-25 1999-04-01 Mitsui Chemicals, Inc. COMPOSITION MEDICINALE DONT LE PRINCIPE ACTIF EST UN INHIBITEUR DE LIAISON DE gp34
WO1999029732A3 (fr) * 1997-12-08 1999-08-26 Lexigen Pharm Corp Proteines de fusion heterodymeres utiles en therapie immune ciblee et a une stimulation immune generale
EP1489100A2 (fr) * 1997-12-08 2004-12-22 Lexigen Pharmaceuticals Corp. Protéines de fusion hétérodimériques utilisable pour l'immunothérapie ciblée et pour l'immunostimulation générale
WO1999029732A2 (fr) * 1997-12-08 1999-06-17 Lexigen Pharmaceuticals Corporation Proteines de fusion heterodymeres utiles en therapie immune ciblee et a une stimulation immune generale
EP1489100A3 (fr) * 1997-12-08 2012-06-06 Merck Patent GmbH Protéines de fusion hétérodimériques utilisable pour l'immunothérapie ciblée et pour l'immunostimulation générale
WO1999058572A1 (fr) 1998-05-08 1999-11-18 Cambridge University Technical Services Limited Molecules de liaison derivees d'immunoglobulines ne declenchant pas de lyse dependante du complement
US7597889B1 (en) 1998-05-08 2009-10-06 Cambridge Enterprise Limited Binding molecules derived from immunoglobulins which do not trigger complement mediated lysis
US6617135B1 (en) 1999-08-09 2003-09-09 Emd Lexigen Research Center Corp. Multiple cytokine protein complexes
US7416726B2 (en) 2000-04-13 2008-08-26 The Rockefeller University Enhancement of antibody-mediated immune responses
US8926973B2 (en) 2001-03-30 2015-01-06 Merck Patent Gmbh Reducing the immunogenicity of fusion proteins
US9770517B2 (en) 2002-03-01 2017-09-26 Immunomedics, Inc. Anti-Trop-2 antibody-drug conjugates and uses thereof
US8124731B2 (en) 2002-03-01 2012-02-28 Xencor, Inc. Optimized Fc variants and methods for their generation
US7662925B2 (en) 2002-03-01 2010-02-16 Xencor, Inc. Optimized Fc variants and methods for their generation
US9999668B2 (en) 2002-03-01 2018-06-19 Immunomedics, Inc. RS7 antibodies
US20120141372A1 (en) * 2002-03-01 2012-06-07 Immunomedics, Inc. RS7 Antibodies
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US10179171B2 (en) 2002-03-01 2019-01-15 Immunomedics, Inc. RS7 antibodies
US20140377287A1 (en) * 2002-03-01 2014-12-25 Immunomedics, Inc. Anti-trop-2 antibody-drug conjugates and uses thereof
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US8093357B2 (en) 2002-03-01 2012-01-10 Xencor, Inc. Optimized Fc variants and methods for their generation
US9833511B2 (en) 2002-03-01 2017-12-05 Immunomedics, Inc. RS7 antibodies
US20140286861A1 (en) * 2002-03-01 2014-09-25 Immunomedics, Inc. RS7 Antibodies
US10322176B2 (en) 2002-03-01 2019-06-18 Immunomedics, Inc. Subcutaneous administration of anti-CD74 antibody for systemic lupus erythematosus
US8734791B2 (en) 2002-03-01 2014-05-27 Xencor, Inc. Optimized fc variants and methods for their generation
US8946387B2 (en) 2002-08-14 2015-02-03 Macrogenics, Inc. FcγRIIB specific antibodies and methods of use thereof
US8187593B2 (en) 2002-08-14 2012-05-29 Macrogenics, Inc. FcγRIIB specific antibodies and methods of use thereof
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US8039592B2 (en) 2002-09-27 2011-10-18 Xencor, Inc. Optimized Fc variants and methods for their generation
US10184000B2 (en) 2002-09-27 2019-01-22 Xencor, Inc. Optimized Fc variants and methods for their generation
US10183999B2 (en) 2002-09-27 2019-01-22 Xencor, Inc. Optimized Fc variants and methods for their generation
US8188231B2 (en) 2002-09-27 2012-05-29 Xencor, Inc. Optimized FC variants
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US8809503B2 (en) 2002-09-27 2014-08-19 Xencor, Inc. Optimized Fc variants and methods for their generation
US8093359B2 (en) 2002-09-27 2012-01-10 Xencor, Inc. Optimized Fc variants and methods for their generation
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US9353187B2 (en) 2002-09-27 2016-05-31 Xencor, Inc. Optimized FC variants and methods for their generation
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US10113001B2 (en) 2003-03-03 2018-10-30 Xencor, Inc. Fc variants with increased affinity for FcyRIIc
US9657106B2 (en) 2003-03-03 2017-05-23 Xencor, Inc. Optimized Fc variants
US8388955B2 (en) 2003-03-03 2013-03-05 Xencor, Inc. Fc variants
US10584176B2 (en) 2003-03-03 2020-03-10 Xencor, Inc. Fc variants with increased affinity for FcγRIIc
US8735545B2 (en) 2003-03-03 2014-05-27 Xencor, Inc. Fc variants having increased affinity for fcyrllc
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US9714282B2 (en) 2003-09-26 2017-07-25 Xencor, Inc. Optimized Fc variants and methods for their generation
US9617349B2 (en) 2004-01-22 2017-04-11 Merck Patent Gmbh Anti-cancer antibodies with reduced complement fixation
US10017579B2 (en) 2004-01-22 2018-07-10 Meck Patent Gmbh Anti-cancer antibodies with reduced complement fixation
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US11820830B2 (en) 2004-07-20 2023-11-21 Xencor, Inc. Optimized Fc variants
US7740847B2 (en) 2004-08-04 2010-06-22 Applied Molecular Evolution, Inc. Variant Fc regions
US7501496B1 (en) 2004-09-17 2009-03-10 Roche Palo Alto Llc Anti-OX40L antibodies
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US9102733B2 (en) 2004-09-17 2015-08-11 Roche Palo Alto Llc Anti-OX40L antibodies
WO2006029879A3 (fr) * 2004-09-17 2006-09-08 Hoffmann La Roche Anticorps anti-ox40l
US8101720B2 (en) 2004-10-21 2012-01-24 Xencor, Inc. Immunoglobulin insertions, deletions and substitutions
US7632497B2 (en) 2004-11-10 2009-12-15 Macrogenics, Inc. Engineering Fc Antibody regions to confer effector function
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US8367805B2 (en) 2004-11-12 2013-02-05 Xencor, Inc. Fc variants with altered binding to FcRn
US8338574B2 (en) 2004-11-12 2012-12-25 Xencor, Inc. FC variants with altered binding to FCRN
US8324351B2 (en) 2004-11-12 2012-12-04 Xencor, Inc. Fc variants with altered binding to FcRn
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US9884907B2 (en) 2005-11-14 2018-02-06 Teva Pharmaceuticals International Gmbh Methods for treating headache using antagonist antibodies directed against calcitonin gene-related peptide
EP3178493A1 (fr) * 2005-11-14 2017-06-14 Labrys Biologics Inc. Antagonistes d'anticorps dirigés contre un peptide associé au gène de la calcitonine et procédés les utilisant
US10329343B2 (en) 2005-11-14 2019-06-25 Teva Pharmaceuticals International Gmbh Methods for treating headache using antagonist antibodies directed against calcitonin gene-related peptide
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US11208496B2 (en) 2005-12-30 2021-12-28 Cancer Research Technology Ltd. Anti-CD19 antibodies with reduced immunogenicity
US10072092B2 (en) 2005-12-30 2018-09-11 Merck Patent Gmbh Methods of use of anti-CD19 antibodies with reduced immunogenicity
US9029330B2 (en) 2005-12-30 2015-05-12 Merck Patent Gmbh Methods of treating cancer using interleukin-12p40 variants having improved stability
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US7786270B2 (en) 2006-05-26 2010-08-31 Macrogenics, Inc. Humanized FcγRIIB-specific antibodies and methods of use thereof
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US11932685B2 (en) 2007-10-31 2024-03-19 Xencor, Inc. Fc variants with altered binding to FcRn
US8795667B2 (en) 2007-12-19 2014-08-05 Macrogenics, Inc. Compositions for the prevention and treatment of smallpox
US10323085B2 (en) 2008-03-04 2019-06-18 Teva Pharmaceuticals International Gmbh Methods of treating fibromyalgia
US9695236B2 (en) 2008-04-02 2017-07-04 Macrogenics, Inc. BCR-complex-specific antibodies and methods of using same
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US8907066B2 (en) 2009-04-22 2014-12-09 Merck Patent Gmbh Antibody fusion proteins with a modified FcRn binding site
US10597448B2 (en) 2009-08-28 2020-03-24 Teva Pharmaceuticals International Gmbh Methods for treating visceral pain associated with interstitial cystitis by administering antagonist antibodies directed against calcitonin gene-related peptide
US11401348B2 (en) 2009-09-02 2022-08-02 Xencor, Inc. Heterodimeric Fc variants
US20110071276A1 (en) * 2009-09-24 2011-03-24 Xbiotech, Inc. Method of modifying a monoclonal antibody
US9096877B2 (en) 2009-10-07 2015-08-04 Macrogenics, Inc. Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use
US9475881B2 (en) 2010-01-19 2016-10-25 Xencor, Inc. Antibody variants with enhanced complement activity
US9441049B2 (en) 2010-03-04 2016-09-13 Macrogenics, Inc. Antibodies reactive with B7-H3 and uses thereof
US9714296B2 (en) 2010-03-04 2017-07-25 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
US9896508B2 (en) 2010-03-04 2018-02-20 Macrogenics, Inc. Antibodies reactive with B7-H3 and uses thereof
US9150656B2 (en) 2010-03-04 2015-10-06 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
US10730945B2 (en) 2010-03-04 2020-08-04 Macrogenics, Inc. Antibodies reactive with B7-H3 and users thereof
US10683364B2 (en) 2010-03-04 2020-06-16 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
US9714295B2 (en) 2010-03-04 2017-07-25 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
US9180205B2 (en) 2011-05-02 2015-11-10 Immunomedics, Inc. Stable compositions of high-concentration allotype-selected antibodies for small-volume administration
US9683050B2 (en) 2011-05-02 2017-06-20 Immunomedics, Inc. Stable compositions of high-concentration allotype-selected antibodies for small-volume administration
US8658773B2 (en) 2011-05-02 2014-02-25 Immunomedics, Inc. Ultrafiltration concentration of allotype selected antibodies for small-volume administration
US9468689B2 (en) 2011-05-02 2016-10-18 Immunomedics, Inc. Ultrafiltration concentration of allotype selected antibodies for small-volume administration
US9963516B2 (en) 2011-05-02 2018-05-08 Immunomedics, Inc. Stable compositions of high-concentration allotype-selected antibodies for small-volume administration
US9376495B2 (en) 2011-05-21 2016-06-28 Macrogenics, Inc. Deimmunized serum-binding domains and their use in extending serum half-life
US9487587B2 (en) 2013-03-05 2016-11-08 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells of a companion animal that express an activating receptor and cells that express B7-H3 and uses thereof
US9908938B2 (en) 2013-03-14 2018-03-06 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells that express an activating receptor and an antigen expressed by a cell infected by a virus and uses thereof
US10730947B2 (en) 2013-03-14 2020-08-04 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells that express an activating receptor and an antigen expressed by a cell infected by a virus and uses thereof
US11421031B2 (en) 2013-03-14 2022-08-23 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells that express an activating receptor and an antigen expressed by a cell infected by a virus and uses thereof
US11384149B2 (en) 2013-08-09 2022-07-12 Macrogenics, Inc. Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof
US10344092B2 (en) 2013-08-09 2019-07-09 Macrogenics, Inc. Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof
US10858430B2 (en) 2013-08-23 2020-12-08 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding to gpA33 and CD3, and uses thereof
US9932400B2 (en) 2013-08-23 2018-04-03 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding to gpA33 and CD3, and uses thereof
US9822181B2 (en) 2013-08-23 2017-11-21 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding CD123 and CD3, and uses thereof
US10787521B2 (en) 2013-08-23 2020-09-29 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding CD123 and CD3, and uses thereof
US11555064B2 (en) 2014-03-21 2023-01-17 Teva Pharmaceuticals International Gmbh Treating headache comprising administering an antibody to calcitonin gene-related peptide
US10556945B2 (en) 2014-03-21 2020-02-11 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US10519224B2 (en) 2014-03-21 2019-12-31 Teva Pharmaceuticals International Gmbh Treating headache comprising administering an antibody to calcitonin gene-related peptide
US9896502B2 (en) 2014-03-21 2018-02-20 Teva Pharmaceuticals International Gmbh Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US10717778B2 (en) 2014-09-29 2020-07-21 Duke University Bispecific molecules comprising an HIV-1 envelope targeting arm
US9797907B2 (en) 2015-04-22 2017-10-24 Immunomedics, Inc. Isolation, detection, diagnosis and/or characterization of circulating Trop-2-positive cancer cells
US10436788B2 (en) 2015-04-22 2019-10-08 Immunomedics, Inc. Isolation, detection, diagnosis and/or characterization of circulating Trop-2-positive cancer cells
US11591400B2 (en) 2016-04-15 2023-02-28 Macrogenics, Inc. B7-H3 directed antibody drug conjugates
US10961311B2 (en) 2016-04-15 2021-03-30 Macrogenics, Inc. B7-H3 binding molecules, antibody drug conjugates thereof and methods of use thereof
US11028160B2 (en) 2016-09-23 2021-06-08 Teva Pharmaceuticals International Gmbh Treating refractory migraine
US11028161B2 (en) 2016-09-23 2021-06-08 Teva Pharmaceuticals International Gmbh Treating refractory migraine
US10392434B2 (en) 2016-09-23 2019-08-27 Teva Pharmaceuticals International Gmbh Treating refractory migraine
US10799597B2 (en) 2017-04-03 2020-10-13 Immunomedics, Inc. Subcutaneous administration of antibody-drug conjugates for cancer therapy
US12024569B2 (en) 2021-05-05 2024-07-02 Macrogenics, Inc. HER2/neu-specific antibodies and methods of using same

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