WO1998022141A2 - Enhanced effects for hapten conjugated therapeutics - Google Patents
Enhanced effects for hapten conjugated therapeutics Download PDFInfo
- Publication number
- WO1998022141A2 WO1998022141A2 PCT/US1997/018475 US9718475W WO9822141A2 WO 1998022141 A2 WO1998022141 A2 WO 1998022141A2 US 9718475 W US9718475 W US 9718475W WO 9822141 A2 WO9822141 A2 WO 9822141A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- therapeutic compound
- peptide
- therapeutic
- moiety
- haptenic
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
Definitions
- the field of this invention is modification of the pharmacokinetics and pharmacodynamics of drugs or biologicals in vivo, specifically, for enhancing the effective in vitro half-life of therapeutic compounds in mammals .
- a "Xenoject” compound is a conjugate of a therapeutic compound and a haptenic moiety which, when administered to a mammalian host, is recognized and bound by circulating antibodies directed against the haptenic moiety, thereby effectively increasing the in vivo half-life of the therapeutic compound in the vascular system.
- Therapeutic compounds are conjugated to haptenic moieties that are recognized and bound by circulating antibodies in vivo.
- the therapeutic compound/hapten conjugates referred to herein as "Xenoject compounds”
- Xenoject compounds have an increased effective in vivo half-life as compared to that of the unconjugated therapeutic compound.
- the increase in in vivo duration is due, at least in part, to binding of the haptenic moiety of the Xenoject compound to the antigen binding site of a circulating antibody, thereby resulting in a stabilization of the drug in the serum.
- the drug then remains in the circulation with a half-life more closely resembling that of an immunoglobulin molecule rather than of a free small molecule. This allows lower doses of the therapeutic to be used which is of particular benefit when the compound is inherently toxic.
- Figure 1 illustrates the enhanced effects of binding a therapeutic compound to circulating antibodies via a haptenic moiety.
- Transplanted ⁇ -galactosyltransferase knock-out mice each of which had high-titers of circulating anti- ⁇ -Gal antibodies, were treated for 10 days with 1 mg/Kg of D-Allotrap/ ⁇ -Gal conjugate (•) , unconjugated D-Allotrap (O) , or no peptide (D) .
- Cardiac graft survival was measured by direct palpation of the hearts through the peritoneum. Results were plotted as the percent graft survival over time after transplantation.
- methods for prolonging the effective in vivo half-life of a therapeutic compound in a mammal comprise conjugating the therapeutic compound to a haptenic moiety to provide a therapeutic compound-hapten conjugate (herein also referred to as a "Xenoject compound") .
- a therapeutic compound-hapten conjugate herein also referred to as a "Xenoject compound”
- the haptenic moiety of the conjugate is recognized and bound by a circulating antibody present in the mammal which is directed against that hapten, thereby serving to stabilize the conjugate in the mammalian vascular system.
- the therapeutic compound thereby exhibits an effective half-life that more closely resembles that of an immunoglobulin molecule rather than that of a free small molecule in the vascular system.
- therapeutic compound refers to any compound that, when administered to a mammalian subject, gives rise to a desired therapeutic effect.
- Therapeutic compounds that find use in the presently described methods include, for example, peptides, including for example, Allotrap peptides and cyclosporines, peptidomimetics, proteins, including for example, immunoglobulins or therapeutically effective fragments thereof, hormones, including for example estrogens, progesterones, growth hormone, and the like, enzymes, enzyme inhibitors, interleukins, including interleukin-2 , cytokines, growth factors, nucleic acids, chemical compounds, including organic compounds, metallic compounds, chemotherapeutic compounds, and the like, and radioactively labeled compounds.
- the therapeutic compound is not critical to the invention in that virtually any therapeutic compound can be successfully conjugated to a hapten provided that the compound possesses a site at which the hapten can be conjugated without substantially affecting the therapeutic activity of the compound.
- Therapeutic compounds which find use in the methods of the present invention may be naturally occurring or synthetic. Such compounds may also be "biologically active" in their native state, meaning that the compound itself possesses the ability to provide a desired therapeutic effect without any modification of that compound. On the other hand, therapeutic compounds that find use may also be biologically inactive or in a latent precursor state when administered as part of a therapeutic compound/hapten conjugate, but may acquire biological or therapeutic activity when a portion of the therapeutic compound is hydrolyzed, enzy ⁇ natically cleaved or is otherwise modified in the mammalian vascular system or at the specific target site.
- the therapeutic compound may be a "pro-drug" , meaning that the compound is essentially therapeutically inactive when administered but becomes active upon modification in the vascular system.
- specific hydrolyzable groups may be attached to therapeutic compounds by methods known in the art, said hydrolyzable groups being hydrolyzed after administration of the conjugate to the mammal, thereby resulting in activation of the therapeutic compound.
- the essentially inactive therapeutic compound may be enzymatically cleaved or otherwise modified in the vascular system to provide for the biologically active compound.
- An example of such a precursor therapeutic compound is, for example, pro-insulin.
- the pro-drug may be modified in the vascular system over time to provide a large depot of active drug or may remain inactive until it reaches a specific target site.
- the therapeutic compound Once activated by hydrolysis, enzymatic cleavage or by other modification, the therapeutic compound may act at the surface of a target cell or may be transported into the target cell to act intracellularly.
- prolonging the in vivo half life of a therapeutic compound By “prolonging the in vivo half life of a therapeutic compound” , “stabilizing" a therapeutic compound or grammatical equivalents thereof is meant that the in vivo half -life of a therapeutic compound when conjugated to a haptenic moiety is increased relative to the in vivo half- life of the same therapeutic compound that is not conjugated to a haptenic moiety.
- Techniques for determining the in vivo half life of therapeutic compounds are well known and conventionally used in the art and include, for example, determining the presence and/or activity of the therapeutic compound in the vascular system over time.
- Haptenic moieties that find use for conjugation to a therapeutic compound of interest are specifically recognized and bound by circulating antibodies present in the mammalian vascular system and include, for example, xenoantigens, including, for example, sugar moieties typically found on glycoproteins such as Gal ⁇ l-3 Gal and mimetics of those sugar moieties (e.g., see Vauehan et al . , Xeno transplantation 3:18-23 (1996)), blood group antigens, and the like.
- Haptenic moieties may also comprise immunodominant epitopes of vaccines including, for example, epitopes derived from diphtheria or tetanus toxin, influenza virus hemagglutinin, HBs antigen, hepatitis A or B virus, polio virus, rubella virus, measles virus, tuberculosis virus, and the like.
- the haptenic moiety may comprise an alloantigen such as, for example, a fragment of a major histocompatibility antigen to which the host has been previously sensitized.
- Conjugation of the therapeutic compound to the haptenic moiety results in the production of a "therapeutic compound- hapten conjugate".
- the therapeutic compound and the haptenic moiety may be covalently or non-covalently attached and may be joined directly through a chemical bond or through a bridge of not more than about 50 members in the chain, usually not more than about 20 members in the chain, where the members of the chain may be carbon, nitrogen, oxygen, sulfur, phosphorus, and the like.
- various techniques may be used to join the two members of the therapeutic compound-hapten conjugate, depending upon the nature of the members of the conjugate, the binding sites of the members of the conjugate, convenience, and the like.
- Functional groups that may be involved in the covalent conjugation of the members include esters, amides, ethers, phosphates, amino, hydroxy, thio, aldehyde, keto, and the like.
- the bridge may involve aliphatic, alicyclic, aromatic, or heterocyclic groups.
- the haptenic moiety may be "built into” the therapeutic compound during synthesis of that compound or may be conjugated to the therapeutic compound after that compound has been fully synthesized or otherwise obtained.
- the haptenic moiety may be conjugated to a reactive site on one or more of the amino acids which are present in the compound, either on a reactive side chain of an amino acid or at the C- or N-terminus of the peptide or protein.
- amino acids such as lysine, arginine, glutamic acid, aspartic acid and others possess chemically reactive sites available for covalent conjugation to the haptenic moiety.
- Non-covalently linked conjugates may be prepared, for example, through biotin-avidin interactions, and the like.
- Conjugates involving only proteins or glycoproteins can be chimeric or fusion recombinant molecules resulting from expression of ligated open reading frames of natural sequences, synthetic sequences, or combinations thereof.
- the particular manner in which the haptenic moiety is joined to the therapeutic compound will not be critical to the invention so long as the haptenic moiety is available for binding to circulating antibodies in the vascular system.
- the ⁇ -galactosyl group may be conjugated to the therapeutic compound in a variety of ways.
- the number of therapeutic compounds conjugated to each haptenic moiety may vary. In some situations, it may be desirable to have more than one therapeutic compound joined .to each haptenic moiety to provide, for example, for a higher avidity between the conjugate and the target of interest. Generally, the number of therapeutic compounds conjugated to a haptenic moiety will be a function of the size and structure of the therapeutic compound and will usually be less than about 5, more usually less than about 3, frequently less than about 2 and most frequently 1. Moreover, in some instances, a higher ratio of haptenic moieties to therapeutic compounds may also be employed.
- the subject Xenoject compounds can be used for the treatment of a wide variety of pathologies simply by varying the therapeutic compound employed.
- treatments may include such things as immunosuppression for organ transplantation, treatment of neoplasias such as carcinomas, leukemias, lymphomas, sarcomas, melanomas, and the like, hormonal therapy, treatment of bacterial or viral infection, etc .
- the Xenoject compounds of the present invention will usually be administered to a mammalian subject as a bolus, but may be introduced slowly over time by infusion using metered flow, or the like.
- the Xenoject compounds will usually be administered in a physiologically acceptable medium, e.g. deionized water, phosphate buffered saline, saline, aqueous ethanol or other alcohol, plasma, proteinaceous solutions, mannitol, aqueous glucose, alcohol, vegetable oil, or the like.
- additives which may also find use include buffers, where the media are generally buffered at a pH in the range of about 5 to 10, where the buffer will generally range in concentration from about 50 to 250 mM salt, where the concentration of salt will generally range from about 5 to 500 mM, physiologically acceptable stabilizers, biocides, and the like, these additives being conventional and used in conventional amounts.
- the Xenoject compounds described herein will for the most part be administered parenterally, such as intravascularly, intravenously, intraarterially, intramuscularly, subcutaneously, or the like, however, administration may also be orally, nasally, rectally, transdermally or inhalationally via an aerosol.
- the Xenoject compounds may be administered by any convenient means, including syringe, trocar, catheter, or the like. The particular manner of administration will vary depending upon the amount to be administered, whether a single bolus or continuous administration, or the like. Often the administration will be intravascularly, where the site of introduction is not critical to this invention, preferably at a site where there is rapid blood flow so as to provide for systemic dissolution of the compound, e.g. intravenously, peripheral or central vein. The Xenoject compounds may also be administered locally so as to direct the compounds to a specific site.
- the haptenic moiety of the therapeutic compound-hapten conjugate will be specifically recognized and bound by a circulating antibody present in the mammalian host.
- the circulating antibodies which serve to bind to and stabilize the Xenoject compound can be naturally occurring antibodies such as antibodies directed against, for example, blood group antigens, and the like, or anti-xenogenic antibodies.
- Antibodies that serve to bind to and stabilize the Xenoject compound may also be those induced in response to a prior presensitization of the mammalian host by, for example, a fragment of a major histocompatibility antigen, or in response to a prior vaccination of the mammalian host by, for example, diphtheria or tetanus antitoxin, influenza virus hemagglutinin, HBs antigen, hepatitis A or B virus, polio virus, rubella virus, measles virus, tuberculosis virus, etc.
- the host can be presensitized to the particular hapten of interest prior to administration of the Xenoject compound.
- Allotrap efficacy by prolongation of its in vivo half-life Potent immunosuppressive peptides have been identified from the amino acid sequence of the human leukocyte antigen class I molecule. Clayberger and Krensky, supra . These peptides are known as Allotrap peptides and have been demonstrated to have immunosuppressive effects leading to the prolongation of organ allograft survival. Recent reports have demonstrated that there is a significant therapeutic advantage to effectively increasing the in vivo half life of Allotrap peptides by rendering those peptides resistant to hydrolysis by serum proteases. Gao et al . , supra. This was accomplished by synthesizing the D-amino acid isomer of the natural peptide (D-Allotrap peptide) .
- D-Allotrap peptide sequence was linked to the haptenic moiety Gal ⁇ l-3 Gal-NHS and tested in mice having naturally occurring circulating anti- ⁇ -Gal antibodies.
- the D-Allotrap/ ⁇ -Gal Xenoject conjugates were demonstrated to bind to the circulating antibodies, survive for a significantly longer period in the circulation than do the unconjugated D- Allotrap peptides and have enhanced immunosuppressive effects as compared to the unconjugated D-Allotrap peptide.
- Gal antigen, peptides and conjugates The synthesis of the peptide-sugar conjugate first required the generation of an ⁇ -Gal disaccharide with a reactive group on the first carbon of the galactosyl ring. Briefly, this was accomplished by generating two bromine protected ring compounds (2,3,4, 6-tetra-0-benzyl- ⁇ -D-galactopyranosyl bromide and 4,6-0- benzylidene-1, 2-0-isopylidene- ⁇ -D-galactopyranose) .
- this structure was added to the secondary amine on the epsilon carbon of lysine (termed ⁇ -Gal-s-Lys where Lys is lysine) .
- the Allotrap D-B2702 amino acid sequence (Arg-Glu-Asn-Leu-Arg-Ile-Ala-Leu-Arg-Tyr) was then constructed with an automated peptide synthesizer (Synpep, Dublin, CA) such that the ⁇ -Gal-s-Lys was incorporated into the final peptide product. This resulted in a conjugate retaining its peptide immunosuppressive function that was capable of binding to anti- ⁇ -Gal antibodies.
- mice were available that had an inactivated ⁇ -galactosyltransferase gene
- mice were treated for 10 days (lmg/Kg) with the unconjugated D-Allotrap peptide or with the D-Allotrap/ ⁇ -Gal conjugate, and the survival of the transplanted hearts was compared to those from mice that received no treatment. As shown in Figure 1, the mice treated with unconjugated D-Allotrap peptide maintained their grafts for roughly 5 days longer (rejection on day 15) than did the untreated anneals.
- mice treated with the D-Allotrap/ ⁇ -Gal conjugate preserved their graft function for 25 days (rejection on day 35) beyond the untreated controls . This indicated that there was a significant advantage to conjugating the therapeutic peptide to a haptenic moiety.
- the purported target for Allotrap peptide action may be an intracellular molecule (such as hsp 70; see Nossner et al . , supra) , it was unlikely that the enhanced activity of the D-Allotrap/ ⁇ -Gal conjugate was due to redirection of the circulating antibodies to a specific target such that the immunoglobulins would then activate, complement and kill the cell. Instead, it was postulated that the therapeutic peptide was benefiting from a prolonged half -life in the serum when the haptenic moiety of the conjugate was bound to circulating serum immunoglobulins.
- (+) indicates that the D-Allotrap peptide was recovered from the serum sample, and (-) indicates that it was not.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97949336A EP1027073A2 (en) | 1996-11-19 | 1997-11-06 | Enhanced effects for hapten conjugated therapeutics |
AU72983/98A AU7298398A (en) | 1996-11-19 | 1997-11-06 | Enhanced effects for hapten conjugated therapeutics |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US75267196A | 1996-11-19 | 1996-11-19 | |
US08/752,671 | 1996-11-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1998022141A2 true WO1998022141A2 (en) | 1998-05-28 |
WO1998022141A3 WO1998022141A3 (en) | 1999-01-07 |
Family
ID=25027301
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/018475 WO1998022141A2 (en) | 1996-11-19 | 1997-11-06 | Enhanced effects for hapten conjugated therapeutics |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1027073A2 (en) |
AU (1) | AU7298398A (en) |
WO (1) | WO1998022141A2 (en) |
Cited By (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001032207A1 (en) * | 1998-10-30 | 2001-05-10 | United States Army Medical Research And Materiel Command | Methods for conferring active/passive immunotherapy |
WO2001045746A2 (en) * | 1999-12-24 | 2001-06-28 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
US6818611B1 (en) | 1998-10-13 | 2004-11-16 | University Of Georgia Research Foundation, Inc. | Stabilized bioactive peptides and methods of identification, synthesis and use |
EP1757701A1 (en) * | 1999-12-24 | 2007-02-28 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
US7365162B2 (en) | 1998-10-13 | 2008-04-29 | University Of Georgia Research Foundation, Inc. | Stabilized bioactive peptides and methods of identification, synthesis, and use |
WO2010010119A1 (en) | 2008-07-22 | 2010-01-28 | Ablynx Nv | Amino acid sequences directed against multitarget scavenger receptors and polypeptides |
WO2011064382A1 (en) | 2009-11-30 | 2011-06-03 | Ablynx N.V. | Improved amino acid sequences directed against human respiratory syncytial virus (hrsv) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections |
WO2011073180A1 (en) | 2009-12-14 | 2011-06-23 | Ablynx N.V. | Single variable domain antibodies against ox40l, constructs and therapeutic use |
WO2011083140A1 (en) | 2010-01-08 | 2011-07-14 | Ablynx Nv | Immunoglobulin single variable domain directed against human cxcr4 |
WO2011098520A1 (en) | 2010-02-10 | 2011-08-18 | Novartis Ag | Agonist dr5 binding polypeptides |
EP2365000A2 (en) | 2005-05-18 | 2011-09-14 | Ablynx N.V. | Improved nanobodiesTM against tumor necrosis factor-alpha |
WO2011144749A1 (en) | 2010-05-20 | 2011-11-24 | Ablynx Nv | Biological materials related to her3 |
EP2428226A1 (en) | 2001-10-22 | 2012-03-14 | The Scripps Research Institute | Antibody targeting compounds |
WO2012062713A1 (en) | 2010-11-08 | 2012-05-18 | Novartis Ag | Cxcr2 binding polypeptides |
EP2514767A1 (en) | 2006-12-19 | 2012-10-24 | Ablynx N.V. | Amino acid sequences directed against a metalloproteinase from the ADAM family and polypeptides comprising the same for the treatment of ADAM-related diseases and disorders |
WO2012156219A1 (en) | 2011-05-05 | 2012-11-22 | Ablynx Nv | Amino acid sequences directed against il-17a, il-17f and/or il17-a/f and polypeptides comprising the same |
WO2012175740A1 (en) | 2011-06-23 | 2012-12-27 | Ablynx Nv | Immunoglobulin single variable domains directed against ige |
EP2557090A2 (en) | 2006-12-19 | 2013-02-13 | Ablynx N.V. | Amino acid sequences directed against GPCRs and polypeptides comprising the same for the treatment of GPCR-related diseases and disorders |
WO2013168108A2 (en) | 2012-05-09 | 2013-11-14 | Novartis Ag | Chemokine receptor binding polypeptides |
WO2014087010A1 (en) | 2012-12-07 | 2014-06-12 | Ablynx N.V. | IMPROVED POLYPEPTIDES DIRECTED AGAINST IgE |
EP2947097A1 (en) | 2008-04-07 | 2015-11-25 | Ablynx N.V. | Amino acid sequences directed against the Notch pathways and uses thereof |
WO2015193452A1 (en) | 2014-06-18 | 2015-12-23 | Ablynx Nv | Kv1.3 binding immunoglobulins |
EP3205670A1 (en) | 2009-06-05 | 2017-08-16 | Ablynx N.V. | Improved amino acid sequences directed against human respiratory syncytial virus (hrsv) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections |
WO2018091606A1 (en) | 2016-11-16 | 2018-05-24 | Ablynx Nv | T cell recruiting polypeptides capable of binding cd123 and tcr alpha/beta |
WO2018220225A1 (en) | 2017-06-02 | 2018-12-06 | Ablynx Nv | Aggrecan binding immunoglobulins |
EP3461844A2 (en) | 2009-04-10 | 2019-04-03 | Ablynx N.V. | Improved amino acid sequences directed against il-6r and polypeptides comprising the same for the treatment of il-6r related diseases and disorders |
WO2022178255A2 (en) | 2021-02-19 | 2022-08-25 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies that neutralize sars-cov-2 |
US11447573B2 (en) | 2016-07-20 | 2022-09-20 | Nanjing Legend Biotech Co., Ltd. | Multispecific antigen binding proteins and methods of use thereof |
US11472881B2 (en) | 2016-10-11 | 2022-10-18 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against CTLA-4 |
US11713353B2 (en) | 2018-01-15 | 2023-08-01 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against PD-1 |
US11905327B2 (en) | 2017-12-28 | 2024-02-20 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against TIGIT |
US11958903B2 (en) | 2018-03-30 | 2024-04-16 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies against LAG-3 and uses thereof |
WO2024083843A1 (en) | 2022-10-18 | 2024-04-25 | Confo Therapeutics N.V. | Amino acid sequences directed against the melanocortin 4 receptor and polypeptides comprising the same for the treatment of mc4r-related diseases and disorders |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993017699A1 (en) * | 1992-03-02 | 1993-09-16 | The Board Of Trustees Of The Leland Stanford Junior University | Lymphocyte activity regulation by hla peptides |
DE4238416A1 (en) * | 1992-11-13 | 1994-05-19 | Max Planck Gesellschaft | Determination of peptide motifs on MHC molecules |
WO1995034321A1 (en) * | 1994-06-16 | 1995-12-21 | The Board Of Trustees Of The Leland Stanford Junior University | Immune modulation with class ii alpha-chain fragments |
WO1996035443A1 (en) * | 1995-05-12 | 1996-11-14 | Sangstat Medical Corporation | Treatment for inhibiting the progression of autoimmune disease |
WO1997024140A1 (en) * | 1996-01-02 | 1997-07-10 | The Board Of Trustees Of Leland Stanford Junior University | Interaction of hla proteins with members of the hsp70 family of proteins |
WO1997037690A2 (en) * | 1996-04-10 | 1997-10-16 | Sangstat Medical Corporation | Cytomodulating conjugates of members of specific binding pairs |
-
1997
- 1997-11-06 EP EP97949336A patent/EP1027073A2/en not_active Withdrawn
- 1997-11-06 WO PCT/US1997/018475 patent/WO1998022141A2/en not_active Application Discontinuation
- 1997-11-06 AU AU72983/98A patent/AU7298398A/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993017699A1 (en) * | 1992-03-02 | 1993-09-16 | The Board Of Trustees Of The Leland Stanford Junior University | Lymphocyte activity regulation by hla peptides |
DE4238416A1 (en) * | 1992-11-13 | 1994-05-19 | Max Planck Gesellschaft | Determination of peptide motifs on MHC molecules |
WO1995034321A1 (en) * | 1994-06-16 | 1995-12-21 | The Board Of Trustees Of The Leland Stanford Junior University | Immune modulation with class ii alpha-chain fragments |
WO1996035443A1 (en) * | 1995-05-12 | 1996-11-14 | Sangstat Medical Corporation | Treatment for inhibiting the progression of autoimmune disease |
WO1997024140A1 (en) * | 1996-01-02 | 1997-07-10 | The Board Of Trustees Of Leland Stanford Junior University | Interaction of hla proteins with members of the hsp70 family of proteins |
WO1997037690A2 (en) * | 1996-04-10 | 1997-10-16 | Sangstat Medical Corporation | Cytomodulating conjugates of members of specific binding pairs |
Non-Patent Citations (2)
Title |
---|
BUELOW R ET AL: "PROLONGATION OF SKIN ALLOGRAFT SURVIVAL IN MICE FOLLOWING ADMINISTRATION OF ALLOTRAP" TRANSPLANTATION, vol. 59, no. 4, 27 February 1995, pages 455-460, XP000652975 * |
LUSSOW A R ET AL: "REDIRECTING CIRCULATING ANTIBODIES VIA LIGAND-HAPTEN CONJUGATES ELIMINATES TARGET CELLS IN VIVO" JOURNAL OF IMMUNOTHERAPY: WITH EMPHASIS ON TUMOR IMMUNOLOGY, vol. 19, no. 4, July 1996, pages 257-265, XP002050531 cited in the application * |
Cited By (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8030464B2 (en) | 1998-10-13 | 2011-10-04 | The University Of Georgia Research Foundation, Inc | Stabilized bioactive peptides and methods of identification, synthesis, and use |
US7365162B2 (en) | 1998-10-13 | 2008-04-29 | University Of Georgia Research Foundation, Inc. | Stabilized bioactive peptides and methods of identification, synthesis, and use |
US7122516B2 (en) | 1998-10-13 | 2006-10-17 | University Of Georgia Research Foundation, Inc. | Stabilized bioactive peptides and methods of identification, synthesis and use |
US10018618B2 (en) | 1998-10-13 | 2018-07-10 | Peptide Biosciences, Inc. | Stabilizied bioactive peptides and methods of identification, synthesis and use |
US6818611B1 (en) | 1998-10-13 | 2004-11-16 | University Of Georgia Research Foundation, Inc. | Stabilized bioactive peptides and methods of identification, synthesis and use |
US9322829B2 (en) | 1998-10-13 | 2016-04-26 | Peptide Biosciences, Inc. | Stabilized bioactive peptides and methods of identification, synthesis, and use |
US8440201B2 (en) | 1998-10-13 | 2013-05-14 | University Of Georgia Research Foundation, Inc. | Stabilized bioactive peptides and methods of identification, synthesis, and use |
WO2001032207A1 (en) * | 1998-10-30 | 2001-05-10 | United States Army Medical Research And Materiel Command | Methods for conferring active/passive immunotherapy |
AU784285B2 (en) * | 1999-12-24 | 2006-03-02 | Genentech Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
JP2007289187A (en) * | 1999-12-24 | 2007-11-08 | Genentech Inc | Method and composition for prolonging elimination half-time of bioactive compound |
JP2007289200A (en) * | 1999-12-24 | 2007-11-08 | Genentech Inc | Method and composition for prolonging elimination half-time of bioactive compound |
US7608681B2 (en) | 1999-12-24 | 2009-10-27 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
US7635749B2 (en) | 1999-12-24 | 2009-12-22 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
EP1757701A1 (en) * | 1999-12-24 | 2007-02-28 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
EP2180054A1 (en) * | 1999-12-24 | 2010-04-28 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
JP2003518075A (en) * | 1999-12-24 | 2003-06-03 | ジェネンテック・インコーポレーテッド | Methods and compositions for extending the elimination half-life of bioactive compounds |
WO2001045746A3 (en) * | 1999-12-24 | 2001-10-11 | Genentech Inc | Methods and compositions for prolonging elimination half-times of bioactive compounds |
WO2001045746A2 (en) * | 1999-12-24 | 2001-06-28 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
EP2428226A1 (en) | 2001-10-22 | 2012-03-14 | The Scripps Research Institute | Antibody targeting compounds |
US8252902B2 (en) | 2001-10-22 | 2012-08-28 | The Scripps Research Institute | Antibody targeting compounds |
EP2949668A1 (en) | 2005-05-18 | 2015-12-02 | Ablynx N.V. | Improved nanobodiestm against tumor necrosis factor-alpha |
EP2365000A2 (en) | 2005-05-18 | 2011-09-14 | Ablynx N.V. | Improved nanobodiesTM against tumor necrosis factor-alpha |
EP2479191A2 (en) | 2005-05-18 | 2012-07-25 | Ablynx N.V. | Improved nanobodiesTM against tumor necrosis factor-alpha |
EP3613767A1 (en) | 2005-05-18 | 2020-02-26 | Ablynx N.V. | Improved nanobodiestm against tumor cecrosis factor-alpha |
EP2514767A1 (en) | 2006-12-19 | 2012-10-24 | Ablynx N.V. | Amino acid sequences directed against a metalloproteinase from the ADAM family and polypeptides comprising the same for the treatment of ADAM-related diseases and disorders |
EP2557090A2 (en) | 2006-12-19 | 2013-02-13 | Ablynx N.V. | Amino acid sequences directed against GPCRs and polypeptides comprising the same for the treatment of GPCR-related diseases and disorders |
EP2947097A1 (en) | 2008-04-07 | 2015-11-25 | Ablynx N.V. | Amino acid sequences directed against the Notch pathways and uses thereof |
WO2010010119A1 (en) | 2008-07-22 | 2010-01-28 | Ablynx Nv | Amino acid sequences directed against multitarget scavenger receptors and polypeptides |
EP3461844A2 (en) | 2009-04-10 | 2019-04-03 | Ablynx N.V. | Improved amino acid sequences directed against il-6r and polypeptides comprising the same for the treatment of il-6r related diseases and disorders |
EP3205670A1 (en) | 2009-06-05 | 2017-08-16 | Ablynx N.V. | Improved amino acid sequences directed against human respiratory syncytial virus (hrsv) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections |
WO2011064382A1 (en) | 2009-11-30 | 2011-06-03 | Ablynx N.V. | Improved amino acid sequences directed against human respiratory syncytial virus (hrsv) and polypeptides comprising the same for the prevention and/or treatment of respiratory tract infections |
WO2011073180A1 (en) | 2009-12-14 | 2011-06-23 | Ablynx N.V. | Single variable domain antibodies against ox40l, constructs and therapeutic use |
EP3309176A1 (en) | 2009-12-14 | 2018-04-18 | Ablynx N.V. | Immunoglobulin single variable domain antibodies against ox40l, constructs and therapeutic use |
WO2011083140A1 (en) | 2010-01-08 | 2011-07-14 | Ablynx Nv | Immunoglobulin single variable domain directed against human cxcr4 |
WO2011098520A1 (en) | 2010-02-10 | 2011-08-18 | Novartis Ag | Agonist dr5 binding polypeptides |
EP3546483A1 (en) | 2010-05-20 | 2019-10-02 | Ablynx N.V. | Biological materials related to her3 |
WO2011144749A1 (en) | 2010-05-20 | 2011-11-24 | Ablynx Nv | Biological materials related to her3 |
EP3575321A1 (en) | 2010-11-08 | 2019-12-04 | Ablynx N.V. | Cxcr2 binding polypeptides |
EP3578568A2 (en) | 2010-11-08 | 2019-12-11 | Ablynx N.V. | Cxcr2 binding polypeptides |
WO2012062713A1 (en) | 2010-11-08 | 2012-05-18 | Novartis Ag | Cxcr2 binding polypeptides |
WO2012156219A1 (en) | 2011-05-05 | 2012-11-22 | Ablynx Nv | Amino acid sequences directed against il-17a, il-17f and/or il17-a/f and polypeptides comprising the same |
EP4105231A1 (en) | 2011-05-05 | 2022-12-21 | Merck Patent GmbH | Amino acid sequences directed against il-17a, il-17f and/or il17-a/f and polypeptides comprising the same |
EP3363815A1 (en) | 2011-05-05 | 2018-08-22 | Merck Patent GmbH | Amino acid sequences directed against il-17a, il-17f and/or il17-a/f and polypeptides comprising the same |
WO2012175740A1 (en) | 2011-06-23 | 2012-12-27 | Ablynx Nv | Immunoglobulin single variable domains directed against ige |
WO2013168108A2 (en) | 2012-05-09 | 2013-11-14 | Novartis Ag | Chemokine receptor binding polypeptides |
WO2014087010A1 (en) | 2012-12-07 | 2014-06-12 | Ablynx N.V. | IMPROVED POLYPEPTIDES DIRECTED AGAINST IgE |
WO2015193452A1 (en) | 2014-06-18 | 2015-12-23 | Ablynx Nv | Kv1.3 binding immunoglobulins |
US11447573B2 (en) | 2016-07-20 | 2022-09-20 | Nanjing Legend Biotech Co., Ltd. | Multispecific antigen binding proteins and methods of use thereof |
US11472881B2 (en) | 2016-10-11 | 2022-10-18 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against CTLA-4 |
WO2018091606A1 (en) | 2016-11-16 | 2018-05-24 | Ablynx Nv | T cell recruiting polypeptides capable of binding cd123 and tcr alpha/beta |
WO2018220225A1 (en) | 2017-06-02 | 2018-12-06 | Ablynx Nv | Aggrecan binding immunoglobulins |
US11905327B2 (en) | 2017-12-28 | 2024-02-20 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against TIGIT |
US11713353B2 (en) | 2018-01-15 | 2023-08-01 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies and variants thereof against PD-1 |
US11958903B2 (en) | 2018-03-30 | 2024-04-16 | Nanjing Legend Biotech Co., Ltd. | Single-domain antibodies against LAG-3 and uses thereof |
WO2022178255A2 (en) | 2021-02-19 | 2022-08-25 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies that neutralize sars-cov-2 |
WO2024083843A1 (en) | 2022-10-18 | 2024-04-25 | Confo Therapeutics N.V. | Amino acid sequences directed against the melanocortin 4 receptor and polypeptides comprising the same for the treatment of mc4r-related diseases and disorders |
Also Published As
Publication number | Publication date |
---|---|
AU7298398A (en) | 1998-06-10 |
EP1027073A2 (en) | 2000-08-16 |
WO1998022141A3 (en) | 1999-01-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1027073A2 (en) | Enhanced effects for hapten conjugated therapeutics | |
AU706723B2 (en) | Amplification of the VB-12 uptake system using polymers | |
KR100290632B1 (en) | Immunogenic antigen conjugates and synthetic peptide carriers and vaccines containing them | |
US20070134259A1 (en) | Methods and compositions for pharmacologially controlled targeted immunotherapy | |
EP2245047B1 (en) | Hydrophobic modified pres-derived peptides of hepatitis b virus (hbv) and their use as vehicles for the specific delivery of compounds to the liver | |
Kowalczyk et al. | Peptide lipidation–a synthetic strategy to afford peptide based therapeutics | |
EP1034795A2 (en) | Conjugates of lipids and biologically active compounds | |
JPH0674210B2 (en) | Enhancement of immunogenicity of antigen | |
EP2673004A1 (en) | Hydrophobic modified peptides and their use for liver specific targeting | |
ES2210514T3 (en) | SPECIFIC UNION COUPLE MEMBER CYCLING CONJUGATES | |
US5043158A (en) | Immunogenic compositions containing ordered carriers | |
EP1237580A2 (en) | Amphiphilic polymers and polypeptide conjugates comprising same | |
JP2020037701A (en) | Glycopolysialylation of non-blood coagulation protein | |
US9849174B2 (en) | Methods and compositions related to immunogenic fibrils | |
CN104936613B (en) | Sugar chain addition connexon, the compound or its salt containing sugar chain addition connexon and physiological activator and its manufacturing method | |
DE69534382T2 (en) | PEPTIDES, USED AS SUPPORT IN IMMUNOGENIC CONSTRUCTS SUITABLE IN THE DEVELOPMENT OF SYNTHETIC VACCINES | |
KR20070122563A (en) | Monovalent and polyvalent synthetic polysaccharide antigens for immunological intervention in disease | |
JP2001521733A (en) | Fusion protein of human epidermal growth factor and human angiogenin and method for producing the same | |
JP2011518840A (en) | Peptidyl diacylglyceride | |
JPH07507541A (en) | How to treat diabetes | |
CA2124217A1 (en) | Inactivation of cytotoxic drugs | |
JP2837866B2 (en) | Synthetic vaccine against foot-and-mouth disease and production method thereof | |
JPH0585942A (en) | Interferon-hyaluronic acid and/or its salt combined material | |
CA2155953A1 (en) | Protein conjugates, compositions containing them and their applications as medicament | |
WO2004011486A2 (en) | Method for solubilizing hydrophobic peptides and use thereof for inducing an antitumoral and/or anti-infectious ctl response |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AU CA JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AU CA JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1997949336 Country of ref document: EP |
|
NENP | Non-entry into the national phase in: |
Ref country code: CA |
|
WWP | Wipo information: published in national office |
Ref document number: 1997949336 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1997949336 Country of ref document: EP |