EP0419462A1 - Therapies ameliorees a base d'immunotoxines utilisant des especes a chaine-a de ricine purifiee - Google Patents

Therapies ameliorees a base d'immunotoxines utilisant des especes a chaine-a de ricine purifiee

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Publication number
EP0419462A1
EP0419462A1 EP88906547A EP88906547A EP0419462A1 EP 0419462 A1 EP0419462 A1 EP 0419462A1 EP 88906547 A EP88906547 A EP 88906547A EP 88906547 A EP88906547 A EP 88906547A EP 0419462 A1 EP0419462 A1 EP 0419462A1
Authority
EP
European Patent Office
Prior art keywords
rta
immunotoxin
ricin
composition according
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP88906547A
Other languages
German (de)
English (en)
Other versions
EP0419462A4 (en
Inventor
Patrick J. Scannon
Russell T. Kawahata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xoma Royalty Corp
Original Assignee
Xoma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xoma Corp filed Critical Xoma Corp
Publication of EP0419462A1 publication Critical patent/EP0419462A1/fr
Publication of EP0419462A4 publication Critical patent/EP0419462A4/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A61K51/1096—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A61K47/6819—Plant toxins
    • A61K47/6825—Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin
    • A61K47/6827—Ricin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention relates generally to the use of im unotoxins in chemotherapy and other human treat- ment applications and, more particularly, to improving the pharmacokinetics and toxicity characteristics of ricin-based immunotoxins.
  • cancerous cells or other diseased cel ⁇ lular material could be selectively killed without the nonspecific side-effects rampant with most common treatment regimes.
  • This "magic bullet" combination of a monoclonal antibody conjugated to a toxin is known as an immunotoxin.
  • the most widely used toxin component of immu ⁇ notoxins is the ricin toxin A-chain.
  • Ricin is a plant lectin produced by castor beans (Ricinus communis) and consists of two polypeptides; chains A and B, linked by a single disulphide bond. Both chains are important in native ricin toxicity.
  • the B-chain of ricin binds to glycoproteins and glycolipids on cell surfaces, and the A-chain then penetrates the cell. Once incorporated into the cytosol, the A-chain can catalytically inacti ⁇ vate ribosomal protein synthesis , ultimately causing cell death.
  • researchers separate out the B-chain , and conjtigate just the A-chain to the antibody.
  • RTA-based immunotoxins are highly specific cytotoxic agents, capable of removing more than 99% of the target cells without damaging unrelated cells.
  • RTA-based immunotoxins have generally been less than ideal, perhaps because of rapid clearance from the blood stream which would re ⁇ cute the amount of immunotoxin available to interact with the tumor.
  • any addi ⁇ tional processing steps in the production of a pharma ⁇ ceutical product particularly those entailing removing certain moieties and thus altering naturally occurring proteins (such as ricin) require extensive monitoring of the reaction to ensure minimal heterogeneity in the final product.
  • the potential for quality control problems becomes greatly magnified.
  • the immunotoxin should retain high speci- fie cytotoxicity, yet minimize the host's nonspecific toxicity. It should also be relatively simple and in ⁇ expensive to manufacture reproducibly. Ideally, the immunotoxin will still retain certain natural clearance properties, however, because some clearance is prefer- red to minimize nonspecific toxicity in the host.
  • the present invention fulfills these needs.
  • the present invention provides novel methods for the _in vivo treatment of a patient utilizinq immu ⁇ notoxins comprising a specific bindinq component com- plexed with a ricin toxin A-chain (RTA) component, wherein the relative amount of RTA-30 species within the RTA of the immunotoxins is increased over the amount of RTA-30 species found in naturally-occurring ricin.
  • the RTA-30 species may be separated from other RTA species found in ricin by standard chromatographic techniques to achieve RTA-30 concentrations up to sub ⁇ stantial homogeneity, about 95% or more.
  • the novel RTA-30-based immunotoxins can be utiliz ⁇ ed to selectively remove harmful cell populations from a patient, with minimal nonspecific toxicity.
  • Pharma ⁇ ceutical compositions are also provided for use in the treatments.
  • Figure 1 shows the pharmacokinetics of immunotoxins having different RTA species.
  • FIGS 2-4 show the biodistribution of immunotoxins having different RTA species.
  • Figures 5 and 6 show the results of perfusion studies utilizing immunotoxins having different RTA species.
  • Novel methods are provided for improving ricin toxin A-chain (RTA)-based immunotoxin therapy in human patients by utilizing an enriched concentration of the RTA-30 species of RTA as a toxic component of immunotoxins.
  • RTA-30 species in concen ⁇ trations higher than round in naturally-occurring ricin, increased blood residence time of the immuno ⁇ toxin is achieved, without significantly increasing nonspecific toxicity.
  • the immunotoxins of the puesent invention have less non-specific toxicity.
  • the methods and compositions of the present in- vention provide means for substantially improved treat ⁇ ments for, e.g., the removal of undesired cell popula ⁇ tions from a patient, such as cancerous cells in tumors or cells responsible for graft versus host disease.
  • RTA-30 refers to a species of ricin toxin A-chain havinq a molecular weight of approximately 30 kD, such as described in de ⁇ tail by Fulton et al. J. Biol. Chem. , 281:5314-5319 (1986) and Vidal e_t al. Int. J. Cancer, 36:705'>-711 (1985) , both of which are incorporated herein by refer ⁇ ence.
  • RTA-30 typically com ⁇ prises about 65% of the protein obtained from naturally occurring ricin, with RTA-33 (about 33 kD) comprising most of the remaining protein.
  • the two species have the same isoelectric point (about 7.6) and exhibit sim ⁇ ilar _ir ⁇ vitro activities, such as protein synthesis in ⁇ hibition and cell toxicity.
  • a substantial difference between the two species is that RTA-30 experimentally exhibits lower glycosylation than RTA-33, with the RTA- 30 species having a single complex oligosaccharide, and the RTA-33 having a high mannose type oligosaccharide in addition to the complex unit found on the RTA-30 (see , Foxwell e_t a .. , Biochem. Biophys. Acta., 840:193- 203 (1985) , which is incorporated herein by reference) .
  • the lower carbohydrate content of RTA-30 provides long ⁇ er blood clearance for the immunotoxin. The presence of some sugars can provide a reasonable clearance rate, however, minimizing kidney damage and other nonspecific toxicity.
  • RTA-30 separation may be accomplished by a variety of well known separation pro ⁇ cedures (see , e.g. , Fulton e_t al. , Vidal e_t al. , and Foxwell e_t al. , supra) . These can include gel filtra ⁇ tion, anion or cation exchange chromatography, electro- phoresis, hydrophobic chromatography, affinity chroma ⁇ tography, and the like.
  • a preferred means of RTA-30 separation is based on the different glycosylation pat- terns between RTA-30 and RTA-33. Carboxymethylcellu- lose columns run with a sodium chloride gradient readi ⁇ ly separate the two predominant species.
  • Concanavalin A may allow for separation when used in an affinity chromatography procedure, because of different affinities for RTA-33 and RTA-30. It will be readily apparent to those skilled in the art that these separation procedures are reproducible and economical, and do not produce contaminating by-products , unlike many chemical modification processes.
  • RTA-30 concentrations in the immunotoxin preparations may be increased well above the level in naturally occurring ricin (i.e., about 65%) .
  • Purified RTA-30 of concentra ⁇ tions of about 75% or greater are preferred, with con ⁇ centrations of 85 to 95%, or more, most preferred.
  • other species of RTA may be added to purified RTA-30 to control the relative species concentrations.
  • the RTA species will be utilized at concen ⁇ trations that maximize in vivo localization, yet mini ⁇ mize nonspecific toxicity.
  • the terms "immunotoxin” re- fers to the combination of a specific binding component complexed with a cytotoxic agent (e.g. , RTA-30) .
  • the specific binding component provides the means for de ⁇ livering the toxic agent to a particular cell type, typically preselected, such as cells forming a carci- noma.
  • the two components are complexed in a manner that is likely to ensure that the toxic agent is not separated from the binding agent until attachment of the entire immunotoxin to a cell within a preselected cell population.
  • the two components are usually chemi- cally " bonded together by any of a variety of well-known chemical procedures.
  • the linkage may be by way of heterobifunctional linkers, such as, N-succi- nimidyl 3- (2-pyridyldithio) propionate (SPDP) , carbodi- imide, gluteraldehyde, 2-iminothiolane or the like, to form peptide, amide, ester, thioester, disulfide bridg ⁇ es or other bonds.
  • the linkage may also be between amino acid and sugar moieties of the two components, depending upon the particular application.
  • each immuno ⁇ lobulin will contain at least about 1-2 RTA-30 moieties, preferably 2-3 or more, and, most preferably, about 2.6.
  • Production of various immunotoxins is well-known within the art and can be found, for example, in "Monoclonal Antibody-Toxin Con- jugates; Aiming the Magic Bullet," Thorpe et a_l. , Mono ⁇ clonal Antibodies in Clinical Medicine, Academic Press, pp. 168-190 (1982) , and U.S. Patents 4,671,958, and 4,590,071, all of which are incorporated herein by ref ⁇ erence.
  • the specific binding agent acting as the de ⁇ livery vehicle for the cytotoxic agent in the immuno ⁇ toxin, can be obtained from a number of sources.
  • intact immunoglobulins or their fragments such as Fv, Fab, F(ab_) , half antibody molecules, (i.e., a single heavy/light chain pair) , will be used.
  • immunoglobulins are monoclonal anti ⁇ bodies of the IgM or IgG isotype, of mouse, human or other mammalian origin. Other proteins or agents capa ⁇ ble of binding to markers, including growth factor or hormone receptors, on selected cell populations may be utilized.
  • the antibodies are capable of binding to epitopes of markers on selected cell popula ⁇ tions, such as neoplastic cells or T-cells.
  • the marker is generally a unique surface protein, but a large variety of markers, such as other proteins, gl copro- teins, lipoproteins, polysaccharides and the like, which are produced by or displayed by the cells to be recognized by the immunotoxin, can be utilized in ac- cordance with the present invention.
  • the general immu ⁇ nization, fusion, screening and expansion methods of monoclonal antibody technology, as well as the choice of markers, are well known to those skilled in the art and do not form part of the present invention.
  • the immunotoxin may be utilized in prophylac ⁇ tic and therapeutic settings to aid in the killing or removal of a wide variety of predetermined cell popula ⁇ tions in a mammal, including infectious organisms, de ⁇ pending upon the disease state.
  • the specific binding protein of a immunotoxin may recognize markers on tumor cells, immune cells (e.g., T-cells or B-cells) , hormone responsive cells (e.g. , to insulin) and growth factor responsive cells (e.g. , to interleu- kins) , fungi, bacteria, parasites, or virus infected cells.
  • Immunotoxins are utilized in cancer therapy as follows: Antimelanoma immunotoxin XMMME-001-RTA-30 can be prepared and then tested extensively _in vitro, on human tissues, and in animals to establish precise dosages for the treatment of human melanoma as describ ⁇ ed in U.S. Patent No. 4,590,071. Hybridoma cell line XMMME-001 was deposited with the American Type Culture Collection (ATCC) and given ATCC Accession No. HB 8759.
  • ATCC American Type Culture Collection
  • XMMME-001-RTA in conjunction with a standard oncologic dose of an immu- nosuppressive agent, such as methotrexate , cyclophos- phamide, prednisone, or cyclosporine, in order to blunt the immune system to prevent ' immune response against the immunotoxin.
  • an immu- nosuppressive agent such as methotrexate , cyclophos- phamide, prednisone, or cyclosporine
  • the treatment may be repeated, up to three times.
  • Immunotoxins incorporat ⁇ ing enhanced levels of RTA-30 will require substantial- ly smaller dosages to be effective, typically at least about 10-25% less, but in some therapies about 30 to 50% less.
  • immunotoxins are utilized prophylac- tically in improving bone marrow transplantation, by reducing the likelihood of graft versus host disease (GVHD) , as follows:
  • BMT bone marrow transplanta ⁇ tions
  • diseases such as hematological malignancies, aplastic anemia, Severe Combined Immunodeficiency (SCID) or variants, certain inborn errors of metabolism, or certain solid tumors.
  • SCID Severe Combined Immunodeficiency
  • bone marrow donors fall into categories of genotypically haplotype matched or unrelated partially-phenotypic HLA matched. These categories of donors result in a 100% incidence of GVHD in the recipient.
  • BMT treatment with allogeneically matched sibling donors results in an incidence of GVHD of about 30% or more.
  • a preferred immunotoxin, XMMLY-H65-RTA-30 consists of an anti-CD5 (pan T lymphocyte) specific monoclonal antibody conju ⁇ gated to RTA-30.
  • the immunotoxin can be infused start- ing on day 10 post-transplant for 7 consecutive days (days 10-17) at a dose of about 0.05 to 0.1 mg/kg/day. Preparation of the immunotoxin XMMLY-H65-RTA is described in U.S. Serial No.
  • XMMLY-H65-RTA immunotoxin will kill T-cells when incu ⁇ bated with human marrow without causing toxicity to hematopoietic progenitor cells.
  • the biologic activity of this pan-T-cell immunotoxin indicates that it can be a potent anti-T-cell cytotoxin, able to abrogate T-cell reactions contributing to the pathogenesis of GVHD, particularly when the RTA component is enriched with RTA-30.
  • a pharmaceutical carrier can be any compati ⁇ ble nontoxic substance suitable to deliver the immuno ⁇ toxins to the patients.
  • Sterile water (with or without excipients) , alcohol, fats, waxes and inert cells may be used as the carrier, often in conjunction with ac ⁇ ceptable adjuvants, such as buffering agents, dispers ⁇ ing agents, and the like.
  • the immunotoxins of the present invention may be used as separately administered compositions or in conjunction with other cytotoxic agents. These can in ⁇ clude various immunotoxins and che otherapeutic drugs , such as vindesine, methotrexate, adriamycin, and cis- platinum, various radionuclides , and the like.
  • Pharma- ceutical compositions can include "cocktails" of vari ⁇ ous immunotoxins with cytotoxic agents in conjunction with the immunotoxins of the present invention.
  • a typical pharmaceutical composition for intravenous infusion could be made up to contain about 150 ml of normal saline and about 0.1 mg of immunotoxin.
  • An amount adequate to accomplish at least partial killing of a cell population is defined as a "therapeutically effective dose.” Amounts needed to achieve this dosage will depend upon the severity of the disease and the general state of the patient's own immune system, but generally range from about 0.005 to about 5.0 mg of immunotoxin per kilogram of body weight, with doses of about 0.05 to 2.0 mg/kg/dose being more commonly used. For prophylactic applica- tions, compositions containing the present immunotoxins or cocktails, may also be administered in similar dosaqes . For treatment of melanomas, preferred dose regimens are about 0.4 mg/kg, administered daily for five days, or about 0.1 mg/kg to 2.0 mg/kg in a single dose.
  • immunotoxin dosages are preferably 0.05-0.3 mg/kg/day for up to about 14 days. Doses may be repeated as often as tol- erated.
  • Actual methods for preparing and administering pharmaceutical compositions, including preferred dilu ⁇ tion techniques for injections of the present composi ⁇ tions, are well known or will be apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science, 16th
  • Kits can also be supplied utilizing the sub ⁇ ject immunotoxins in the treatment of various disease states.
  • the subject immunotoxins of the present invention may be provided in containers, usually in a lyophilized form, either alone or in conjunction with additional immunotoxins or non-complexed antibodies specific for desired epitopes.
  • the immunotoxins and antibodies which may be conjugated to a label or un ⁇ conjugated, are included in the kits with physiologi ⁇ cally acceptable buffers, in accordance with the teach ⁇ ing of the art.
  • these materials will be present in less than about 5% wt. based on the amount of active ingredient, and usually present in total amount of at least about 0.001% wt. based again on the active ingredient concentration.
  • an inert extender or excipient to dilute the active ingredients , where the excipient may be present in from about 1% to 99% wt. of the total composition.
  • the diafiltrate is applied to a Sepharose 4B column (Pharmacia Fine Chemicals, Piscataway, N.J.) and the nonbinding flow-through containing ricin was loaded onto an acid-treated Sepharose column in order to sepa- rate, the ricin toxin A-chain from the whole ricin (as described in U.S. 4,590,071, column 3, lines 26-52).
  • the eluant thus obtained was diafiltered against Tris buffer (lOmM Tris, lOmM NaCl) , and the resulting fil ⁇ trate was passed through a QAE Sepharose Fast Flow col- umn (Pharmacia Fine Chemicals) equilibrated to the same buffer.
  • the RTA obtained above was adjusted in NaCl concentration to 0.9 w . %, and purified to remove toxin B-chain impurities by applying to a Sepharose column previously coupled to goat anti-RTB antibodies. 3. RTA Species Separation.
  • the cell line XMMME-001 which secretes a human melanoma specific monoclonal antibody, was depos ⁇ ited with the A.T.C.C. and designated Accession No. HB8759. Immunotoxins utilizing that monoclonal anti- body were prepared as detailed in U.S. Patent No.
  • H-65 anti ⁇ body A.T.C.C. No. HB9286
  • An H-65 tissue culture harvest was concen ⁇ trated and the pH adjusted to 8.5. The solution was applied to an immobilized Staph. Protein A Column and eluted with 0.1 M Citrate, pH 4.5. The eluate was dia ⁇ filtered against lOmM Hepes Buffer, 0.25 M NaCl, pH 7.3, and then applied to a QAE Sepharose Fast Flow column. The antibody passed through the column, and was diafiltered against PBS, pH 7.0, 5% dextrose. The antibody was activated for coupling to the RTA with SPDP (as described in U.S.
  • XMMME-OOl-RTA-30 and XMMME-00l-RTA-33 puri- fied on Cibacron TM blue (Ciba-Geigy, Los Angeles, CA)
  • Iodo-Gen was dissolved in dichloromethane to a concentration of 1.0 mg/ml, and 50ml (i.e. , lOmg/lOOmg protein) was dried onto the bottom of each reaction vial under a stream of N_ .
  • the vials were rinsed once with lOmM phosphate-buffered saline (PBS) , pH 7.0.
  • XMMME-001-RTA-30 0.50mg in 0.40ml, was then added to one of the vials, followed by 0.50mCi of I.
  • XMMME-001-RTA 0.50mg in 0.40ml
  • XMMME-001-RTA-33 was determined to be 1.65x10 cpm/mg.
  • the isotopes were counted using an LKB Autogam a counter, set for dual isotope counting and automatic decay and spillover correction. These data were used to calculate the percent of the injected dose and the percent of dose/gm in the serum and organs.
  • the labelled immunotoxins were run on a 3-12% gradient SDS-PAGE gel with molecular weight markers.
  • the gels were stained with Coomassie blue and auto- radiographed, then cut into sections for counting. There were four bands visible on the stained gradient gels. These bands corresponded to an albumin band and three immunotoxin bands representing antibody conjugated to 1, 2, or 3 RTA chains. Autoradiography of these gels indicated that a majority of the radio ⁇ activity was associated with the immunotoxin bands. When the gels were cut and counted, 88% of the activity was recovered in the immunotoxin bands (approximately 27% in each band) . The remaining activity was associ- ated with an area of the gel corresponding to free antibody (6%) or the area between free antibody and the dye front (6%) .
  • the pharmacokinetics of the immunotoxins are shown in Figure 1.
  • the plasma clearance curve of each isotope was biphasic, showing an initial rapid decrease followed by a slower phase.
  • the biodistribution data are shown in Figures 2-4.
  • the percentage of the injected dose in the plasma compart ⁇ ment was two-fold higher than that of the XMMME-001- ' RTA-33 during the study period.
  • the use of immunotoxins enriched in RTA-30 for in vivo therapy substantially reduces the blood clear- ance time of the immunotoxin, without interfering with the immunotoxin' s specific toxicity.
  • smaller doses of immunotoxin treatments are feasible, which reduce the side effects of immunotoxin therapy and improve the patient's prognosis for the entire treat- ment.
  • allergic reactions and other harmful aspects of an immune response generated against the immunotoxin are diminished.
  • the production of RTA-30 enriched immunotoxins remains substantially the same as for prior RTA-based immunotoxins, minimizing additional quality control and economic considerations.

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Abstract

On obtient des thérapies améliorées à base d'immunotoxines en utilisant des immunotoxines comprenant de la ricine enrichie dans des espèces à chaîne-A de ricine purifiée, conjointement avec des éléments de liaison spécifique, tels que notamment des anticorps monoclonaux réagissant spécifiquement avec des marqueurs de populations de cellules prédéterminées.
EP19880906547 1987-07-17 1988-07-12 Improved immunotoxin therapies utilizing purified ricin a-chain species Ceased EP0419462A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7482487A 1987-07-17 1987-07-17
US74824 1987-07-17

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EP0419462A1 true EP0419462A1 (fr) 1991-04-03
EP0419462A4 EP0419462A4 (en) 1991-07-17

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NZ (1) NZ225372A (fr)
WO (1) WO1989000583A1 (fr)
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Publication number Priority date Publication date Assignee Title
IL95578A (en) * 1989-09-15 1998-08-16 Gen Hospital Corp Conjugate vaccine formed from a polysaccharide and a c protein of b-streptococcus
US5648241A (en) * 1989-09-15 1997-07-15 The General Hospital Corporation Conjugate vaccine against group B streptococcus
ZA937034B (en) * 1992-09-24 1995-06-23 Brigham & Womens Hospital Group B streptococcus type II and type V polysaccharide-protein conjugate vaccines
ES2160601T3 (es) * 1992-09-24 2001-11-16 Brigham & Womens Hospital Vacunas de conjugado de polisacaridos de estreptococos del grupo b tipo ii y tipo v-proteina.
US6284884B1 (en) 1995-06-07 2001-09-04 North American Vaccine, Inc. Antigenic group B streptococcus type II and type III polysaccharide fragments having a 2,5-anhydro-D-mannose terminal structure and conjugate vaccine thereof

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Publication number Priority date Publication date Assignee Title
US4481946A (en) * 1980-08-14 1984-11-13 Altshuler John H Bone marrow transplant method and apparatus
US4612007A (en) * 1981-06-16 1986-09-16 Edelson Richard Leslie Method and system for externally treating the blood
US4489710A (en) * 1981-06-23 1984-12-25 Xoma Corporation Composition and method for transplantation therapy
US4520226A (en) * 1982-07-19 1985-05-28 The United States Of America As Represented By The Department Of Health And Human Services Treatment of graft versus host disease using a mixture of T-lymphocyte specific monoclonal antibody: ricin conjugates
US4590071A (en) * 1984-09-25 1986-05-20 Xoma Corporation Human melanoma specific immunotoxins
US4689401A (en) * 1986-03-06 1987-08-25 Cetus Corporation Method of recovering microbially produced recombinant ricin toxin a chain
JPH01502195A (ja) * 1987-01-27 1989-08-03 ゾーマ・コーポレーション 細胞毒性結合物の増強法
JPH03503887A (ja) * 1988-02-03 1991-08-29 エクソウマ　コーポレーション 自己免疫疾患に対する抗ｔ細胞イムノトキシンの治療的使用

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NZ225372A (en) 1991-04-26
WO1989000583A1 (fr) 1989-01-26
EP0419462A4 (en) 1991-07-17

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