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WO1991005568A1 - Materiaux et procedes de traitement de tissu etranger - Google Patents

Materiaux et procedes de traitement de tissu etranger Download PDF

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Publication number
WO1991005568A1
WO1991005568A1 PCT/GB1990/001621 GB9001621W WO9105568A1 WO 1991005568 A1 WO1991005568 A1 WO 1991005568A1 GB 9001621 W GB9001621 W GB 9001621W WO 9105568 A1 WO9105568 A1 WO 9105568A1
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WO
WIPO (PCT)
Prior art keywords
preparation
monoclonal antibodies
antibody
cells
skin
Prior art date
Application number
PCT/GB1990/001621
Other languages
English (en)
Inventor
Hermann Waldmann
Kenneth Ian Welsh
Michael Gordon Thick
David Hirsch Taube
Geoffrey Hale
Original Assignee
Lynxvale Ltd.
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
Priority claimed from GB898923712A external-priority patent/GB8923712D0/en
Application filed by Lynxvale Ltd. filed Critical Lynxvale Ltd.
Priority to BR909007769A priority Critical patent/BR9007769A/pt
Priority to FI921746A priority patent/FI921746L/fi
Priority to MX9203715A priority patent/MX9203715A/es
Priority to CA002069342A priority patent/CA2069342A1/fr
Publication of WO1991005568A1 publication Critical patent/WO1991005568A1/fr
Priority to NO92921507A priority patent/NO921507L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/289—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD45
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the problem of rejection of foreign tissue.
  • it provides materials and methods for the amelioration of rejection of foreign tissue.
  • Transplantation of organs and tissues between identical twins can be successfully achieved and does not lead to graft rejection.
  • allogenic tissue and organ transplants are carried out, or where allogeneic cadaver skin is used as a wound dressing
  • the immune system of the recipient recognises the graft or dressing as foreign, and mounts an immune response against the foreign tissue. This response depends upon genetically determined antigenic differences between the donor and the recipient and rejection can take place in at least two ways. The first involves antibody and complement and has been referred to as hyperacute graft rejection, while the second involves activated T-cells and is referred to as acute graft rejection.
  • a donor organ for transplantation is selected, which closely matches both the tissue and blood types of the recipient patient. Therefore, before the transplant operation, blood and tissue samples of both the patient and donor will be matched as closely as possible with respect to at least the ABO and Rh blood group systems and the MHC tissue type system.
  • the rejection of the donor organ will occur very quickly- (within minutes and up to 48 hours). This phenomenon is known as hyperacute graft rejection and it seems to occur when the recipient patient is pre- sensitized against the donors blood and/or tissue types. Such pre-sensitization of the recipient patient may occur spontaneously, or by virtue of previous grafts, blood transfusions or pregnancy. In such cases of pre- sensitization, the recipient patient will usually have pre-formed circulating antibodies specifically directed against the blood and/or tissue type of the donor. The pre-existing antibodies will then bind to the foreign cells transported into the recipient patient by the donor organ, and this cell-antibody binding will then stimulate complement mediated cytotoxici'ty or antibody-dependent cell-mediated cytotoxicity (ADCC).
  • ADCC complement mediated cytotoxici'ty or antibody-dependent cell-mediated cytotoxicity
  • the antibody coated foreign cells are recognized by cytotoxic cells (e.g., monocytes and polymorphonuclear cells) having Fc receptors. Binding will occur between the foreign cells and cytotoxic cells via the antibody- Fc receptor bridge and lysis of the foreign cells will follow.
  • cytotoxic cells e.g., monocytes and polymorphonuclear cells
  • donor organs may be perfused with monoclonal antibodies against MHC antigens or dendritic cells.
  • the authors also suggested however, that even if human donor kidneys were depleted of dendritic cells, the presence of the HLA-DR antigen on human endothelial cells may still cause rejection.
  • the human kidney endothelium expresses MHC class II antigens, so that although the dendritic cells are strongly MHC II positive, monoclonal antibodies against these antigens cannot be used in the same way for human renal transplantation to destroy the interstitial dendritic cells, since the endothelial cells of the graft are likely to be damaged and as a consequence, the graft deprived of its blood supply and lost.
  • interstitial dendritic cells can be distinguished from kidney endothelial cells by their expression of leucocyte common antigen, (LC or LCA, also known as CD45 and T200) studies have been carried out in which human kidney allografts were perfused with anti-LC monoclonal antibodies prior to transplantation, in an effort to inactivate or destroy the dendritic cells.
  • LC or LCA leucocyte common antigen
  • the former antibody is non-lytic via the route of complement fixation and lytic via the route of ADCC, whilst the latter is not lytic via either route. Lysis via ADCC depends on various host leucocytes moving into the kidney to exert their cytotoxic effects.
  • the results suggested (test numbers were small and the study was neither randomized nor controlled) that the mouse IgG2a anti-LC had favourable effects in reducing the incidence of graft rejection and improving renal function as compared to non-perfused controls.
  • the mouse IgG3 anti-LC appeared to have no such effect. (Taube D., et al. Transplantation Proceedings Vol.XIX, No.l pl961-1963 1987).
  • an antibody should be used which mediates" as many mechanisms as possible of the immune response.
  • pairs of antibodies in achieving synergistic lysis has been investigated.
  • combinations of antibodies recognizing different epitopes of the LC antigen were investigated in an attempt to improve the lytic potency of the antibodies.
  • the study showed that certain pairs of rat antibodies of isotype IgG2b although not lytic separately in the presence of human complement, became lytic when used together.
  • the study also showed that the presence of a rat IgG2a antibody interfered with the lytic ability of the synergistic pair.
  • the authors suggested that such pairs of synergistic antibodies may be useful for purging organ grafts of interstitial passenger leucocytes to reduce their immunogenicity, although there was no practical disclosure of such use.
  • allograft function was significantly better in patients with allografts having a >50% uptake of antibody.
  • the present inventors have now produced as an embodiment of the present invention, a monoclonal antibody system which mediates cell lysis by both the complement and antibody-dependent cell-mediated pathways, but which has no effect in the stimulation of rejection of the grafted donor organ.
  • the monoclonal antibody system is anti-LC (also called anti-CD45) .
  • the present invention provides a preparation for the treatment of foreign tissue which comprises an anti- CD45 specific antibody system which mediates complement- dependent cell lysis in the presence of human complement.
  • the treatment may be ex-vivo.
  • the foreign tissue may be any tissue which would be seen by a recipient as not originating from said recipient.
  • the foreign tissue may be xenogeneic or allogeneic.
  • the antibody ' system may comprise a single antibody having the necessary specificity or polyclonal antiserum which provides antibodies having the required specificity.
  • the antibody system may comprise two or more monoclonal antibodies, which most preferably act synergistically in effecting complement- mediated cell lysis, but may not mediate complement- dependent cell lysis separately.
  • the synergistic monoclonal antibodies may be against different epitopes selected from the P, Q, R, S or T epitopes of CD45.
  • synergistic pairs of monoclonal antibodies may be of any of the following combinations: anti-P: anti-Q anti-P: anti-R anti-P: anti-S anti-Q: anti-R anti-Q: anti-S anti-Q: anti-T anti-R: anti-S,
  • the synergistic pair may be anti-P and anti-Q.
  • the antibodies may be rat monoclonal antibodies, particularly of isotype IgG2b.
  • the present invention also provides a method of preparing foreign tissue ex-vivo prior to transplantation or use as a dressing material, which comprises treating the tissue with a preparation as described.
  • the foreign tissue may be xenogeneic or allogeneic.
  • the foreign tissue may be skin, in which case the skin is soaked in said preparation.
  • the foreign tissue may be an organ such as the kidney, in which case the organ may be perfused with said preparation.
  • the method and preparations as provided by the invention are applicable to any foreign tissue where there is a need to reduce the immunogenic effect of cells (such as passenger leucocytes) which express leucocyte common antigen (CD45).
  • the present invention also provides a method of treating a patient which comprises transplanting or dressing said patient with foreign tissue which has been treated with a preparation as described.
  • the patient may be suffering from conditions related to the defective or inefficient operation of an organ such as the kidney.
  • the patient may be suffering from a skin condition such as burns, leg ulcers or the like.
  • Cell suspensions was prepared from human tonsil by chopping with a scalpel blade, followed by passage through a sieve to remove connective tissue. The cells were washed twice in lOmM tris HC1 pH 7.3 containing 0.15 M NaCl, and resuspended in the same buffer at 5xl0°/ml_. Cell membranes were prepared by lysis with Tween 40 (Standring R., et al. Biochim. Biophys Acta 1978; 50-85) and stored at -70°C until required.
  • an anti-LC monoclonal antibody e.g. YTH 54.12, YTH 24.5 and F10-89-4 all available from Serotec, Bankside, Station Approach, Kidlington, Oxford, England, 0X5 1JE
  • CNBr- activated Sepharose Pharmacia
  • Cell membranes (approximately lO 1 '- * cell equivalents) were resuspended in lysis buffer PBS containing 0.5% Nonidet P40, 0.1% SDS, and ImM phenyl methyl sulphonyl fluoride) and mixed with 2ml of antibody coupled Sepharose.
  • a DA rat was immunized subcutanously with 5-10 x 10° human peripheral mononuclear cells enriched for T cells. One month and . 2 months later, it received similar cells intravenously. Three days after the final dose, the rat spleen cells were fused with the rat myeloma line Y3 Ag 1.2.3. using polyethylenglycol. (Galfre G. , et al. Nature 277:131, 1979). The fusion was labelled YTH. Hybrid cells were grown in selective medium and the hybrid myelomas were cloned and recloned on soft agar.
  • Immunoglobin fractions were isolated from the ascitic fluids by precipitation with (NH)2S ⁇ and were redissolved in phosphate-buffered saline (PBS) containing 0.02% sodium azide for storage at 4°C or -30°C.
  • PBS phosphate-buffered saline
  • Binding to fixed cells or to purified LC antigen was carried out using a solid-phase enzyme-linked binding assay (Cobbold S.P. et al 1981 J. Immunol. Methods 44: 125).
  • the test monoclonal antibody was incubated in microtiter plates containing adsorbed purified antigen (lO ⁇ -lO ⁇ cell equivalents per well) or fixed cells, followed by a detection reagent of monoclonal mouse anti(rat lg) coupled to ⁇ -galactosidase. Finally the enzyme substrate was added and a colour change measured in a spectrophotometer.
  • the central well contained 10 ⁇ l of subclass-specific antiserum, and each outer well contained 10 ⁇ l of -'-' ⁇ C-labelled culture supernatant plus sufficient carrier rat lg previously titrated to give optimal precipitation.
  • the precipitin lines had developed, the plate was dried and exposed to X-ray film for about 5 days. For each monoclonal antibody, only one antiserum gave a radioactive precipitin line corresponding with the subclass of that antibody.
  • the renal allografts were perfused with a mixture of the anti-CD45 monoclonal antibodies YTH 54.12 and YTH 24.5 which had been purified from ascites fluid using HPLC chromatography according to standard techniques. They are complement-fixing rat monoclonal antibodies of isotype lgG2b which together are lymphocytotoxic in the presence of human complement (Bindon, et al. Transplantation 1985; 40: 538-546).
  • Vials containing 2mg of each antibody in 2ml phosphate buffered saline were prepared.
  • a solution of human albumin was used as a control because it looks superficially the same as the antibody solution and was stored in identical vials. The vials were marked with a code. The relation of the code to the contents was not known to the clinical team until the end of the trial. Thus pretreatment of the graft with the monoclonal antibody pair or albumin was random. A modification of a previously described technique was used (Taube D., et al. Transplant Proc. 1987; XIX: 1961-1963). The allograft was prepared for transplantation by the standard method. The renal veins were clamped.
  • Cs cyclosporin
  • prednisolone All patients were immunosupressed with cyclosporin (Cs) and prednisolone. 8mg/kg of Cs was given orally before transplantation, followed by 16mg/kg per day, in 2 divided doses, for three days following the operation. The dose was reduced to lOmg/kg per day for the next four days and then adjusted to maintain whole blood trough levels of 200-300 ng/ml measured by the standard radioimmunoassay (Sandoz). Patients received 20mg/day of prednisolone for the first month, 15mg/day for the second month and 10 mg/day subsequently.
  • Sandoz standard radioimmunoassay
  • Actuarial patient survival in the two groups was similar. Patent survival was 97% and 92% at 1 year and 18 months post-transplant, respectively, in the group of patients receiving monoclonal antibody perfused allografts and 94% at 1 year and 18 months post- transplant in the controls. 2 patients receiving monoclonal antibody perfused allografts died (1 after an intracerebral haemorrhage, 3 months post-transplant and 1 from carcinomatosis 18 months post-transplant). Both patients had functioning allografts. 2 control patients died, both at 1 month post-transplant (1 from cytomegalovirus pneumonitis and 1 from systemic candidiasis) . Neither of their allografts was functioning.
  • Allograft survival was the same in both groups (Table II). 5 patients (3 with monoclonal antibody perfused allografts and 2 controls) lost their grafts within 48 hours of transplantation for technical reasons; 1 patient had uncontrollable bleeding at the time of surgery; 3 patients lost allografts (2 monoclonal antibody perfused and 1 control) as a result of primary renal arterial or venous thromboses; 1 patient had an ischaemic leg after surgery, the graft was abandoned and later removed.
  • the 3 monoclonal antibody perfused graft were lost beyond 48 h, none as a result of rejection, one from irreversible renal artery stenosis, a second graft was abandoned because the patient developed Pneumocystis carinii pneumonia and immunosuppression stopped, a third graft was lost due to probable chronic Cs nephrotoxicity.
  • Biopsy specimens were analysed for CD45 monoclonal antibody uptake. The results suggest that rejection may be associated with a low uptake of the antibody. However the numbers are too small for statistical analysis. In this trial, pretreatment of human renal allografts with rat CD45 monoclonal antibodies reduced the incidence of rejection and possibly improved allograft function.
  • the technique can be applied to other skin transplant/skin dressing situations. For example, in preparing leg ulcers for final grafting with expanded syngeneic skin cultures.
  • the first is to provide a wound dressing which remains in place, prevents water-loss, and reduces the risks of infection.
  • the second application is to replace the need for the patient's skin to grow back over the wound.
  • the skin can be prepared in different ways: either used directly, stored at 4° for up to 7 days, or frozen in glycerol; cultured to produce a sheet of growing epithelial cells but probably lacking dermal cells; and finally as a freeze-dried strip preparation which is used exclusively with pig skin.
  • artificial skin preparations which are non-viable and really represent a biological dressing rather than skin graft.
  • Allo and xenografts are simply dressings.
  • an autograft acts both as a dressing and as potentially new skin for the recipient if the graft takes.
  • an autograft acts both as a dressing and as potentially new skin for the recipient if the graft takes.
  • leg ulcers it may be useful to dress the ulcer with allograft skin prior to an attempted autograft treatment.In these circumstances to prolong the survival of an allograft would have considerable advantage. Previous attempts to achieve this have involved topical application of steroids and UV irradiation of the allograft.
  • the present applicants teach that the problem of rejection of non-patient derived skin as a wound dressing or as a graft, can be overcome by pretreating the non-patient derived skin with the antibody systems as previously described in the specification.
  • Skin grafts may be taken from donors according to techniques well known in the art and less than 24 hours after death. Strict aseptic procedure must be observed. Generally, the grafts are wrapped in a saline soaked swab and placed in a container for transport to eg. a skin culture laboratory. There the skin may be treated with 15% (v/v) glycerol in an isotonic solution eg. 0.9% NaCl or a tissue culture medium such as DMEM (Dulbecco's Modified Eagles Medium) , sealed in polythene bags and frozen under controlled conditions. The aim of the freezing process is to control the rate of cooling to one degree per minute, down to below -30°c. The frozen skin packs are then stored until use in a -70°c freezer.
  • DMEM Dulbecco's Modified Eagles Medium
  • the skin When required for use, the skin is removed from the freezer and plunged into a water bath at 37°c, where it thaws rapidly. The bag can then be opened and. the skin used in the desired way. Once thawed the skin cannot be refrozen.
  • the present applicants provide that at some stage in the preparation of the skin for use as a dressing or graft, it is soaked in an antibody system as provided by the present invention.
  • the soaking may be carried out either before freezing the skin for storage or after defrosting the skin.
  • the soaking may be carried out for a period of time which allows the binding of the anti- CD45 antibodies to cells (eg. passenger leucocytes) expressing the CD45 antigen.
  • the soaking may be for 1 to 24 hours.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

On décrit des matériaux et des procédés destinés au traitement de tissu étranger au moyen d'une préparation qui comprend un système d'anticorps spécifiques anti-CD45 à médiation de la lyse des cellules à dépendance complémentaire en présence de compléments humains.
PCT/GB1990/001621 1989-10-20 1990-10-22 Materiaux et procedes de traitement de tissu etranger WO1991005568A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
BR909007769A BR9007769A (pt) 1989-10-20 1990-10-22 Preparacao para o tratamento de tecido alheio,processo para a preparacao de tecido alheio ex-vivo antes de transplante ou de seu uso como material curativo,processo para o tratamento de um paciente,e,processo para realizacao de transplantes de orgaos alogenicos ou xenogenicos a um paciente humano,ou para fornecimento de curativo alogenico ou xenogenico a este paciente
FI921746A FI921746L (fi) 1989-10-20 1990-10-22 Material och metoder foer behandling av fraemmande vaevnad.
MX9203715A MX9203715A (es) 1989-10-20 1990-10-22 Preparciones para el tratamiento del tejido aloinjertado.
CA002069342A CA2069342A1 (fr) 1989-10-20 1990-10-22 Materiel et methodes pour le traitement de tissus etrangers
NO92921507A NO921507L (no) 1989-10-20 1992-04-15 Materialer og fremgangsmaater for behandling av fremmed vev

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US42474889A 1989-10-20 1989-10-20
US424,748 1989-10-20
GB898923712A GB8923712D0 (en) 1989-10-20 1989-10-20 Compounds and methods for the amelioration of graft rejection
GB8923712.7 1989-10-20

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WO1991005568A1 true WO1991005568A1 (fr) 1991-05-02

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PCT/GB1990/001621 WO1991005568A1 (fr) 1989-10-20 1990-10-22 Materiaux et procedes de traitement de tissu etranger

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EP (1) EP0496806A1 (fr)
JP (1) JPH05501256A (fr)
AU (1) AU631272B2 (fr)
BR (1) BR9007769A (fr)
CA (1) CA2069342A1 (fr)
FI (1) FI921746L (fr)
OA (1) OA09658A (fr)
WO (1) WO1991005568A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007900A1 (fr) * 1991-10-18 1993-04-29 Cantab Pharmaceuticals Research Limited Perfusion in vitro de greffes de reins avec des anticorps
US6024957A (en) * 1993-06-02 2000-02-15 Research Corporation Technologies, Inc. Immunomodulators and methods for the prevention and reversal of organ transplant rejection using same
US6030960A (en) * 1993-06-10 2000-02-29 Wake Forest University Method of treating hepatitis virus infections
US6106834A (en) * 1993-06-02 2000-08-22 Research Corporation Technologies, Inc. Use of anti-CD45 leukocyte antigen antibodies for immunomodulation
US6479640B2 (en) * 1990-03-14 2002-11-12 Cold Spring Harbor Laboratory Antibody specific for a protein tyrosine phosphatase that localizes to focal adhesions
CN107849141A (zh) * 2015-07-16 2018-03-27 Ucb生物制药私人有限公司 结合cd45的抗体分子
US10954312B2 (en) 2015-12-03 2021-03-23 UCB Biopharma SRL Method employing bispecific protein complex
US11261252B2 (en) 2014-07-16 2022-03-01 UCB Biopharma SRL Molecules with specificity for CD79 and CD22
US11286312B2 (en) 2015-12-03 2022-03-29 UCB Biopharma SRL Multispecific antibodies
WO2022079199A1 (fr) * 2020-10-15 2022-04-21 UCB Biopharma SRL Molécules de liaison multimérisant cd45
US11472879B2 (en) 2015-07-16 2022-10-18 UCB Biopharma SRL Antibody molecules which bind CD22

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6106835A (en) * 1991-04-19 2000-08-22 Tanox, Inc. Modified binding molecules specific for T or B lymphocytes and their use as in vivo immune modulators
CA2065658A1 (fr) * 1991-04-19 1992-10-20 Tse-Wen Chang Conjugues de liposomes ou microbilles et anticorps specifiques pour les lymphocytes t et leur utilisation in vivo en tant que modulateurs de l'immunite
US5872222A (en) * 1991-04-19 1999-02-16 Tanox Biosystems, Inc. Conjugates of polymers and antibodies specific for T lymphocytes, and their use as adjuvants
US6197298B1 (en) 1991-04-19 2001-03-06 Tanox, Inc. Modified binding molecules specific for T lymphocytes and their use as in vivo immune modulators in animals
US6129916A (en) * 1991-04-19 2000-10-10 Tanox, Inc. Method of Increasing activation on proliferation of T cells using antibody-microbead conjugates

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Biological Reviews (Biosis), vol. 38, 1989, (Philadelphia, US), A. Palmer et al.: "Randomized controlled trial of the pre-treatment of human renal allografts with the CD45 mono-clonol antibodies YTH54.12 and 24.5", see abstract no. 81937 & Nephrol. Dial. Transplant. 4 (9), 1989, p. 838 *
BIOLOGICAL REVIEWS (BIOSIS), vol. 38, 1989, Philadelphia, PA (US); A. PALMER et al., no. 81937/ *
Molecular Immunology, vol. 24, no. 6, June 1987, Pergamon Journals Ltd, (Oxford, GB), C.I. Bindon et al.: "Synergistic complement lysis by monoclonal anti-bodies to the human leukocyte common antigen requires both the classical and alternative pathways", pages 587-594 *
Transplantation, vol. 40, no. 5, November 1985, The Williams & Wilkins Co., (Baltimore, US), C.I. Bindon et al.: "Therapeutic potential of monoclonal antibodies to the leukocyte-common antigen", pages 538-544 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6479640B2 (en) * 1990-03-14 2002-11-12 Cold Spring Harbor Laboratory Antibody specific for a protein tyrosine phosphatase that localizes to focal adhesions
WO1993007900A1 (fr) * 1991-10-18 1993-04-29 Cantab Pharmaceuticals Research Limited Perfusion in vitro de greffes de reins avec des anticorps
US6024957A (en) * 1993-06-02 2000-02-15 Research Corporation Technologies, Inc. Immunomodulators and methods for the prevention and reversal of organ transplant rejection using same
US6099838A (en) * 1993-06-02 2000-08-08 Reasearch Corporation Technologies, Inc. Pharmaceutical compositions comprising anti-CD45RB antibodies for the inhibition of T-cell mediated immune responses
US6106834A (en) * 1993-06-02 2000-08-22 Research Corporation Technologies, Inc. Use of anti-CD45 leukocyte antigen antibodies for immunomodulation
US6379668B1 (en) 1993-06-02 2002-04-30 Research Corporation Technologies, Inc. Use of anti-CD45 leukocyte antigen antibodies for immunomodulation
US7160987B2 (en) 1993-06-02 2007-01-09 Alimunne, L.L.C. Use of anti-CD45 leukocyte antigen antibodies for immunomodulation
US6030960A (en) * 1993-06-10 2000-02-29 Wake Forest University Method of treating hepatitis virus infections
US11261252B2 (en) 2014-07-16 2022-03-01 UCB Biopharma SRL Molecules with specificity for CD79 and CD22
CN107849141A (zh) * 2015-07-16 2018-03-27 Ucb生物制药私人有限公司 结合cd45的抗体分子
CN107849141B (zh) * 2015-07-16 2022-01-14 Ucb生物制药有限责任公司 结合cd45的抗体分子
US11472879B2 (en) 2015-07-16 2022-10-18 UCB Biopharma SRL Antibody molecules which bind CD22
US11692041B2 (en) 2015-07-16 2023-07-04 UCB Biopharma SRL Antibody molecules which bind CD45
US10954312B2 (en) 2015-12-03 2021-03-23 UCB Biopharma SRL Method employing bispecific protein complex
US11286312B2 (en) 2015-12-03 2022-03-29 UCB Biopharma SRL Multispecific antibodies
WO2022079199A1 (fr) * 2020-10-15 2022-04-21 UCB Biopharma SRL Molécules de liaison multimérisant cd45

Also Published As

Publication number Publication date
OA09658A (en) 1993-05-15
EP0496806A1 (fr) 1992-08-05
CA2069342A1 (fr) 1991-04-21
JPH05501256A (ja) 1993-03-11
AU631272B2 (en) 1992-11-19
FI921746A0 (fi) 1992-04-16
AU6623590A (en) 1991-05-16
FI921746L (fi) 1992-04-16
BR9007769A (pt) 1992-08-11

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