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WO2018199378A1 - Procédé immunosuppresseur combiné impliquant un anticorps monoclonal anti-cd20 et du tacrolimus dans une xénogreffe cornéenne - Google Patents

Procédé immunosuppresseur combiné impliquant un anticorps monoclonal anti-cd20 et du tacrolimus dans une xénogreffe cornéenne Download PDF

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Publication number
WO2018199378A1
WO2018199378A1 PCT/KR2017/006091 KR2017006091W WO2018199378A1 WO 2018199378 A1 WO2018199378 A1 WO 2018199378A1 KR 2017006091 W KR2017006091 W KR 2017006091W WO 2018199378 A1 WO2018199378 A1 WO 2018199378A1
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surgery
corneal
xenograft
months
immune response
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PCT/KR2017/006091
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English (en)
Korean (ko)
Inventor
김미금
김재영
최세현
윤창호
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서울대학교 산학협력단
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Priority to CN201780001730.5A priority Critical patent/CN109475621B/zh
Publication of WO2018199378A1 publication Critical patent/WO2018199378A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39566—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against immunoglobulins, e.g. anti-idiotypic antibodies
    • 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
    • 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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is directed to a protocol for inhibiting immune rejection responses that may occur in xenograft transplantation.
  • the cornea is a transparent membrane located in front of the eye wall and occupies about 1/6 of the front of the fiber wall.
  • the cornea is round when looking backward and flat oval when looking forward.
  • the cornea is the foremost transparent part of the eyeball, covering the iris, pupil, and entire anterior chamber and ensuring precise focus of light on the retina.
  • corneal blindness due to loss of corneal transparency is known as a major cause of vision loss. Eye wounds and corneal ulcers also lead to blindness in 1.5 to 2 million patients annually.
  • the only effective treatment for this type of blindness is human corneal transplantation (also called keratoplasty).
  • Xenotransplantation is one of the many alternatives to human organs.
  • xenotransplantation has developed around the field of organ transplantation.
  • many primates such as Baboons, were used around 1963 when xenotransplantation was first attempted.
  • Reemtsma the father of xenotransplantation, transplanted chimpanzees' kidneys into children with kidney failure, and survived for up to nine months. I have survived.
  • primates are not only endangered species, but also difficult to breed, have a high social rejection to use as a heterogeneous long-term source, and have a high risk of infection.
  • the present inventors have studied various drug combinations and their administration protocols that can effectively suppress the immune response that may occur in corneal xenografts, and when the drug is administered according to the appropriate drug combination and the timing of administration, The present invention was completed by confirming that engraftment of the transplanted cornea can be effectively maintained without inducing an immune response.
  • an object of the present invention is to provide a method for inhibiting immune response by mammalian corneal xenograft.
  • the present invention in the corneal xenograft surgery, the step of administering an anti-CD20 antibody intravenously; Intravenously administering an anti IL2R antibody; Intravenously administering intravenous immunoglobulin (Intravenous Immunoglobulin); Intramuscular injection of taclolimus; And administering a steroid; It provides a method for inhibiting the immune response by corneal xenograft of a mammal, except for human.
  • Rituximab is administered at 10 to 30mg / kg on the day of surgery and 1 week after corneal xenograft surgery, intravenous administration every two months for 8 to 24 weeks of surgery; Intravenously administering basiliximab at 0.1 to 0.5 mg / kg on the day of surgery and on day 4 post-surgery; Intravenous immunoglobulin (Intravenous Immunoglobulin) is administered intravenously at 0.1 to 5 g / kg on days 1 and 14 after surgery; Intramuscularly injecting taclolimus at 0.01 to 0.5 mg / kg twice daily for 12 months after surgery; Intramuscular administration of methylprednisolone daily with reduced dose from 2 mg / kg to 0.25 mg / kg for 5 weeks after surgery; Injecting prednisolone acetate daily up to 3 months after surgery; And subconjunctival injection of dexamethasone at 1.0 mg /
  • the immune response inhibition method of the present invention not only can the immune rejection reaction by the cornea transplanted after corneal xenograft xenograft be effectively suppressed in the recipient, but also the engraftment of the cornea is stably maintained for a long time, and the corneal thickness and intraocular pressure Since such indicators can be effectively maintained, it can be usefully used for transplanting corneas between heterologous pigs including pigs-primates and pigs-humans.
  • FIG. 1 is a diagram showing a drug administration protocol for inhibiting immune response by corneal xenograft.
  • FIG. 2 is a diagram schematically illustrating a method of performing a whole layer corneal graft.
  • Figure 3 shows the clinical results of recipients following corneal transplantation according to the drug administration protocol of the present invention.
  • Figure 4 is a view showing the results of comparing the change of B cells and T cells according to the drug administration protocol of the present invention with the immunosuppression method using an anti-CD40 antibody.
  • the present invention relates to a method for inhibiting an immune response by corneal xenograft.
  • immune rejection reactions that may occur in the recipient after corneal xenograft xenograft can be effectively suppressed, so that engraftment of the cornea can be stably maintained for a long time and the central corneal thickness and intraocular pressure can be very stable.
  • an immune response can be used interchangeably in the sense including an immune rejection response.
  • the method of the present invention comprises the steps of intravenous administration of an anti-CD20 antibody in corneal xenograft; Intravenously administering an anti IL2R antibody; Intravenously administering intravenous immunoglobulin (Intravenous Immunoglobulin); Intramuscular injection of taclolimus; And administering a steroid; It relates to a method for inhibiting the immune response by corneal xenograft of a mammal, except human.
  • the anti-CD20 antibody is preferably rituximab, and when the anti-CD20 antibody is rituximab, it is 10-30 mg / kg, preferably 20 mg on the day of corneal xenograft surgery and 1 week after the surgery. / kg, and 8 weeks after surgery, the same dose can be repeated every 8 weeks, and in subsequent repeated administrations to determine whether there is an IgG antibody rise in the appropriate dose according to the judgment of those skilled in the art Can be administered in a controlled manner.
  • the anti-IL2R antibody may be basiliximab, and the basiliximab is preferably administered on the day of surgery and on the fourth day after surgery.
  • the basiliximab may be administered at 0.1 to 0.5 mg / kg, more preferably at 0.3 mg / kg once daily.
  • the intravenous immunoglobulin can be used interchangeably with the intravenous immunoglobulin, an IgG antibody extracted from blood donation plasma, an IgG antibody used to treat immunodeficiency, autoimmune diseases and infections, etc. Means.
  • the intravenous immunoglobulin may be administered at 0.1 to 5 g / kg on days 1 and 14 after surgery, and preferably at a dose of 1 g / kg on days 1 and 14 after surgery. It may be characterized by administering. Intravenous immunoglobulins may be further administered depending on the individual's immune response.
  • the present invention may be characterized by administering taclolimus by intramuscular injection at 0.01 to 0.5mg / kg twice daily for 12 months after surgery.
  • the taclolimus may be administered to the recipient from 3 to 5 days prior to xenograft surgery, preferably 2 days prior to surgery, preferably twice daily for 12 months after surgery.
  • the administration of taclolimus can be appropriately adjusted according to the regular blood concentration test.
  • the present invention is characterized in that taclolimus is administered by intramuscular injection at 0.01 to 0.5mg / kg, but in the case of subjects showing side effects to taclolimus, the taclolimus dose is adjusted to 0.035mg / kg 2 per day Most preferably, it is administered once.
  • the present invention also provides administration of a steroidal agent, which may be used without limitation, a licensed steroidal agent known in the art, but preferably as a steroidal agent methylprednisolon, prednisolone acetate and dexa It may be characterized by using one or more selected from the group consisting of metazones. More preferably, the steroid preparation may be administered all of methylprednisolon, prednisolone acetate and dexamethasone, in which case methylprednisolone may be used at 2 mg / kg to 0.25 mg / kg daily for 5 weeks after surgery. It can be administered intramuscularly with gradually decreasing dose.
  • a steroidal agent which may be used without limitation, a licensed steroidal agent known in the art, but preferably as a steroidal agent methylprednisolon, prednisolone acetate and dexa It may be characterized by using one or more selected from the group consisting of metazones. More
  • prednisolone acetate is an ophthalmic formulation, preferably a prednisolone acetate 1% eye drops formulation, which can be instilled daily up to 3 months after surgery, and 3 months after surgery, 2-3 times a week up to 6 months after surgery, 6 after surgery After months, it can be dispensed with a weekly interval.
  • the dexamethasone may be injected subconjunctially at 1.0 mg / 0.3 ml to 1.5 mg / 0.45 ml, preferably 1.5 mg / 0.3 ml for 6 months after surgery, on the day of surgery, 1 day, 4 days, 7 days It can be administered for 6 months in the form of administration in days, 10 days, 15 days, 21 days and 21 days after 7 days.
  • Dexamatozone can be further administered 6 months after surgery, according to the knowledge of one of ordinary skill in the art.
  • the method of the present invention can effectively suppress the immune rejection response that may occur in all corneal xenografts, wherein the corneal xenografts may include both partial corneal xenografts and full-layer corneal xenografts, preferably the entire cornea Xenograft, more preferably penetrating corneal xenograft of the periosteum.
  • the nasal membranes can be used for transplantation after sterilization and disinfection by removing pig's eye and soaking in 5% betadine solution for 1 minute and washing with 20cc of 10% cefazoline and 2% gentamicin solution. Refers to the organization that has become.
  • the present invention relates to a method for inhibiting an immune response by mammalian liver corneal xenograft.
  • pigs may be donors of the cornea and primates may be recipients of the cornea, and the primates may include, without limitation, humans, monkeys, chimpanzees, gorillas, orangutans, laxus monkeys, and the like.
  • the present invention can be usefully used to xenograft porcine corneas in primates, preferably monkeys or humans.
  • the present invention comprises administering rituximab at 10 to 30 mg / kg on the day of surgery and 1 week after corneal xenograft surgery, and intravenously every 2 months for 8 to 24 weeks of surgery; Intravenously administering basiliximab at 0.1 to 0.5 mg / kg on the day of surgery and on day 4 post-surgery; Intravenous immunoglobulin (Intravenous Immunoglobulin) is administered intravenously at 0.1 to 5 g / kg on days 1 and 14 after surgery; Intramuscularly injecting taclolimus at 0.01 to 0.5 mg / kg twice daily for 12 months after surgery; Intramuscular administration of methylprednisolone daily with reduced dose from 2 mg / kg to 0.25 mg / kg for 5 weeks after surgery; Injecting prednisolone acetate daily up to 3 months after surgery; And subconjunctival injection of dexamethasone at 1.0 mg / 0.3 ml to 1.5 mg / 0.45
  • an anti-CD20 combination systemic immune suppression protocol was devised as follows.
  • anti-CD20 Ab, anti-IL2R Ab, Intravenous Immunoglobulin (IVIG), taclolimus, methylprednisolon (Methylprednisolon) were administered at regular intervals.
  • IVIG Intravenous Immunoglobulin
  • taclolimus methylprednisolon
  • methylprednisolon Methylprednisolon
  • the protocol according to the present invention is shown in Figure 1, specifically as follows.
  • Anti CD20 Ab Phosphorus rituximab was injected via iv slow infusion, administered at 20 mg / kg on the day of xenograft surgery and 1 week after surgery, and repeated 8-week cycles after 8 weeks of surgery. Dosage was checked more frequently if needed.
  • the anti-IL2R antibody, basiliximab was administered once daily via slow intravenous infusion at the dose of 0.3 mg / kg and on the day of xenograft surgery and on the fourth postoperative day.
  • IVIG Intravenous Immunoglobulin
  • Taclolimus was administered at a dose of 0.05 mg / kg twice daily via intramuscular injection twice daily for 12 months prior to surgery, and the dose was controlled by regular blood taclolimus concentration tests. The dose was reduced to 0.035 mg / kg for individuals with adverse effects on taclolimus.
  • Methylprednisolon, prednisolone acetate eye drops and dexamethasone were also administered as steroid preparations.
  • intramuscular administration was performed gradually decreasing the dose from 2 mg / kg to 0.25 mg / kg daily for 5 weeks after surgery, and more specifically, the dose was gradually reduced as follows: 2 mg / kg from the day of surgery to 7 days after surgery, 1.5 mg / kg from the 8th to 14th postoperative days, 1.0mg / kg from the 15th to 21st postoperative days, and 0.5mg from the 22nd to 28th postoperative days. / kg, 0.25 mg / kg from day 29 to day 35 postoperatively.
  • Prednisolone Acetate 1% eye drops were given as a drop every day until the third month after surgery, gradually increasing intervals two to three times a week for three to six months after surgery and once a week after six months after surgery. Dosing proceeded.
  • Dexamethasone was administered at 1.5 mg / 0.3ml by subconjunctival injection on the 0, 1, 4, 7, 10, 15, and 21 days after surgery. It was administered for 6 months.
  • the recipient's cornea was cut into a diameter of 7.0 mm through trephination, and a donor's 7.5 mm cornea was placed and then sutured using nylon yarn.
  • Implantation of heterologous corneas to primates was performed according to the administration protocol of the present invention, and immunosuppression was performed.
  • the results of the postoperative clinical trials were confirmed by immunorejection, corneal thickness, and intraocular pressure test.
  • the corneas of primates that had undergone heterokeratoplasty were examined with slit lamp microscopes, focusing on keratoplasty transparency, edema and neovascularization, and regularly checked for rejection and other infections.
  • Central corneal thickness and intraocular pressure were measured with ultrasonic corneal thickness meters (Quantel Medical, Clermont-Ferrand, France) and Tono-Pen (Medtronic Solan, Jacksonville, FL). The mean corneal thickness was measured five times, the intraocular pressure was measured twice, and the results are shown in FIG. 3.
  • the subjects who received immunosuppression by the protocol of the present invention after corneal transplantation did not show an immune rejection response after 184 to 443 days after the surgery.
  • the thickness of the central cornea remained stable at a constant thickness even after the surgery, and the intraocular pressure (IOP) was able to maintain a normal range not exceeding 20 mmHg.
  • IOP intraocular pressure
  • the individual treated according to the protocol of the present invention was confirmed that effective immune suppression was achieved by maintaining the T, B cell concentration in the blood lower than the protocol using the conventional anti-CD40 antibody.
  • the immunosuppressive protocol of the present invention it is possible to effectively suppress the immune rejection reaction that may occur when performing inter-penetrating corneal transplantation, thereby increasing the safety of hetero-penetrating corneal transplantation and significantly improving the success rate. It was confirmed that there is.

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Abstract

La présente invention concerne un protocole visant à supprimer une réponse immunitaire de rejet susceptible de se produire lors d'une xénogreffe cornéenne. Le procédé de suppression de la réponse immunitaire selon la présente invention peut non seulement supprimer efficacement une réponse immunitaire de rejet associée à un greffon cornéen chez un receveur après une xénogreffe cornéenne pénétrante, mais peut également permettre de préserver de manière stable la prise de greffe du greffon cornéen pendant une longue durée et permettre de préserver efficacement des indicateurs tels que l'épaisseur cornéenne, la pression intraoculaire, etc., ce qui permet de lui trouver des applications utiles dans une transplantation cornéenne entre des espèces différentes.
PCT/KR2017/006091 2017-04-27 2017-06-12 Procédé immunosuppresseur combiné impliquant un anticorps monoclonal anti-cd20 et du tacrolimus dans une xénogreffe cornéenne WO2018199378A1 (fr)

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CN201780001730.5A CN109475621B (zh) 2017-04-27 2017-06-12 异种眼角膜移植中的抗cd20单克隆抗体及他克莫司的复合免疫抑制方法

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KR10-2017-0054072 2017-04-27
KR1020170054072A KR101968246B1 (ko) 2017-04-27 2017-04-27 이종 각막 이식에서 항 cd20 단일클론항체 및 타클로리무스의 복합면역억제 방법

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Citations (2)

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Publication number Priority date Publication date Assignee Title
US6338851B1 (en) * 1997-11-07 2002-01-15 Transplantation Technologies Inc. Method of suppressing an immune response to a transplanted organ or tissue by administering an OX-2 protein
KR20100041849A (ko) * 2007-07-25 2010-04-22 알렉시온 파마슈티칼스, 인코포레이티드 Ｃｄ200에 대한 항체와 면역 반응의 저해에서 이들의 용도

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
US9382327B2 (en) * 2006-10-10 2016-07-05 Vaccinex, Inc. Anti-CD20 antibodies and methods of use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6338851B1 (en) * 1997-11-07 2002-01-15 Transplantation Technologies Inc. Method of suppressing an immune response to a transplanted organ or tissue by administering an OX-2 protein
KR20100041849A (ko) * 2007-07-25 2010-04-22 알렉시온 파마슈티칼스, 인코포레이티드 Ｃｄ200에 대한 항체와 면역 반응의 저해에서 이들의 용도

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHOI, H. J. ET AL.: "Blockade of CD 40- CD 154 Costimulatory Pathway Promotes Long-term Survival of Full-thickness Porcine Corneal Grafts in Nonhuman Primates: Clinically Applicable Xenocorneal Transplantation", AMERICAN JOURNAL OF TRANSPLANTATION, vol. 15, 2015, pages 628 - 641, XP055528370 *
KIM, J. ET AL.: "Administration of Rituximab and Tacrolimus Promotes Intermediate-term Survival of Full-thickness Porcine Corneal Grafts in Non-human Primates", THE 5TH ASIA CORNEA SOCIETY BIENNIAL SCIENTIFIC MEETING (ACS 2016, 9 December 2016 (2016-12-09), Seoul, Korea *
KIM, JAE YEONG ET AL.: "Long-term Effectiveness Comparison Analysis for Anti CD 40 Monoclonal. Antibodies treatment Group and Combined Immunosuppressive Therapy treatment Group of Rituximab and Tacrolimus in Heterogeneous Full-thickness Corneal Grafts between Pigs and Primates", ANNUAL MEETING OF THE KOREAN OPHTHALMOLOGICAL SOCIETY, 15 April 2017 (2017-04-15), Korea *
KIM, JAE YEONG ET AL.: "Mid-term Clinical Outcome of Heterogeneous Full-thickness Corneal Grafts between Pigs and Primates Using Combined Immunosuppressive Therapy of Rituximab and Tacrolimus", ANNUAL MEETING OF THE KOREAN OPHTHALMOLOGICAL SOCIET Y, 5 November 2016 (2016-11-05), Korea *
KIM, M. K.: "Commentary: Current Status and Future of Corneal Xenotransplantation", JOURNAL OF TRANSPLANTATION TECHNOLOGIES & RESEARCH, vol. 6, no. 3, 20 June 2016 (2016-06-20), pages 1 - 3, XP055528374 *
KOO, T. Y. ET AL.: "Current Progress in ABO-incompatible Kidney Transplantation", KIDNEY RESEARCH AND CLINICAL PRACTICE, vol. 34, 2015, pages 170 - 179, XP055528363 *
SHEN, T. ET AL.: "A Modified Protocol with Rituximab and Intravenous Immunoglobulin in Emergent ABO-incompatibie Liver Transplantation for Acute Liver Failure", HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL, vol. 13, no. 4, 2014, pages 395 - 401, XP055528356 *

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KR101968246B1 (ko) 2019-04-11
CN109475621A (zh) 2019-03-15
KR20180120337A (ko) 2018-11-06
CN109475621B (zh) 2022-03-15

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