[go: up one dir, main page]

WO2018199378A1 - Combined immunosuppressive method of anti-cd20 monoclonal antibody and tacrolimus in corneal xenotransplantation - Google Patents

Combined immunosuppressive method of anti-cd20 monoclonal antibody and tacrolimus in corneal xenotransplantation Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
surgery
corneal
xenograft
months
immune response
Prior art date
Application number
PCT/KR2017/006091
Other languages
French (fr)
Korean (ko)
Inventor
김미금
김재영
최세현
윤창호
Original Assignee
서울대학교 산학협력단
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 서울대학교 산학협력단 filed Critical 서울대학교 산학협력단
Priority to CN201780001730.5A priority Critical patent/CN109475621B/en
Publication of WO2018199378A1 publication Critical patent/WO2018199378A1/en

Links

Images

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The present invention relates to a protocol for suppressing an immune rejection response that could occur at corneal xenotransplantation. The immune response suppressing method of the present invention can not only effectively suppress an immune rejection response attributed to a corneal graft in a recipient after penetrating corneal xenotransplantation, but also can stably maintain the engraftment of the corneal graft for a long period of time and allow the effective maintenance of indices such as a corneal thickness, an intraocular pressure, and the like, thus finding useful applications in corneal transplantation between difference species.

Description

이종 각막 이식에서 항 CD20 단일클론항체 및 타클로리무스의 복합면역억제 방법Combination Immunosuppression of Anti-CD20 Monoclonal Antibody and Taclolimus in Hepatic Corneal Transplantation
본 발명은 이종 각막 이식 시 발생할 수 있는 면역 거부 반응을 억제하기 위한 프로토콜에 관한 것이다.The present invention is directed to a protocol for inhibiting immune rejection responses that may occur in xenograft transplantation.
각막 (Cornea)은 안구 벽의 앞쪽에 위치하는 투명한 막으로써, 섬유 벽 앞쪽의 약 1/6을 차지한다. 각막은 뒤쪽을 보는 경우 원형, 앞쪽을 보는 경우 납작한 타원형을 이룬다. 각막은 안구의 가장 앞쪽에 위치하는 투명한 부분으로, 홍채, 동공, 및 전 안방을 덮고 망막 위에 빛의 정확한 초점이 맺히도록 한다. 한편, 각막 투명성의 상실에 따른 각막 실명 (corneal blindness)은 시력 상실의 주요한 원인으로 알려져 있다. 또한 안구 창상 및 각막 궤양은 매년 1.5 내지 2 백만의 환자를 실명에 이르게 한다. 이러한 종류의 실명에 효과적인 유일한 치료법으로는 각막이식술 (human corneal transplantation, keratoplasty 라고도 명명함)이 있다. 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. On the other hand, 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).
그러나 유일한 치료법임에도 불구하고 임상에서는 각막 이식재의 공급과 수요간 큰 차이를 보이고 있다. 동종 이계 (allogenic)의 각막이 매우 부족하고, 단기간 내 이러한 상황을 변화시키기 어려운 환경 하에서, 연구자들은 각막 부족의 문제를 해결하기 위하여 대안적인 새로운 이식재를 개발하는데 다각적인 노력을 하고 있다. 보고되거나 입증된 새로운 이식재로는 주로 생물학적 이식재 및 이종 각막 이식재가 있다. 종래의 보고에 따르면, 생물학적 이식재는 불만족스런 조직 적합성을 가지므로 대규모 조건에서는 이용될 수 없다. 이와 비교하여, 이종 각막 이식재는 보다 넒은 응용 가능성을 가지고 있다. However, despite being the only treatment, there is a big difference between the supply and demand of corneal grafts. In an environment in which allogenic corneas are very scarce and difficult to change this situation in the short term, researchers are making a multifaceted effort to develop alternative new implants to address the problem of corneal deficiency. Reported or proven new implants are mainly biological and xenograft implants. According to conventional reports, biological implants have unsatisfactory tissue compatibility and therefore cannot be used in large scale conditions. In comparison, xenograft has a wider application potential.
이종 이식(Xenotransplantation)은 인간의 장기를 대체할 수 있는 여러 가지 방법 중 하나로, 최근까지 이종 이식은 장기 이식 분야를 중심으로 발전하였다. 이종 장기나 세포의 공급원으로, 이종 장기이식이 처음 시도되던 1963년경에는 바분 원숭이(Baboons)와 같은 영장류가 많이 이용되었다. 특히, 이종 이식의 아버지라 불리는 Reemtsma는 침팬지의 신장을 신부전 환아에게 이식하여 최장 9개월의 생존을 유지하였으며, 1984년에는 Bailey가 선천성 심장질환이 있는 Baby Fae에게 바분 원숭이의 심장을 이식하여 20일간 생존을 유지한 바 있다. 그러나 영장류는 멸종 위기 종일뿐만 아니라 번식이 어렵고, 이종 장기 공급원으로 활용하기에는 사회적 거부감이 높으며, 높은 감염의 위험성이 있다. 이에 영장류 이외의 동물 중에서 장기의 크기가 사람과 매우 유사하고, 임신 기간이 127일로 짧아서 번식이 용이하며, 한꺼번에 많은 수의 새끼(6 내지 12 마리)를 낳을 수 있는 장점을 가진 돼지가 이종장기 공급원으로 선정되어 많은 연구가 진행되었으나, 돼지의 장기를 인체에 이식할 경우, 동종이식보다 훨씬 심각한 이종이식 거부반응(xenograft rejection)이 일어나는 문제점이 존재하였다. Xenotransplantation is one of the many alternatives to human organs. Until recently, xenotransplantation has developed around the field of organ transplantation. As a source of heterologous organs or cells, many primates, such as Baboons, were used around 1963 when xenotransplantation was first attempted. In particular, Reemtsma, the father of xenotransplantation, transplanted chimpanzees' kidneys into children with kidney failure, and survived for up to nine months. I have survived. However, 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. Among animals other than primates, the size of organs is very similar to that of humans, and the gestation period is short (127 days), so it is easy to breed, and pigs, which have the advantage of producing a large number of pups (6 to 12) at once, are heterogeneous sources. Although many studies have been carried out, there was a problem that xenograft rejection occurs when transplanting pig organs into human body, which is much more severe than allograft.
즉, 이종 이식을 수행함에 있어, 거부 반응으로 언급되는 면역 반응을 조절하는 것은 당분야에 직면한 과제이며, 각막 이종 이식에 있어 발생될 수 있는 전신성 면역반응 및 이에 의한 치사를 방지할 수 있는 효과적인 면역 억제 반응에 대한 필요성이 있다. That is, in performing xenotransplantation, controlling an immune response, referred to as a rejection reaction, is a challenge in the art, and is effective in preventing systemic immune responses and death by which can occur in corneal xenograft transplantation. There is a need for an immunosuppressive response.
본 발명자들은 각막 이종이식에 있어 발생될 수 있는 면역반응을 효과적으로 억제할 수 있는 다양한 약물 조합 및 이의 투여 프로토콜에 대하여 연구하던 중, 적절한 약물 조합 및 투여 시기에 따라 약물 투여를 수행하는 경우 수여자에서 면역 반응을 유발하지 않고 이식된 각막의 생착이 효과적으로 유지될 수 있음을 확인하고 본 발명을 완성하였다. 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.
따라서 본 발명은 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법을 제공하는 것을 목적으로 한다. Accordingly, an object of the present invention is to provide a method for inhibiting immune response by mammalian corneal xenograft.
상기 목적을 제공하기 위하여, 본 발명은 각막 이종이식 수술에 있어서, 항 CD20 항체를 정맥 투여하는 단계; 항 IL2R 항체를 정맥 투여하는 단계; 정맥 면역글로불린 (Intravenous Immunoglobulin)을 정맥 투여하는 단계; 타클로리무스를 근육 주사하는 단계; 및 스테로이드를 투여하는 단계; 를 포함하는 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법을 제공한다. In order to provide the above object, 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.
또한 본 발명은 각막 이종이식 수술에 있어서, 리툭시맙을 각막 이종 이식 수술 당일 및 수술 후 1 주차에 10 내지 30mg/kg 로 투여하며, 수술 8주 내지 24주 동안에는 2개월마다 정맥 투여하는 단계; 바실릭시맙을 수술 당일 및 수술 후 4일차에, 0.1 내지 0.5mg/kg으로 정맥 투여하는 단계; 정맥 면역글로불린 (Intravenous Immunoglobulin)을 수술 후 1 일 및 14 일차에 0.1 내지 5g/kg 으로 정맥 투여하는 단계; 타클로리무스를 수술 후 12개월 동안 매일 하루 2회씩 0.01 내지 0.5mg/kg 으로 근육 주사하는 단계; 메틸프레드니슬론을 수술 후 5주 동안 2mg/kg 부터 0.25mg/kg 까지 투여량을 감소시키며 매일 근육 내 투여하는 단계; 프레드니솔론 아세테이트를 수술 후 3개월까지 매일 점안하는 단계; 및 덱사메타존을 수술 후 6개월 동안 1.0mg/0.3ml 내지 1.5mg/0.45ml 로 결막 하 주입하는 단계; 를 포함하는 인간을 제외한 포유류의 전층 각막 이종이식에 의한 면역반응을 억제하는 방법을 제공한다. In addition, the present invention, in the corneal xenograft surgery, 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 / 0.3 ml to 1.5 mg / 0.45 ml for 6 months after surgery; It provides a method for inhibiting the immune response by a full-layer corneal xenograft of a mammal, except for human.
본 발명의 면역반응 억제 방법에 따르면, 각막 전층 이종 이식 후에 이식된 각막에 의한 면역 거부 반응을 수여자에서 효과적으로 억제할 수 있을 뿐만 아니라, 이를 통해 각막의 생착이 장기간 안정적으로 유지되고 각막 두께 및 안압 등의 지표를 효과적으로 유지할 수 있으므로, 돼지-영장류간, 돼지-인간간을 포함하는 이종간 각막 이식에 유용하게 활용될 수 있다. According to 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.
도 1은 각막 이종이식에 의한 면역반응 억제를 위한 약물 투여 프로토콜을 나타낸 도이다. 1 is a diagram showing a drug administration protocol for inhibiting immune response by corneal xenograft.
도 2는 전체 층 각막 이식술 수행 방법을 모식화한 도이다. 2 is a diagram schematically illustrating a method of performing a whole layer corneal graft.
도 3은 본 발명의 약물 투여 프로토콜에 따른 각막 이식 후 수여자의 임상 결과를 나타낸 도이다. Figure 3 shows the clinical results of recipients following corneal transplantation according to the drug administration protocol of the present invention.
도 4는 본 발명의 약물 투여 프로토콜에 따른 B 세포 및 T 세포의 변화를 항 CD40 항체를 이용한 면역 억제 방법과 비교한 결과를 나타낸 도이다. 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.
본 발명은 각막 이종이식에 의한 면역반응을 억제하는 방법에 관한 것이다. The present invention relates to a method for inhibiting an immune response by corneal xenograft.
본 발명의 방법에 따르면, 각막 전층 이종 이식 후에 수여자에서 나타날 수 있는 면역 거부 반응이 효과적으로 억제될 수 있으며, 이에 따라 각막의 생착이 장기간 안정적으로 유지되고 중심 각막 두께 및 안압이 매우 안정적으로 유지할 수 있다. 본 발명에 있어, 면역 반응은 면역 거부 반응을 포함하는 의미로 상호 교환적으로 사용될 수 있다. According to the method of the present invention, 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. have. In the present invention, an immune response can be used interchangeably in the sense including an immune rejection response.
보다 구체적으로 본 발명의 방법은 각막 이종이식에 있어서, 항 CD20 항체를 정맥 투여하는 단계; 항 IL2R 항체를 정맥 투여하는 단계; 정맥 면역글로불린 (Intravenous Immunoglobulin)을 정맥 투여하는 단계; 타클로리무스를 근육 주사하는 단계; 및 스테로이드를 투여하는 단계; 를 포함하는 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법에 관한 것이다. More specifically, 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.
본 발명에 있어, 항 CD20 항체는 리툭시맙인 것이 바람직하며, 항 CD20 항체가 리툭시맙인 경우, 이는 각막 이종 이식 수술 당일 및 수술 후 1주 차에 10 내지 30mg/kg, 바람직하게는 20mg/kg 으로 투여되며, 수술 8주 이후부터는 같은 용량으로 8주 마다 반복 투여될 수 있고, 이후의 반복 투여 시에는 IgG 항체 상승 유무를 확인하여 당 분야의 통상의 기술자의 판단에 따라 투여량을 적절하게 조절하여 투여될 수 있다. In the present invention, 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.
본 발명에 있어, 항 IL2R 항체는 바실릭시맙 (basiliximab)일 수 있고, 상기 바실릭시맙은 수술 당일 및 수술 후 4일차에 투여되는 것이 바람직하다. 또한, 상기 바실릭시맙은 0.1 내지 0.5mg/kg 으로 투여될 수 있으며, 더욱 바람직하게는 0.3mg/kg 으로 하루 1회 투여될 수 있다. In the present invention, 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. In addition, the basiliximab may be administered at 0.1 to 0.5 mg / kg, more preferably at 0.3 mg / kg once daily.
본 발명에 있어, 상기 정맥 면역글로불린 (IVIG) 은 정맥 내 면역글로불린과 상호 교환적으로 사용될 수 있으며, 헌혈 혈장에서 추출한 IgG 항체로 면역결핍, 자가면역질환 및 감염 등을 치료하는 데 사용되는 IgG 항체를 의미한다. In the present invention, the intravenous immunoglobulin (IVIG) 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.
상기 정맥 면역글로불린은 수술 후 1 일 및 14 일차에, 0.1 내지 5 g/kg으로 투여되는 것을 특징으로 할 수 있으며, 바람직하게는 수술 후 1일 및 14일 차에 1 g/kg의 투여량으로 투여하는 것을 특징으로 할 수 있다. 정맥 면역글로불린은 개체의 면역 반응에 따라 추가 투여될 수 있다. 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.
또한 본 발명은 타클로리무스를 수술 전 내지 수술 후 12개월 동안 매일 하루 2회씩 0.01 내지 0.5mg/kg 으로 근육 주사를 통해 투여하는 것을 특징으로 할 수 있다. 상기 타클로리무스는 이종 각막 이식 수술 3일 내지 5일 전, 바람직하게는 수술 2일 전부터 수여자에 투여될 수 있으며, 수술 후 12개월 동안 매일 하루 2회씩 투여되는 것이 바람직하다. 상기 타클로리무스의 투여는 정기적인 혈중 농도 검사에 따라 투여량을 적절하게 조절할 수 있다. In another aspect, 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.
본 발명은 타클로리무스를 0.01 내지 0.5mg/kg 으로 근육 주사를 통해 투여하는 것을 특징으로 하나, 타클로리무스에 부작용을 나타내는 개체의 경우, 타클로리무스 용량을 0.035mg/kg 으로 조절하여 하루 2회 투여하는 것이 가장 바람직하다. 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.
또한 본 발명은 스테로이드 제제의 투여를 함께 제공하며, 상기 스테로이드 제제는 당 분야에 알려진 허가된 스테로이드 제제를 제한없이 사용할 수 있으나, 바람직하게는 스테로이드 제제로 메틸프레드니슬론(Methylprednisolon), 프레드니솔론 아세테이트 및 덱사메타존으로 이루어진 군에서 선택된 1 종 이상을 사용하는 것을 특징으로 할 수 있다. 보다 바람직하게는 스테로이드 제제로 메틸프레드니슬론(Methylprednisolon), 프레드니솔론 아세테이트 및 덱사메타존을 모두 투여할 수 있으며, 이 경우 메틸프레드니슬론은 수술 후 5 주 동안 매일 2mg/kg 내지 0.25mg/kg 으로 투여량을 점차적으로 감소시키며 근육 내 투여될 수 있다. 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.
또한 프레드니솔론 아세테이트는 안약 제형, 바람직하게는 프레드니솔론 아세테이트 1% 안약 제형으로 수술 후 3개월째까지는 매일 점안될 수 있고, 수술 후 3개월이 지나면, 수술 후 6개월까지 주 2 내지 3회, 수술 후 6개월 이후에는 주 1회로 점차적으로 간격을 늘려가며 점안될 수 있다. In addition, 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.
상기 덱사메타존은 수술 후 6개월 동안 1.0mg/0.3ml 내지 1.5mg/0.45ml, 바람직하게는 1.5mg/0.3ml 로 결막 하 주입될 수 있으며, 수술 당일, 수술 후 1일, 4일, 7일, 10일, 15일, 21일째에 투여하고 21일 이후부터는 7일 단위로 투여하는 형식으로 6개월 동안 투여할 수 있다. 덱사마타존은 수술 6 개월이 지난 후에도 당 분야의 통상의 기술자의 상식에 따라 추가적으로 투약할 수 있다. 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.
본 발명의 방법은 모든 각막 이종이식에 있어 발생할 수 있는 면역 거부 반응을 효과적으로 억제할 수 있으며, 상기 각막 이종이식은 부분 각막 이종이식, 전층 각막 이종 이식을 모두 포함할 수 있고, 바람직하게는 전층 각막 이종 이식, 보다 바람직하게는 생각막의 전층 각막 이종이식일 수 있다. 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.
본 발명에 있어 생각막이란, 돼지의 안구를 적출한 후 5% 베타딘 용액에 1분간 담그고, 10% 세파졸린 및 2% 젠타마이신 용액 각 20cc 로 세척하는 멸균, 소독 과정을 거쳐 이식에 사용할 수 있게 된 조직을 말한다. In the present invention, 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.
본 발명은 포유류 간 각막 이종이식에 의한 면역 반응을 억제하는 방법에 관한 것이다. 본 발명의 이종이식에서는 돼지를 각막의 공여자로, 영장류를 각막의 수여자로 할 수 있으며, 상기 영장류는 인간, 원숭이, 침팬치, 고릴라, 오랑우탄, 랙서스 원숭이 등을 모두 제한없이 포함할 수 있다. 따라서 본 발명은 돼지 각막을 영장류, 바람직하게는 원숭이 또는 인간에 이종이식하는 데 유용하게 사용될 수 있다. The present invention relates to a method for inhibiting an immune response by mammalian liver corneal xenograft. In the xenograft of the present invention, 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. Thus, the present invention can be usefully used to xenograft porcine corneas in primates, preferably monkeys or humans.
보다 구체적으로 본 발명은 리툭시맙을 각막 이종 이식 수술 당일 및 수술 후 1 주차에 10 내지 30mg/kg 로 투여하며, 수술 8주 내지 24주 동안에는 2개월마다 정맥 투여하는 단계; 바실릭시맙을 수술 당일 및 수술 후 4일차에, 0.1 내지 0.5mg/kg으로 정맥 투여하는 단계; 정맥 면역글로불린 (Intravenous Immunoglobulin)을 수술 후 1 일 및 14 일차에 0.1 내지 5g/kg 으로 정맥 투여하는 단계; 타클로리무스를 수술 후 12개월 동안 매일 하루 2회씩 0.01 내지 0.5mg/kg 으로 근육 주사하는 단계; 메틸프레드니슬론을 수술 후 5주 동안 2mg/kg 부터 0.25mg/kg 까지 투여량을 감소시키며 매일 근육 내 투여하는 단계; 프레드니솔론 아세테이트를 수술 후 3개월까지 매일 점안하는 단계; 및 덱사메타존을 수술 후 6개월 동안 1.0mg/0.3ml 내지 1.5mg/0.45ml 로 결막 하 주입하는 단계; 를 포함하는 인간을 제외한 포유류의 전층 각막 이종이식에 의한 면역반응을 억제하는 방법에 관한 것일 수 있으며, 각 단계에 대한 추가 설명은 앞서 설명된 내용과의 중복 기재를 피하기 위하여 생략한다. More specifically, 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 ml for 6 months after surgery; It may be related to a method for inhibiting the immune response by the epithelial corneal xenograft of a mammal other than a human, including a further description of each step will be omitted to avoid overlapping with the above description.
실시예 1. 돼지-영장류간 이종이식 항-CD20 조합 전신면역 억제 프로토콜Example 1 Porcine-Primate Xenograft Anti-CD20 Combination Systemic Immune Suppression Protocol
1.1 전신 면역 억제 프로토콜의 확립1.1 Establishment of Systemic Immune Suppression Protocol
이종이식용 각막 제조에 있어 면역 반응을 억제할 수 있는 프로토콜을 구축하기 위하여, 다음과 같이 항-CD20 조합 전신 면역 억제 프로토콜을 고안하였다. 본 프로토콜에서는 항 CD20 Ab, 항 IL2R Ab, 정맥 면역글로불린 (Intravenous Immunoglobulin; IVIG), 타클로리무스, 메틸프레드니슬론(Methylprednisolon) 을 정해진 주기에 맞춰 투여하였다. 항-CD20 mAb로 리툭시맙을 이용하였으며, 항 IL2R Ab로는 바실릭시맙을 이용하였다. 본 발명에 따른 프로토콜은 도 1에 나타내었으며, 구체적으로 다음과 같다. In order to establish a protocol that can suppress the immune response in xenograft cornea preparation, an anti-CD20 combination systemic immune suppression protocol was devised as follows. In this protocol, anti-CD20 Ab, anti-IL2R Ab, Intravenous Immunoglobulin (IVIG), taclolimus, methylprednisolon (Methylprednisolon) were administered at regular intervals. Rituximab was used as the anti-CD20 mAb and basiliximab was used as the anti IL2R Ab. The protocol according to the present invention is shown in Figure 1, specifically as follows.
항 CD20 Ab 인 리툭시맙은 느린 정맥 주입 (iv slow infusion) 을 통해 주입하였으며, 이종 이식 수술 당일 및 수술 후 1주 차에 20mg/kg으로 투여하였고, 수술 8주 후부터는 8주의 주기로 반복 투여하였으며, IgG 항체 상승 유무를 확인하여 필요시 더 자주 투약하였다.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.
항 IL2R 항체인 바실릭시맙 (basiliximab) 은 0.3mg/kg의 투여량으로 이종 이식 수술 당일 및 수술 후 4일차에 느린 정맥 주입을 통해 하루 1회 투여하였다.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.
정맥 면역글로불린 (Intravenous Immunoglobulin; IVIG) 은 1 g/kg의 투여량으로 투여하였으며, 수술 후 1일과 2주차에 투여하고, 면역 반응에 따라 추가 투여하였다. Intravenous Immunoglobulin (IVIG) was administered at a dose of 1 g / kg, one and two weeks after surgery, and additionally administered according to the immune response.
타클로리무스는 0.05mg/kg 의 투여량으로 수술 2일 전부터 12개월 동안 매일 하루 두 번씩 근육 주사를 통해 주입하였으며, 정기적인 혈중 타클로리무스 농도 검사를 시행하여 투여량을 조절하였다. 타클로리무스에 부작용을 나타내는 개체에 대해서는 0.035mg/kg로 투여량을 감량하였다.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.
이 외 스테로이드 제제로 메틸프레드니슬론(Methylprednisolon), 프레드니솔론 아세테이트 안약 및 덱사메타존을 함께 투여하였다. Methylprednisolon, prednisolone acetate eye drops and dexamethasone were also administered as steroid preparations.
메틸프레드니슬론의 경우 수술 후 5 주 동안 매일 2mg/kg 내지 0.25mg/kg 으로 투여량을 점차적으로 감소시키며 근육 내 투여를 진행하였고, 보다 구체적으로 일주일 간격으로 투여량을 다음과 같이 단계적으로 감소시켰다: 수술 당일부터 수술 후 7일차까지는 2mg/kg, 수술 후 8일차부터 14일차까지는 1.5mg/kg, 수술 후 15일차부터 21일차까지는 1.0mg/kg, 수술 후 22일차부터 28일차까지는 0.5mg/kg, 수술 후 29일차부터 35일차까지는 0.25mg/kg. In the case of methylprednisolone, 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.
프레드니솔론 아세테이트 1% 안약의 경우 수술 후 3개월째까지는 가급적 매일 한 방울씩 점안하였고, 수술 후 3개월부터 6개월까지는 주 2 내지 3회, 수술 후 6개월 이후에는 주 1회로 점차적으로 간격을 늘려가며 투약을 진행하였다. 덱사메타존의 경우 결막 하 주입을 통해 1.5mg/0.3ml 로 수술 후 0일, 1일, 4일, 7일, 10일, 15일, 21일차에 투여하고 21일 이후부터는 7일 단위로 투여하는 형식으로 6개월 동안 투여하였다.  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.
1.2 면역억제 효과의 확인1.2 Identification of immunosuppressive effects
1.2.1 이종 각막 이식 방법 1.2.1 Heterogeneous corneal transplantation method
이종 각막의 이식을 위하여 유전적으로 변형되지 않은 성체 SNU 미니어처 피그를 공여자로 하고, Chinese rhesus macaques 를 수여자 (n=5)로 하여 전체층 각막이식술(Penetrating keratoplasty) 을 통해 수행하였다. 전체 층 각막 이식술의 방법은 도 2에 나타내었다. For transplantation of heterologous cornea, adult unpaired adult SNU miniature pigs were used as donors and Chinese rhesus macaques as donors (n = 5) were performed by Penetrating keratoplasty. The method of whole layer corneal transplantation is shown in FIG. 2.
도 2에 나타낸 바와 같이, 먼저 수여자의 각막을 원형절제술 (Trephination) 을 통해 지름 7.0mm 로 절단하고, 공여자의 7.5mm 크기의 각막을 위치시킨 후 이를 나일론사를 이용하여 봉합하였다. As shown in FIG. 2, first, 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.
1.2.2 이종이식 각막 면역억제 효과 확인 1.2.2 Confirmation of xenograft corneal immunosuppressive effect
본 발명의 투여 프로토콜에 따라 영장류에 이종 각막을 이식한 후, 면역억제 요법을 수행하였으며, 이에 따른 수술 후 임상 시험 결과를 면역 거부 반응이 나타나는지 여부, 각막 두께, 안압 검사를 통해 확인하였다. 구체적으로 이종각막이식을 받은 영장류의 각막은 세극등현미경으로 각막편 투명도, 부종 및 신생혈관 형성에 중점을 두어 검사하였고, 거부반응 발생 여부 및 그 외 감염 여부 등을 정기적으로 확인하였다. 중심각막두께 및 안압을 초음파 각막두께측정기 (Quantel Medical, Clermont-Ferrand, France)와 Tono-Pen (Medtronic Solan, Jacksonville, FL)으로 측정하였다. 중심각막두께는 5회 측정한 평균값, 안압은 2회 측정한 평균값을 사용하였으며, 그 결과를 도 3에 나타내었다. 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. Specifically, 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.
도 3에 나타낸 바와 같이, 각막 이식 수술 후 본 발명의 프로토콜에 의하여 면역억제 처치를 받은 개체는 수술 후 184 내지 443 일이 지나도록 모두 면역 거부 반응을 나타내지 않았다. 또한 각막 중심부의 두께가 수술 후 시간이 경과되어도 일정한 두께로 안정적으로 유지되었으며, 안압 (IOP) 역시 20mmHg 를 넘지 않는 정상 범위를 지속적으로 유지할 수 있는 것으로 나타났다. As 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. In addition, 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.
또한 본 발명의 프로토콜에 따라 면역억제 반응을 수행한 개체에서 flow cytometry를 이용하여 혈액 내 T 세포 및 B 세포 농도를 확인하였으며, 이를 이미 확립된 항 CD40 항체를 이용한 면역 억제 프로토콜(Kim J, et al. Xenotransplantation. 2017 Apr 10. doi: 10.1111/xen.12298)을 이용한 전층 각막이식 결과와 비교하여 도 4에 나타내었다. In addition, the concentration of T cells and B cells in the blood was confirmed using flow cytometry in the subjects who performed the immunosuppressive reaction according to the protocol of the present invention, and the immunosuppression protocol using the already established anti-CD40 antibody (Kim J, et al. Xenotransplantation. 2017 Apr 10. doi: 10.1111 / xen. 12298) is shown in Figure 4 compared with the results of full-layer corneal transplantation.
도 4에 나타낸 바와 같이, 본 발명의 프로토콜에 따라 처리된 개체에서는 혈액 내 T, B 세포 농도를 기존의 항 CD40 항체를 이용한 프로토콜보다도 더 낮게 유지하여 효과적인 면역 억제를 달성함을 확인하였다. As shown in Figure 4, 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.
상기 결과를 통해, 본 발명의 면역억제 프로토콜에 따르는 경우 이종 간 전층 각막 이식을 수행할 때 발생할 수 있는 면역 거부 반응을 효과적으로 억제할 수 있어 이종 전층 각막 이식의 안전성을 높이고, 성공률을 현저히 향상시킬 수 있음을 확인하였다. Through the above results, according to 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.

Claims (15)

  1. (a) 항 CD20 항체를 정맥 투여하는 단계; (a) intravenously administering an anti CD20 antibody;
    (b) 항 IL2R 항체를 정맥 투여하는 단계;(b) administering an anti-IL2R antibody intravenously;
    (c) 정맥 면역글로불린 (Intravenous Immunoglobulin)을 정맥 투여하는 단계; (c) intravenously administering Intravenous Immunoglobulin;
    (d) 타클로리무스를 근육 주사하는 단계; 및  (d) intramuscularly injecting taclolimus; And
    (e) 스테로이드를 투여하는 단계; 를 포함하는 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.  (e) administering a steroid; Method for inhibiting the immune response by corneal xenograft of mammals other than humans, including.
  2. 제1항에 있어서, 상기 항 CD20 항체는 리툭시맙인 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.The method of claim 1, wherein the anti-CD20 antibody is rituximab, the method of inhibiting the immune response by corneal xenograft of mammals other than humans.
  3. 제2항에 있어서, 상기 리툭시맙은 각막 이종 이식 수술 당일 및 수술 후 1 주차에 10 내지 30mg/kg 로 투여되며, 수술 8주 이후에는 8주마다 투여되는 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.The method of claim 2, wherein the rituximab is administered at 10 to 30mg / kg on the day of surgery and 1 week after corneal xenograft surgery, and every 8 weeks after 8 weeks of surgery, mammals other than humans Method of suppressing immune response by corneal xenograft of
  4. 제1항에 있어서, 항 IL2R 항체는 바실릭시맙인 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.2. The method of claim 1, wherein the anti-IL2R antibody is basilicimab. 3.
  5. 제4항에 있어서, 상기 바실릭시맙은 수술 당일 및 수술 후 4 일차에, 0.1 내지 0.5mg/kg 으로 투여되는 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.5. The method of claim 4, wherein the basiliximab is administered at 0.1 to 0.5 mg / kg on the day of surgery and the 4th day after the surgery, to inhibit the immune response due to corneal xenograft of a mammal other than human. Way.
  6. 제1항에 있어서, 상기 정맥 면역글로불린은 수술 후 1 일 및 14 일차에, 0.1 내지 5 g/kg으로 투여되는 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.The method of claim 1, wherein the intravenous immunoglobulin is administered at 0.1 to 5 g / kg on days 1 and 14 after surgery. .
  7. 제1항에 있어서, 상기 타클로리무스는 수술 전 내지 수술 후 12개월 동안 매일 하루 2회씩 0.01 내지 0.5mg/kg 으로 투여되는 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.According to claim 1, The taclolimus is characterized in that the immune response by corneal xenograft of the mammal, except for human, characterized in that administered twice a day for 0.01 months to 0.5 mg / kg twice a day for preoperative to 12 months after surgery How to suppress.
  8. 제1항에 있어서, 상기 스테로이드는 메틸프레드니슬론, 프레드니솔론 아세테이트 및 덱사메타존으로 이루어진 군에서 선택된 1 종 이상인 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.The method of claim 1, wherein the steroid is at least one member selected from the group consisting of methylprednisolone, prednisolone acetate, and dexamethasone.
  9. 제8항에 있어서, 상기 메틸프레드니슬론은 수술 후 5주 동안 2mg/kg 부터 0.25mg/kg까지 투여량을 감소시키며 매일 근육 내 투여되는 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.The method of claim 8, wherein the methyl prednisolone is administered to the corneal xenograft of mammals other than humans, characterized in that the daily dose is reduced intramuscularly from 2mg / kg to 0.25mg / kg for 5 weeks after surgery To suppress the immune response.
  10. 제1항에 있어서, 상기 프레드니솔론 아세테이트는 수술 후 3개월까지 매일 점안되는 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.The method of claim 1, wherein the prednisolone acetate is instilled daily up to 3 months after surgery, wherein the immune response by corneal xenograft of a mammal other than human is inhibited.
  11. 제1항에 있어서, 상기 덱사메타존은 수술 후 6개월 동안 1.0mg/0.3ml 내지 1.5mg/0.45ml 로 결막 하 주입되는 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.The method of claim 1, wherein the dexamethasone is injected subconjunctival at 1.0 mg / 0.3ml to 1.5mg / 0.45ml for 6 months after surgery, immune response by corneal xenograft of mammals, except humans How to suppress.
  12. 제1항 내지 제11항 중 어느 한 항에 있어서, 상기 각막 이종이식은 전층 각막 이종이식 또는 부분 각막 이종이식인 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.12. The method of any one of claims 1 to 11, wherein the corneal xenograft is a full-layer corneal xenograft or a partial corneal xenograft. .
  13. 제1항 내지 제11항 중 어느 한 항에 있어서, 상기 각막 이종이식은 돼지를 공여자로 영장류를 수여자로 하여 수행하는 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.12. The method according to any one of claims 1 to 11, wherein the corneal xenograft is carried out using a pig as a donor and a primate as a recipient. How to.
  14. 제1항 내지 제11항 중 어느 한 항에 있어서, 상기 각막 이종이식은 생각막의 이종이식인 것을 특징으로 하는, 인간을 제외한 포유류의 각막 이종이식에 의한 면역반응을 억제하는 방법.12. The method of any one of claims 1 to 11, wherein the corneal xenograft is a xenograft of the periosteum.
  15. a) 리툭시맙을 각막 이종 이식 수술 당일 및 수술 후 1 주차에 10 내지 30mg/kg 로 투여하며, 수술 8주 내지 24주 동안에는 2개월마다 정맥 투여하는 단계;a) Rituximab is administered 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;
    b) 바실릭시맙을 수술 당일 및 수술 후 4일차에, 0.1 내지 0.5mg/kg 으로 정맥 투여하는 단계;b) intravenously administering basiliximab at 0.1 to 0.5 mg / kg on the day of surgery and on day 4 post-surgery;
    c) 정맥 면역글로불린 (Intravenous Immunoglobulin)을 수술 후 1 일 및 14 일차에 0.1 내지 5g/kg 으로 정맥 투여하는 단계; c) Intravenous Immunoglobulin is administered intravenously at 0.1 to 5 g / kg on days 1 and 14 after surgery;
    d) 타클로리무스를 수술 후 12개월 동안 매일 하루 2회씩 0.01 내지 0.5mg/kg 으로 근육 주사하는 단계; d) intramuscularly injecting taclolimus at 0.01 to 0.5 mg / kg twice daily for 12 months after surgery;
    e) 메틸프레드니슬론을 수술 후 5주 동안 2mg/kg 부터 0.25mg/kg 까지 투여량을 감소시키며 매일 근육 내 투여하는 단계; e) daily intramuscular administration of methylprednisolone with a reduced dose from 2 mg / kg to 0.25 mg / kg for 5 weeks post-surgery;
    f) 프레드니솔론 아세테이트를 수술 후 3개월까지 매일 점안하는 단계; 및f) topical prednisolone acetate daily up to 3 months postoperatively; And
    g) 덱사메타존을 수술 후 6개월 동안 1.0mg/0.3ml 내지 1.5mg/0.45ml 로 결막 하 주입하는 단계; 를 포함하는 인간을 제외한 포유류의 전층 각막 이종이식에 의한 면역반응을 억제하는 방법.g) injecting dexamethasone subconjunctially at 1.0 mg / 0.3 ml to 1.5 mg / 0.45 ml for 6 months after surgery; Method for inhibiting the immune response by a full-layer corneal xenograft of a mammal, except human.
PCT/KR2017/006091 2017-04-27 2017-06-12 Combined immunosuppressive method of anti-cd20 monoclonal antibody and tacrolimus in corneal xenotransplantation WO2018199378A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780001730.5A CN109475621B (en) 2017-04-27 2017-06-12 Combined immunosuppressive method of anti-CD20 monoclonal antibody and tacrolimus in xenograft corneal transplantation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2017-0054072 2017-04-27
KR1020170054072A KR101968246B1 (en) 2017-04-27 2017-04-27 Anti-CD20 Monoclonal Antibody and Tacrolimus Combination Immunosuppressive Therapy in Xenotransplantation

Publications (1)

Publication Number Publication Date
WO2018199378A1 true WO2018199378A1 (en) 2018-11-01

Family

ID=63918402

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2017/006091 WO2018199378A1 (en) 2017-04-27 2017-06-12 Combined immunosuppressive method of anti-cd20 monoclonal antibody and tacrolimus in corneal xenotransplantation

Country Status (3)

Country Link
KR (1) KR101968246B1 (en)
CN (1) CN109475621B (en)
WO (1) WO2018199378A1 (en)

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 (en) * 2007-07-25 2010-04-22 알렉시온 파마슈티칼스, 인코포레이티드 Antibodies to cd200 and uses thereof in inhibiting immune responses

Family Cites Families (1)

* Cited by examiner, † Cited by third party
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 (en) * 2007-07-25 2010-04-22 알렉시온 파마슈티칼스, 인코포레이티드 Antibodies to cd200 and uses thereof in inhibiting immune responses

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 *

Also Published As

Publication number Publication date
KR101968246B1 (en) 2019-04-11
CN109475621A (en) 2019-03-15
KR20180120337A (en) 2018-11-06
CN109475621B (en) 2022-03-15

Similar Documents

Publication Publication Date Title
Zhou et al. Sustained subconjunctival delivery of infliximab protects the cornea and retina following alkali burn to the eye
Satarian et al. Intravitreal injection of bone marrow mesenchymal stem cells in patients with advanced retinitis pigmentosa; a safety study
Yam et al. Safety and feasibility of intrastromal injection of cultivated human corneal stromal keratocytes as cell-based therapy for corneal opacities
CA3025258C (en) Use of sirolimus to treat exudative age-related macular degeneration with persistent edema
Roesel et al. Uveal and capsular biocompatibility of two foldable acrylic intraocular lenses in patients with endogenous uveitis—a prospective randomized study
Pan et al. Combined transplantation with human mesenchymal stem cells improves retinal rescue effect of human fetal RPE cells in retinal degeneration mouse model
Sakurai et al. Scleral plug of biodegradable polymers containing ganciclovir for experimental cytomegalovirus retinitis
Gerhart et al. Depletion of Myo/Nog cells in the lens mitigates posterior capsule opacification in rabbits
Mannis et al. Herpes simplex dendritic keratitis after keratoplasty
Jadi et al. Tetraspanin CD9-derived peptides inhibit Pseudomonas aeruginosa corneal infection and aid in wound healing of corneal epithelial cells
Vinciguerra et al. Long-term resolution of immunological graft rejection after a dexamethasone intravitreal implant
WO2018199378A1 (en) Combined immunosuppressive method of anti-cd20 monoclonal antibody and tacrolimus in corneal xenotransplantation
Rizzo et al. Safety results for geographic atrophy associated with age-related macular degeneration using subretinal cord blood platelet-rich plasma
Utine et al. TNF-α inhibitors for the management of intractable corneal melt: report of three cases and review of the literature
Wang et al. Celastrol alleviates subconjunctival fibrosis induced by silicone implants mimicking glaucoma surgery
Hayashi et al. Suppression of allograft rejection with soluble VEGF Receptor 2 chimeric protein in a mouse model of corneal transplantation
Hong et al. Substance-P blocks degeneration of retina by stimulating migration and proliferation of retinal pigmented epithelial cells
CN1698898A (en) Biodegradation type eye implantation agent
CN112220749A (en) Mizoribine and application of composition containing mizoribine
CN116492462B (en) Application of PAD4 inhibitor in preventing and treating immune rejection after cornea transplantation
US20190216830A1 (en) Ophthalmic compositions
Duker et al. Initial experience with an eight-month sustained-release intravitreal ganciclovir implant for the treatment of CMV retinitis associated with AIDS
Kose Candida retinitis in a liver transplantation recipient
RU2183120C2 (en) Method to treat neovasculogenesis as a result of through keratoplasty
Larco Jr et al. Management of surgically-induced necrotizing scleritis: case series and review of the literature

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17907710

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17907710

Country of ref document: EP

Kind code of ref document: A1