WO2003068915A2 - Production d'anticorps humains chez des hotes mammiferes non humains immunodeficients - Google Patents

Production d'anticorps humains chez des hotes mammiferes non humains immunodeficients Download PDF

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Publication number
WO2003068915A2
WO2003068915A2 PCT/US2003/003999 US0303999W WO03068915A2 WO 2003068915 A2 WO2003068915 A2 WO 2003068915A2 US 0303999 W US0303999 W US 0303999W WO 03068915 A2 WO03068915 A2 WO 03068915A2
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Prior art keywords
human
cells
immunodeficient
tissue
antibody
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PCT/US2003/003999
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English (en)
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WO2003068915A3 (fr
Inventor
Anke Kretz-Rommel
Hong Xin
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Alexion Pharmaceuticals, Inc.
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Publication date
Application filed by Alexion Pharmaceuticals, Inc. filed Critical Alexion Pharmaceuticals, Inc.
Priority to AU2003215145A priority Critical patent/AU2003215145A1/en
Priority to JP2003568030A priority patent/JP2005517401A/ja
Priority to EP03710962A priority patent/EP1474682A4/fr
Priority to CA002476232A priority patent/CA2476232A1/fr
Publication of WO2003068915A2 publication Critical patent/WO2003068915A2/fr
Publication of WO2003068915A3 publication Critical patent/WO2003068915A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • This disclosure relates to the creation of a functional human immune system in non-human, mammalian recipients, especially immunodeficient mice such as SCID mice.
  • Methods for the production of human antibodies by grafting tissue from a human immune organ into non-human, mammalian recipients, especially immu ⁇ od ⁇ ficient mice such as SCID mice are also described.
  • mAbs monoclonal antibodies
  • the use of monoclonal antibodies (mAbs) as therapeutics has expanded dramatically over the past few years.
  • the vast majority of mAbs are of non-human (largely rodent) origin.
  • non-human mAbs pose the problem of immunogenicity in humans into which the rodent mAbs are introduced.
  • Anti-rodent antibodies produced by the introduction of rodent mAbs can result in enhanced clearance of the serum, blocking of the therapeutic effect of the rodent mAb and hypersensitivity reactions.
  • These limitations have prompted the development of "humanizatio ⁇ " technologies to alter rodent antibodies to make them more related to human antibodies. Nonetheless, the use of fully human antibodies is most desirable.
  • SClD-hu mice have been designed as an animal model to study the human immune system under experimental conditions.
  • the original SClD-hu mouse model injecting human primary blood lymphocytes into SCID mice was followed by many studies transplanting hematopoietic organs (reviewed in Seminars in Immunology 1996, Vol. 8, 207).
  • the SCID-hu-PBL model has been successfully used to elicit secretion of human antibodies into the serum after immunization with viral antigens (e.g., Ducosal et al., Nature 1992, 355, 258).
  • antibody production in the SCID-hu-PBL mouse is limited to the mature, biased immune repertoire of the donor.
  • the lymphoid system comprises organs where immune cells originate, mature or reside.
  • the principle organs of the immune system are thymus, spleen, bone marrow, skin, lymph nodes and in the fetus also in the liver. It has now been found that engraftment of all these organs into an immunodeficient, non-human, mammalian host such as, for example, a SCID mouse, establishes a human immune system capable of mounting an immune response against a variety of immu ⁇ ogens.
  • an adequate growth factor and cytokine environment assists in obtaining an antibody response.
  • cells from the grafted immune organs can be harvested and the cells or genetic material from the cells can be immortalized and/or cloned as desired
  • human antibodies can be produced by grafting tissue from a human immune organ into a non-human, mammalian recipient.
  • the recipient is a SCID mouse.
  • the method of producing a human antibody begins with the step of grafting human tissue into an immunodeficient, non-human, mammalian recipient.
  • the human tissue grafted into the host includes sufficient portions of one or more human immune organ to produce antibodies.
  • the development of a functional human immune system is enabled by the injection of appropriate cytokines and growth factors, such as, for example, provided in methocult and matrigel.
  • the immunodeficient, non-human, mammalian recipient is immunized with an immunogen, preferably after the presence of human antibodies is detected. Cells that produce human antibodies in response to the immunogen are then harvested.
  • the step of harvesting cells that produce human antibodies can be accomplished by removing from the recipient at least a portion of the human tissue previously grafted therein or mouse immune organs to which human cells have migrated. RNA from the removed human tissue can then be isolated using conventional techniques. Once the RNA is isolated, it can be used to construct an antibody library which can be screened to identify one or more antibodies that interact with the immunogen. Alternatively, human B cells are harvested and fused to a hybridoma partner. In another aspect, a new and useful hybrid SCID mouse having human tissue grafted therein is described. The human tissue implanted into the mouse includes at least a sufficient portion of at least one human immune organ to produce a human antibody.
  • antibody libraries derived from human cells that developed from human tissue implanted within an immunodeficient, non-human, mammalian recipient are described.
  • a drug is administered to a non-human mammalian having at least a sufficient portion of thymus, spleen, bone marrow, skin, lymph nodes and fetal liver grafted therein to produce a human antibody and any effects of the drug on human antibody production is observed.
  • Human antibodies are produced by human tissue grafted into a non-human, mammalian recipient.
  • the grafted tissue includes sufficient portions of one or more human immune organs to produce a fully human antibody.
  • the term "human immune organ” is intended to include human tissue from any organ that produces one or more molecules involved in the production of a human antibody.
  • tissue containing or capable of developing cell types that actually produce antibodies are included in the graft.
  • tissue to be grafted is preferably obtained from a fetal source, having a gestational age of at least four months, more usually in the range of 18 to 24 weeks and ranging up to neonate tissue, depending upon the nature of the tissue or organ. Tissue from a single donor is preferred.
  • fetal instead of adult tissues is preferred because it allows development of the immune system directly within the recipient. As the fetal cells develop they are exposed to proteins native to the recipient, and the immune organs become tolerant to the environment within the recipient.
  • thymus, spleen, bone marrow, skin, lymph nodes and fetal liver are all grafted into the recipient to ensure that all aspects of antibody production are provided.
  • Transplanting bone, fetal liver and thymus allows the development of T and B cells, thereby providing a broad repertoire of potential antigen specificity.
  • Addition of skin provides the site of immunogen injection (as described in more detail below) with the highest probability of human antigen presenting cells picking up the immunogen.
  • Lymph nodes can be important for T/B cell interaction and the spleen is a potential resource of B cells to construct a display library.
  • the amount of tissue grafted into the recipient should be an amount sufficient to produce antibodies.
  • the amount of tissue grafted can be as little as 1 mm 3 of each type of tissue.
  • grafts of 100 mm 3 or more can be used, depending on the specific recipient chosen.
  • the tissue may be fresh tissue, obtained within about 48 hours of death, or cryopreserved in a manner that maintains viability of the tissue.
  • the recipient can be any type of animal into which human tissue can be grafted and remain viable. Genetically immunocompromised mice are a particularly preferred - recipient, especially NOD-SCID mice. Where possible, it is preferred to irradiate the recipient before the human tissue is grafted therein. As those skilled in the art will appreciate, irradiation of the recipient will eliminate the native immune function of the recipient. The specific parameters for irradiation will depend on the particular type of recipient, especially the volume of the recipient. It should be understood, of course, that the conditions for irradiation should not be sufficiently severe as to kill the recipient. Irradiation conditions for various types of recipients are known to those skilled in the art. In general, the lowest dose of radiation necessary to cause loss of immune function should be applied.
  • SCID mice can be irradiated with gamma radiation in an amount ranging from 100 to 2000 RAD.
  • Grafting can be accomplished by simply making an incision in the skin of the recipient and placing the human tissue under the skin of the recipient. If desired, the grafted tissue can be secured to a desired location within the recipient's body such as, for example by sutures or staples. The location at which the human tissue is grafted is not critical. Considerations in choosing a location for the graft include the likelihood that the grafted tissue will be vascularized, the ease of implantation and the ease of retrieval of the implanted tissue.
  • the grafting site is a highly vascularized location.
  • the site of grafting can be downstream from a convenient site in the blood or lymphatic system for introduction of an antigen as described below.
  • primary lymph organs e.g., bone, liver and thymus
  • secondary lymph organs e.g., spleen, lymph nodes and skin.
  • the human skin can be placed below the recipient's skin, it is preferred to remove a section of the recipient's skin and provide a surface graft of the human skin to allow injection of an immunogen directly through the human skin graft.
  • the mononuclear fraction of cord blood can be injected into the recipient's blood stream at or around the time of grafting.
  • the immediate environment surrounding the graft is optionally treated to enhance lymphocyte development and antibody production.
  • Suitable treatments include the application of compositions containing components known to enhance vascularization and cell growth, the differentiation of cells and/or the production of antibodies.
  • Suitable compositions include gelling agents (such as, for example, methylcellulose or agar) containing growth factors (such as, for example, Stem Cell Factor, Granulocyte acrophage-Stimulati ⁇ g Factor, IL-3, IL-6, Gra ⁇ ulocyte- Colony Stimulating Factor, and erythropoietin).
  • METHOCULT® GF H4435 available from Stemcell Technologies Inc., Vancouver, British Columbia. Details regarding METHOCULT® products are disclosed in the following articles: Conneally E, Bardy P, Eaves CJ, Thomas T, Chappel S, Shpall EJ, Humphries RK: Rapid and efficient selection of human hematopoietic cells expressing murine heat-stable antigen as an indicator of retroviral-mediated gene transfer. Blood 87: 456, 1996; Eaves CJ: Assays of hemopoietic progenitor cells. Williams Hematology, 5 (eds.
  • compositions capable of supporting cell growth are a composition capable of supporting cell growth.
  • suitable compositions in this category include basement-membrane-derived compositions containing a biologically active polymerizable extract containing lami ⁇ in, collagen IV, nidogen, heparan sulfate proteoglycan and entactin.
  • biologically active as used in connection with this basement-membrane-deriyed composition means capable of supporting normal growth and differentiation of various cell types when cultured including epithelial cells.
  • One such composition is commercially available under the tradename MATR1GEL® Basement Membrane Matrix available from Becton Dickinson Labware, Bedford MA. Details regarding MATRIGEL® products are disclosed in U. S. Patent No. 4,829,000, the disclosure of which is incorporated herein by reference. A combination of such materials can advantageously be employed.
  • composition(s) can be applied directly to the location of grafted organ at the time of grafting and/or subsequent to grafting by injection to the site of grafting.
  • the amount of the composition applied is not critical and will depend on such factors as the type(s) and amount of human tissue grafted, the specific composition employed, the specific recipient, and the location of the graft. Typically from about 100 ⁇ l to about 500 ⁇ l of the composition will be applied at the time of grafting. In particularly useful embodiments, the composition is re-applied after grafting at intervals of between seven and ten days until immunization, as discussed in more detail below.
  • kits for detecting the presence of human antibodies in an animal's serum such as, for example, Easy-Titer® human IgG assay kit are commercially available from Pierce (Rockford, IL).
  • Pierce Pierce (Rockford, IL).
  • the grafted tissue remains viable, has vascularized and is believed to have lymphatic vessels connected thereto.
  • at least one week will transpire, however anywhere from 2 to 20 weeks or more may be allowed to pass before the next step (immunization) is performed.
  • Suitable immunoge ⁇ s include both haptens and antigens, where the haptens are modified to provide for an immune response.
  • Compounds of interest may include small synthetic organic molecules, generally of less than about 5 kD (kilodaltons), usually less than about 2 kD, polypeptides and proteins, lipids, saccharides, and combinations thereof.
  • the compounds may be synthetic or naturally occurring, including drugs, hormones, cytokines, surface membrane proteins, enzymes, sugar side groups, toxins, etc. Cells or tumor tissue can also be used as the immunogen.
  • the immunogen may be combined with a wide variety of adjuvants, such as alim, RIBI, CpG oligodeoxy ⁇ ucleotide, complete Freund's adjuvant, specol, B. pertussis or its toxin, etc.
  • adjuvants such as alim, RIBI, CpG oligodeoxy ⁇ ucleotide, complete Freund's adjuvant, specol, B. pertussis or its toxin, etc.
  • an immunizing composition is prepared by culturing the mononuclear fraction of cord blood to grow dendritic cells. The dendritic cells are then stimulated with an immunogen. The resulting composition is then injected into the recipient to accomplish immunization.
  • the immunogen can be administered systemically to the recipient of the graft or injected locally at the site of the graft. Administration will normally be by injection, either subcutaneous, intramuscular, intraperito ⁇ eal or intravascular, preferably directly into the site of the grafted human tissue.
  • the recipient has received a human skin graft and the immunogen is injected through the grafted skin or adjacent to it
  • the immunogen is injected through the grafted skin or adjacent to it
  • Considerations in determining how much immunogen should be administered include the nature of the immunogen, the amount of tissue grafted into the recipient and the desired degree and swiftness of the immune response sought.
  • One or more booster injections maybe made, usually within 1 to 6, more usually 2 to 4 weeks of the previous injection.
  • the booster injection may have the same composition or different composition than the prior injection. Immunization may also be accomplished by the RIMMS technique which is well known to those skilled in the art.
  • the recipient is then monitored to ascertain whether an immunogen-specific response has been mounted.
  • Techniques for detection of antibodies specific to any given immunogen are within the purview of one skilled in the art.
  • One suitable method of detecting the presence of human immunogen-specific antibodies in an animal's serum is disclosed in Current Protocols in Immunology, Coliga ⁇ et al., Chapter 2.1 (John Wiley & Sons, 2000 ed.), the disclosure of which is incorporated herein by reference.
  • RNA from the removed tissue is isolated using techniques well known to those skilled in the art.
  • the recovered RNA is used to generate one or more antibody libraries and the libraries are screened to identify antibodies that bind to the antigen or a component thereof.
  • the library is screened to identify antibodies that have either an agonistic or antagonistic effect on the antigen.
  • Techniques for producing and screening antibody libraries are well known to those skilled in the art. See, for example, U.S. Patent No. 6,291 ,161 to Lerner et al. and copending U.S. Provisional Application Nos. 60/323,455 and 60/323,400, the disclosures of which are incorporated herein in its entirety by this reference.
  • antibody-producing cells can be selected and fused with non-antibody producing cells such as, for example, immortalized cell lines.
  • non-antibody producing cells such as, for example, immortalized cell lines.
  • fusion partners are typically transformed human cells such as human myeloma cells.
  • human myeloma cell line is disclosed by Karpas, et al., PNAS, vol. 94, no. 4, pages 1799-1804, 2001.
  • fused cells are segregated into individual cultures and propagated, and hybridoma lines which express immunogen-specific monoclonal antibodies are selected.
  • These cell lines can be maintained in culture or cryopreserved using techniques well known to those of ordinary skill in the art.
  • the hybridomas may then be introduced into host animals, e.g.
  • mice or rats to produce ascites fluid or mechanically expanded, using spinner flasks, roller bottles, etc.
  • the host will be immunocompromised, so as to be able to accept the neoplastic graft.
  • the resulting antibodies may be used in a variety of ways, both diagnostic and therapeutic. However, since other antibodies which are normally more easily obtained, such as non-human antibodies can be used in in vitro diagnostics, for the most part the subject antibodies will be used for in vivo diagnostic and therapeutic use in humans.
  • the subject antibodies may be used in the treatment of disease, neutralizing viruses or other pathogens, for in vivo diagnoses, for targeted toxicity against neoplastic cells or precursors to such cells, passive immunization, in conjunction with transplantation, and the like.
  • the subject antibodies may be modified by radiolabeling, conjugation to other compounds, such as biotin, avidin, enzymes, cytotoxic agents, e.g. ricin, diphtheria toxin, arbin, etc., and the
  • the non-human recipients of the grafted human immune organ can be used in methods for testing of the effects of drugs on the human immune system.
  • a drug is administered to the non-human mammalian having at least a sufficient portion of thymus, spleen, bone marrow, skin, lymph nodes and fetal liver grafted therein to produce a human antibody. After a period of time, any effects of the drug on human antibody production is observed.
  • Techniques for determining the effects of a drug on a human immune system are known to and within the purview of those skilled in the art. The following non-limiting example is provided to illustrate one embodiment of the methods described herein. EXAMPLE
  • NOD/LtSz-scid/scid mice were irradiated with 250 RAD to completely eliminate any residual immune function.
  • Fetal tissue from gestation week 18-24 was obtained and small pieces of liver, spleen and thymus cortex and thymus medulla were prepared. Also, bone was processed by cutting off approximately 0.5 cm at the end on both sides of the femur and tibia. Lymph nodes from Peyefs patch were collected and skin pieces of approximately 1 cm 2 were prepared. One incision was made above each leg and bone, liver and thymus pieces were placed under the skin.
  • the system was improved by injecting methocult into the area containing the grafted organs to provide an appropriate cytokine environment for immune cell engraftment.
  • a 1 cm2 patch of skin was removed from the back of the mouse and the human skin was grafted into the deficit. An incision was made adjacent to the human skin graft and lymph node and spleen tissue was placed under the recipient's skin.
  • the system was improved by injecting 200 ⁇ l of MATRIGEL® was injected into the grafted spleen area to provide enhanced blood vessel formation.
  • mice received 10 ⁇ g Hepatitis B ⁇ surface antigen or tetanus toxoid in complete Freund's adjuvant subcutaneously adjacent to the grafted skin.
  • mice were immunized using CpG oligodeoxy ⁇ ucleotides. 100 ⁇ g CpG oligodeoxynucleotides and 10 ⁇ g antigen were injected subcutaneously at one to three week intervals. Serum IgG titers specific for tetanus toxoid or Hepatitis B surface antigen were determined by ELISA. A weak response to tetanus toxoid, but no response to hepatius B surface antigen was observed. To improve the system and enable a new immune response and not just a recall response, matrigel and methocult were introduced as described above.
  • mice two out of three hepatitis B and six out of seven tetanus toxoid immunized mice showed specific human antibodies to the respective antigen after the third immunization. Also, three out of five mice developed an anti-lgE response with substantial titers (up to 1 :5000) after immunization with human IgG Fc. Two out of four mice immunized with LF showed a moderate response to that antigen.
  • RNA is isolated from the collected immune organs and an antibody library is produced. The library is panned using the immunogen with which the mice were immunized. Fully human antibodies which bind to or otherwise interact with the immunogen are thus identified.

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Abstract

Cette invention concerne un procédé de production d'anticorps humains consistant à greffer des tissus provenant d'un ou plusieurs organes immuns humains chez un hôte mammifère non humain immunodéficient tel qu'une souris SCID.
PCT/US2003/003999 2002-02-11 2003-02-10 Production d'anticorps humains chez des hotes mammiferes non humains immunodeficients WO2003068915A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2003215145A AU2003215145A1 (en) 2002-02-11 2003-02-10 Production of human antibodies in immunodeficient non-human,mammalian hosts
JP2003568030A JP2005517401A (ja) 2002-02-11 2003-02-10 免疫欠損非ヒト哺乳動物宿主におけるヒト抗体の産生
EP03710962A EP1474682A4 (fr) 2002-02-11 2003-02-10 Production d'anticorps humains chez des hotes mammiferes non humains immunodeficients
CA002476232A CA2476232A1 (fr) 2002-02-11 2003-02-10 Production d'anticorps humains chez des hotes mammiferes non humains immunodeficients

Applications Claiming Priority (2)

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US35608202P 2002-02-11 2002-02-11
US60/356,082 2002-02-11

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WO2003068915A2 true WO2003068915A2 (fr) 2003-08-21
WO2003068915A3 WO2003068915A3 (fr) 2004-07-29

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JP (1) JP2005517401A (fr)
AU (1) AU2003215145A1 (fr)
CA (1) CA2476232A1 (fr)
WO (1) WO2003068915A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8884096B2 (en) 2006-05-11 2014-11-11 Alexander Lifke Method for the production of antibodies
US20200254077A1 (en) * 2011-05-19 2020-08-13 The Regents Of The University Of Michigan Materials and Methods for Eliciting Targeted Antibody Responses In Vivo

Citations (1)

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US5663481A (en) * 1993-08-06 1997-09-02 Mount Sinai Hospital Corporation Animal model of the human immune system

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IL118625A0 (en) * 1996-06-11 1996-10-16 Xtl Biopharmaceuticals Limited Anti HBV antibodies

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US5663481A (en) * 1993-08-06 1997-09-02 Mount Sinai Hospital Corporation Animal model of the human immune system

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Title
HOGAN C.J. ET AL.: 'Engraftment and development of humand CD34+-enriched cells from umbilical cord blood in NOD/LtSz-Scid/Scid mice' BLOOD vol. 90, no. 1, 01 July 1997, pages 85 - 96, XP002974722 *
HUIE M.A. ET AL.: 'Antibodies to human fetal erythroid cells from a nonimmune phage antibody library' PNAS vol. 98, no. 5, 27 February 2001, pages 2682 - 2687, XP002974719 *
NEIL G.A. ET AL.: 'Immunization of SCID-Hu mice and generation of anti-hepatitis B surface antigen-specific hybridomas by electrofusion' HUMAN ANTIBODIES AND HYBRIDOMAS vol. 3, October 1992, pages 201 - 205, XP002974721 *
REISNER Y. ET AL.: 'The trimera mouse: generating human monoclonal antibodies and an animal model for human diseases' TRENDS IN BIOTECHNOLOGY vol. 16, no. 6, 1998, pages 242 - 246, XP004121064 *
See also references of EP1474682A2 *
SHULTZ L.D. ET AL.: 'Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice' JOURNAL OF IMMUNOLOGY vol. 154, 1995, pages 180 - 191, XP002974720 *
WILLIAMSON R.A. ET AL.: 'Human monoclonal antibodies against a plethora of viral pathogens from single combinatorial libraries' PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES vol. 90, May 1993, pages 4141 - 4145, XP002117442 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8884096B2 (en) 2006-05-11 2014-11-11 Alexander Lifke Method for the production of antibodies
US20200254077A1 (en) * 2011-05-19 2020-08-13 The Regents Of The University Of Michigan Materials and Methods for Eliciting Targeted Antibody Responses In Vivo

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JP2005517401A (ja) 2005-06-16
EP1474682A4 (fr) 2005-10-12
AU2003215145A1 (en) 2003-09-04
CA2476232A1 (fr) 2003-08-21
WO2003068915A3 (fr) 2004-07-29
EP1474682A2 (fr) 2004-11-10

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