CA2219486A1 - Human antibodies derived from immunized xenomice - Google Patents

Human antibodies derived from immunized xenomice

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Publication number
CA2219486A1
CA2219486A1 CA 2219486 CA2219486A CA2219486A1 CA 2219486 A1 CA2219486 A1 CA 2219486A1 CA 2219486 CA2219486 CA 2219486 CA 2219486 A CA2219486 A CA 2219486A CA 2219486 A1 CA2219486 A1 CA 2219486A1
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CA
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Patent type
Prior art keywords
il
analog
immunoglobulin
antigen
group consisting
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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CA 2219486
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French (fr)
Inventor
Sue Klapholz
Daniel G. Brenner
Raju Kucherlapati
Aya Jakobovits
Daniel J. Capon
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Abgenix Inc
Original Assignee
Abgenix, Inc.
Sue Klapholz
Daniel G. Brenner
Raju Kucherlapati
Aya Jakobovits
Daniel J. Capon
Cell Genesys, Inc.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2812Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1267Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
    • C07K16/1282Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Clostridium (G)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241Tumor Necrosis Factors
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244Interleukins [IL]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • C07K16/2854Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72 against selectins, e.g. CD62
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4283Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • C07K16/4291Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Abstract

Antibodies with fully human variable regions against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Description

W O96/3409G PCTnUS95/05500 H~MAN ANTIBODIES DERIVED FROM IMMUNIZED XENOMICE

Technical Field The invention relates to the ~ield of immunology, and in particular to the production o~ antibodies. More speci~ically, it concerns producing such antibodies by a process which includes the step of ;mmlln;zing a transgenic ~n~m~l with an antigen to which antibodies are desired. The transgenic ;m~l has been modi~ied so as to produce human, as opposed to endogenous antibodies.

Backqround Art PCT application WO 94/02602, published 3 February 1994 and incorporated herein by reference, describes in detail the production of transgenic no~hllm~n ~n;m~ls which are modified so as to produce antibodies with fully ~hllmAn variable regions rather than endogenous antibodies in response to antigenic challenge. Briefly, the endogenous loci encoding the light and heavy immunoglobulin t~h~; n~ are incapacitated in the transgenic hosts and loci encoding hnm~n heavy and light chain proteins are inserted into the genome. In general, the ~n;m~l which provides all the desired modi~ications is obtained by cross-breeding int~rm~ te ~n;m~ls cont~;n;ng fewer than the full complement of modifications. The preferred embodiment o~ the nonh~lm~n ~n;m~l described in the specification is a mouse. Thus, mice, specifically, are described which, when a~m;n;~tered immunogens, produce antibodies with hnm~n variable regions, including ~ully hl~m~n antibodies, rather than murine antibodies that are ;mmllnospecific for these antigens.
The availability of such transgenic An;m~ls makes possible new approaches to the production o~ fully htlm~n antibodies. Antibodies with various ;mmllnospecificities are desirable for therapeutic and diagnostic use. Those antibodies intended ~or hnm~n therapeutic and in vivo diagnostic use, in particular, have been problematic because prior art sources ~or such antibodies resulted in ;mmllnoglobulins bearing the characteristic structures of antibodies produced by no~hllm~n W 096/34096 PCTrUS95/05500 hosts. Such antibodies tend to be ;mmllnogenic when used in hnm~ n ~:, The availability o~ the no~hnm~n, ;mmnnogen-responsive c transgenic ~n;m~l 8 described in the above-re~erenced WO 94/02602 make possible convenient production o~ hnm~n antibodies without the necessity o~ employing hnm~n hosts.

Disclosure o~ the Invention The invention is directed to methods to produce human antibodies by a process wherein at least one step o~ the process includes ;mmlln;zing a transgenic nonhllm~n ~n;m~l with the desired antigen. The modi~ied ~n;m~l ~ails to produce endogenous antibodies, but instead produces B-cells which secrete immunoglobulins with ~ully hnm~n variable regions. The antibodies produced include fully human antibodies and can be obtained ~rom the ~n;m~l directly, or ~rom immortalized B-cells derived ~rom the ~n;m~l Alternatively, the genes encoding the ;mmllnoglobulins with hllm~n variable regions can be recovered and expressed to obtain the antibodies directly or modi~ied to obtain analogs o~ antibodies such as, ~or example, single chain Fv molecules.
Thus, in one aspect, the invention is directed to a method to produce an ;mmllnoglobulin with a ~ully human variable region to a speci~ic antigen or to produce an analog o~ said ;mmnnoglobulin by a process which comprises ;mmlln;zing a nonhllm~n ;:~n;m~l with the antigen under conditions that stimulate an ;mmllne response. Fully hllm~n ;mmllnoglobulins are included in this group and are pre~erred. The nonhllm~n ~n;m~l is characterized by being substantially incapable o~ producing endogenous heavy or light ;mmllnoglobulin chain, but capable of producing ;mmllnoglobulins either with both human variable regions and constant regions or with ~ully human variable regions or both. In the resulting ;mmlln~ response, the ~n;m~l produces B cells which secrete ;mmllnoglobulins, with at least variable regions that are ~ully human, speci~ic ~or the antigen.
The human ;mmllnQglobulin o~ desired specif~icity can be directly recovered ~rom the ~n;m~ or example, ~rom the serum, or primary B cells can be obt~;n~ ~rom the ~n;m~l and W 096/34096 PCT~US95/05500 -- 3 im.mortalized. The immortalized B cells can be used directly as the source o~ hl~mAn antibodies or, alternatively, the genes encoding the antibodies can be prepared from the immortalized B
cells or from primary B cells of the blood or lymphoid tissue (spleen, tonsils, lymph nodes, bone marrow) o~ the ;mmlln;zed ~n;m~l and expressed in recombinant hosts, with or without modification, to produce the ;mmllnoglobulin or its analogs. In addition, the genes encoding the repertoire o~ ;mmllnoglobulins produced by the ;mmlln;zed ~n;m~l can be used to generate a library of ;mmnnoglobulins to permit screening for those variable regions which provide the desired af~inity. Clones from the library which have the desired characteristics can then be used as a source of nucleotide sequences encoding the desired variable regions ~or ~urther manipulation to generate antibodies or analogs with these characteristics using st~n~d recombinant techniques.
In another aspect, the invention relates to an immortalized nonhuman B cell line derived from the above described ~n;m~l In still another aspect, the invention is directed to a recombinant host cell which is modified to contain the gene encoding either the human ;mmnnoglobulin with the desired speci~icity, or an analog thereo~ which exhibits the same speci~icity.
In still other aspects, the invention is directed to antibodies or antibody analogs prepared by the above described methods and to recom.binant materials ~or their production.
In still other aspects, the invention is directed to antibodies with ~ully hllm~n variable regions, including ~ully hnm~n antibodies which are ;mmllnospeci~ic with respect to particular antigens set ~orth herein and to analogs which are s;m;l~ly ;mmllnospecific, as well as to the reco-m-binant materials use~ul in the production of the~e antibodies.

~ Brie~ Description o~ the Drawings Figure 1 shows the ~erum titers o~ anti-I~-6 antibodies from a X~nnmr~usen';mmlln;zed with hllm~n IL-6 and which antibodies cont~;n h~lm~n ~ light ch~;n~ and/or hllm~n ~ heavy ~h~;n~.

W 096/34096 PCTrUS95/05500 Figure 2 shows the serum titers o~ anti-Ih-8 antibodies ~rom a x~nnmouse~ ;mmlln;zed with human Ih-8 and which antibodies contain hllm~n K light ~h~;ns and/or human ~ heavy ~h~n~
Figure 3 shows the serum titers o~ anti-TNF~
antibodies ~rom a x~nOmOUse~ ;mmlln;zed with human TNF-~ and which antibodies contain hllm~n K light ch~;n~ and/or human heavy ~h~;n~
Figure 4 shows the serum titers o~ anti-CD4 antibodies ~rom a Xenomouse~ ;mmlln;zed with human CD4 and which antibodies contain human K light Ch~; n~ and/or human ,u heavy rh~;n~:.
Figure 5 shows the serum titers o~ a ~nom~use~
;mmlln;zed with 300.19 cells expressing h-selectin at their sur~ace. In the EhISA assay used, these antibodies are detectable only i~ they carry hllm~n ~ constant region heavy rh~; nc Figure 6 shows the serum titers o~ a X~nnmouse~
;mmlln;zed with 300.19 cells expressing h-selectin at their sur~ace. In the EhISA assay used, these antibodies are detectahle only i~ they carry human ~ light ch~;n~.
Figure 7 shows the serum titers o~ a ~nnmouse~
;mmlln;zed with 300.19 cells expressing h-selectin. In this EhISA, these antibodies are detectable i~ they carry human K
light chain and/or murine ~ constant regions.
Figure 8 shows a FACS analysis o~ human neutrophils coupled to sera ~rom a ~nom~use~ (A195-2) ;mmlln;zed with human h-selectin and labeled with an antibody ;mmllnoreactive with murine heavy chain ~ constant region.
Figure 9 shows a FACS analysis o~ human neutrophils ;ncllh~ted with serum ~rom a ~nnm~Use~ (A195-2) ;mmlln;zed with hllm~n h-selectin and labeled with an antibody ;mmllnoreactive with hnm~n light chain K region.
Figure 10 is a diagram o~ a plasmid used to trans~ect m~mm~lian cells to e~ect the production o~ the human protein gp39.
Figure 11 represents the serum titration curve o~ mice ;mmlln;zed with CH0 cells expressing human gp39. The antibodies detected in this EhISA must be ;mmllnoreactive with gp39 and _ W 096/34096 PCTrUS95/05500 -- 5 -- .
contain hllm~n heavy chain ~ constant regions or hnm~n K light ~:l ;n!:, Figure 12 shows the results of a FACS analysis of antibodies from a Xenomouse~ (labeled A247-4) ;mmlln;zed with hllm~n gp39 reacted with activated hllm~n T cells. Figure 12A
shows the separation of hllm~n activated T cells into CD4+ and CD4- populations. Panel B shows the results of a FACS analysis of the activated CD4+ T cells with antibodies from the XPnclm~use~ ;mmlln;zed with gp39 which contain murine heavy chain ~y constant regions; panel C shows the corresponding results with respect to CD4- populations.
Figure 13 is a titration curve with respect to monoclonal antibodies secreted by the hybridoma clone D5.1.
This clone is obtained from a x~nom~use~ ;mmlln;zed with tetanus toxin C (TTC) and contains hllm;~n K light chain and hnm~n constant region in the heavy chain.
Figure 14 is a titration curve with respect to the hybridoma supernatant from clone K4.1. This hybridoma clone is obt~;n~A from a x~nomousenl ;mmlln;zed with TTC and contains hllmAn K light chain and heavy chain having the murine ~y constant region.
Figure 15 shows binding curves for various concentrations of the K4.1 monoclonal antibody in a determ;n~tion of the affinity of the monoclonal with its antigen in a BIAcore instrument.
Figure 16 shows the complete nucleotide sequence of the heavy chain from the antibody secreted by K4.1.
Figure 17 shows the complete nucleotide sequence of the light chain from the antibody secreted by K4.1.
Figure 18 shows the complete nucleotide sequence of the heavy chain from the antibody secreted by D5.1.
Figure 19 shows the complete nucleotide sequence of the light chain from the antibody secreted by D5.1.

Modes of Carryinq Out the Invention In general, the methods of the invention include ~Am;n;F~tering an antigen for which hllmAn forms of ;mmllnospecific reagents are desired to a transgenic nonhllm;~n ~n;m~l which has -W 096/34096 PCT~US95/05500 -- 6 been modi~ied genetically so as to be capable o~ producing human, but not endogenous, antibodies. Typically, the ~n;m~l has been modi~ied to disable the endogenous heavy and/or light chain loci in its genome, so that these endogenous loci are incapable of the rearrangement required to generate genes encoding ;mmllnoglobulins in response to an antigen. In addition, the ~n;m~l will have been provided, stably, in its genome, at least one hllm~n heavy chain locus and at least one human light chain locus so that in response to an ~m;n;stered antigen, the human loci can rearrange to provide genes encoding hllm~n variable regions ;mmllnospeci~ic ~or the antigen.
The details for constructing such an ~n;m~l useful in the method of the invention are provided in the PCT application 2 referenced above.
For production o~ the desired antibodies, the first step is ~m;n;stration o~ the antigen. Techniques ~or such ;n;stration are conventional and involve suitable ;mmlln;zation protocols and formulations which will depend on the nature o~ the antigen per se. It may be necessary to provide the antigen with a carrier to ~nh~nce its ;mmllnogenicity and/or to include formulations which contain adjuvants and/or to ~m;n;ster multiple injections, and the like. Such techniques are st~n~d and optimization o~ them will depend on the characteristics o~ the particular antigen ~or which ;mmllnospeci~ic reagents are desired.
As used herein, the term ";mmllnospeci~ic reagents~
includes ;mmllnoglobulins and their analogs. The term "analogs"
has a specific m~n;ng in this context. It refers to moieties that contain the ~ully human portions of the ;mmllnoglobulin which account for its ;mmllnospecificity. In particular, variable regions including the complementarity det~rm;n;ng regions (CDRs) are required, along with sufficient portions of the ~ramework regions (FRs) to result in the appropriate three ~;m~n~ional con~ormation. Typical ;mmllnospeci~ic analogs o~
antibodies include F(ab~) 2' Fab,, and Fab regions. Modified îorms of the variable regions to obtain, ~or example, single chain Fv analogs with the appropriate ;mmllnospeci~icity are known. A
review o~ such Fv construction is ~ound, ~or example, in Tibtech CA 022l9486 l997-l0-27 W 096/34096 PCTrUS95/05500 (1991) 9: The construction o~ antibody analogs with multiple ;mml~nospecificities i8 also possible by coupling the human variable regions derived ~rom antibodies with varying speci~icities.
The variable regions with ~ully hllm~n characteristics can also be coupled to a variety o~ additional substances which can provide toxicity, biological functionality, alternative binding speci~icities and the like. The moieties including the ~ully human variable regions produced by the methods o~ the invention include single-chain ~usion proteins, molecules coupled by covalent methods other than those involving peptide linkages, and aggregated molecules. Examples o~ analogs which include variable regions coupled to additional molecules covalently or noncovalently include those in the ~ollowing nonlimiting illustrative list. Traunecker, A. et al. Int J
Cancer Supp (1992) SUPP 7:51-52 describe the bispecific reagent janusin in which the Fv region directed to CD3 is coupled to soluble CD4 or to other ligands such as OVCA and IL- 7.
Similarly, the ~ully hnm~n variable regions produced by the 20 method of the invention can be constructed into Fv molecules and coupled to alternative ligands such as those illustrated in the cited article. Higgins, P.J. et al. J In~ect Disease (1992) 166:198-202 describe a heteroconjugate antibody composed o~ OKT3 cross-linked to an antibody directed to a speci~ic sequence in 25 the V3 region or GP120. Such heteroconjugate antibodies can also be constructed using at least the hllm~n variable regions cont~;ne~ in the ;mmllnoglobulins produced by the invention methods. Additional examples o~ bispeci~ic antibodies include those described by Fanger, M.W. et al. Cancer Treat Res (1993) 30 68:181-194 and by Fanger, M.W. et al. Crit Rev TmmnnQl (1992) 12:101-124. Conjugates that are ;mmllnotoxins including conventional antibodies have been widely described in the art.
The toxins may be coupled to the antibodies by conventional r coupling techniques or ;mml1notoxins cont~;n;ng protein toxin 35 portions can be produced as ~usion proteins. The analogs o~ the present invention can be used in a corresponding way to obtain such ;mm~lnotoxins. Illustrative o~ such ;mmllnotoxins are those W 096/34096 PCTrUS95/OSSOO

described by Byrs, B.S. et al. S~m;n~Ars Cell Biol (1991) 2:59-70 and by Fanger, M.W. et al. TmmllnQl Today (1991) 12:51-54.
It will also be noted that some o$ the ;mmllnQglobulins and analogs o$ the invention will have agonist activity with respect to antigens for which they are ;mmllnospeci$ic in the cases wherein the antigens per$orm signal transducing ~unctions.
Thus, a subset o$ antibodies or analogs prepared according to the methods o$ the invention which are ;mmlln~speci$ic $or, $or example, a cell sur$ace receptor, will be capable o~ eliciting a response ~rom cells bearing this receptor corresponding to that elicited by the native ligand. Furth~rmnre~ antibodies or analogs which are immunospeci$ic ~or substances mimicking transition states o~ chemical reactions will have catalytic activity. Hence, a subset o$ the antibodies and analogs o~ the invention will $unction as catalytic antibodies.
In short, the genes encoding the immunoglobulins produced by the transgenic An;mAls of the invention can be retrieved and the nucleotide sequences encoding the ~ully human variable region can be manipulated according to known techniques to provide a variety o~ analogs such as those described above.
In addition, the immunoglobulins themselves contA;n;ng the human variable regions can be modi~ied using stAn~Ard coupling techniques to provide conjugates retA;n;ng ;mmllnospeci~icity and ~ully hllmAn characteristics in the ;mmllnospeci~ic region.
Thus, ;mmllnoglobulin "analogs" re~ers to moieties which contain those portions o$ the antibodies o$ the invention which retain their hllmAn characteristics and their immunospeci$icity. These will retain su$$icient h~lmAn variable region to provide the desired speci~icity.
As stated above, all o$ the methods o~ the invention include A~m; n; ~tering the appropriate antigen to the transgenic An;mAl The recovery or production o~ the antibodies themselves can be achieved in various ways.
First, and most straight~orward, the polyclonal antibodies produced by the An;mAl and secreted into the bloodstream can be recovered using known techniques. Puri~ied ~orms o$ these antibodies can, o~ course, be readily prepared by stAn~Ard puri$ication techniques, pre$erably including a$$inity W Og~/~lO~G PCTrUS95/05500 g chromatography with respect to the particular antigen, or even with respect to the particular epitope of the antigen for which speci~icity is desired. In any case, in order to monitor the success o~ ;mmlln;zation~ the antibody levels with respect to the antigen in serum will be monitored using stAn~Ard techniques such as ELISA, RIA and the like.
It will be noted, from the examples below, that a portion o~ the polyclonal antiserum obtained may include an endogenous heavy chain constant region derived from the host, even though the variable regions are fully hllmAn~ Under these circumstances, to the extent that an application requires fully h~lmAn antibodies, use of the polyclonal antiserum directly would be inappropriate. However, the presence of these ~h;m~as~
which is believed to result from in vivo isotype switching as described by Gerstein et al . Cell (1990) 63:537, is not problematic, in view of conventional purification and modification methods and in view of the availability of alternative methods to recover fully hnm~n antibodies, if desired, described in the following paragraphs.
First, and most simply, the polyclonal antiserum could be subjected to suitable separation techniques to provide compositions contA;n;ng only ~ully hnmAn immunoglobulins.
Portions of the serum which display characteristics o~ the host species can be removed, for example, using a~finity reagents with the appropriate anti species ;mmllnoglobulins or immunospeci~ic portions thereof. Furth~rmore, ~or applications where only the variable regions o~ the antibodies are required, treating the polyclonal antiserum with suitable reagents so as to generate Fab, Fab,, or F(ab,~ portions results in compositions contA;n;ng ~ully hllmAn characteristics. Such fragments are sufficient for use, for example, in ;mmllnodiagnostic procedures - involving coupling the ;mmllnospeci~ic portions of immunoglobulins to detecting reagents such as radioisotopes.
Thus, ~or some applications, the polyclonal antiserum can be treated to provide compositions with the desired characteristics including compositions consisting essentially o~ fully hllmAn antibodies and compositions including ;mmllnoglobulin analogs wherein the ;mmllnospeci~ic portion is ~ully hllmAn.

, W 096/34096 PCT~US95105500 Alternatively, ;mmllnoglobulins and analogs with desired characteristics can be generated from immortalized B
cells derived from the transgenic ~n;m~ls used in the method of the invention or from the rearranged genes provided by these 5 ~n;m~lS in response to ;mmlln;zation~ It will be apparent that hybridomas derived from the B cells of the ;mmlln;zed ~n;m~l can be screened so as to choose only those secreting fully hllm~n antibodies and that the genetic material can be recovered from the hybridomas or from lymphocytes in spleen, blood, or lymph nodes of the ;mmlln;zed ~n;m~l and manipulated using conventional techniques to replace any endogenous constant region with a hllm~n one or to produce a desired analog.
Thus, as an alternative to harvesting the antibodies directly from the ~n;m~l, the B cells can be obt~;ne~ typically from the spleen, but also, if desired, from the peripheral blood lymphocytes or lymph nodes and immortalized using any of a variety of techniques, most c~mmnnly using the fusion methods described by Kohler and Milstein. The resulting hybridomas (or otherwise immortalized B cells) can then be cultured as single colonies and screened for secretion of antibodies of the desired specificity. As described above, the screen can also include a dete~m;n~tion of the fully human character of the antibody. For example, as described in the examples below, a sandwich ELISA
wherein the monoclonal in the hybridoma supernatant is bound both to antigen and to an ant;hllm~n constant region can be employed. Conversely, hybridomas that secrete antibodies which are ;mmllnoreactive with antispecies antibodies directed to the species of the ;mmlln;zed ~n;m~l can be discarded. After the appropriate hybridomas are selected, the desired antibodies can be recovered, again using conventional techniques. They can be prepared in quantity by culturing the immortalized B cells using conventional methods, either in vitro, or in vivo to produce ascites fluid. Purification of the resulting monoclonal antibody preparations is less burdensome than in the case of serum since each immortalized colony will secrete only a single type of antibody. In any event, st~n~d purification techniques to isolate the antibody from other proteins in the culture medium can be employed.

W O 96/34096 PCTrUS95105500 As an alternative to obtA;n;ng hnm~n ;mmllnoglobulins directly from the culture of immortalized B cells derived from the An;m~l, the immortalized cells can be used as a source of rearranged heavy chain and light chain loci for subse~uent expression and/or genetic manipulation. Isolation of genes from such antibody-producing cells is straightforward since high levels of the appropriate m~RNAS are available for production of a cDNA library. The recovered rearranged loci can be manipulated as desired. For example, the constant region can be ~ch~nged for that of a different isotype or that of a hllm~n antibody, as described above, or eliminated altogether. The variable regions can be linked to encode single chain Fv regions. Multiple Fv regions can be linked to confer binding ability to more than one target or ch;m~ic heavy and light chain combinations can be employed. Once the genetic material is available, design of analogs as described above which retain their ability to bind the desired target, as well as their hllmAn characteristics, is straightforward.
Once the appropriate genetic material is obtA; n~A and, if desired, modified to encode an analog, the coding sequences including those that encode, at a m; n; mllm, the variable regions of the hllm~n heavy and light chain can be inserted into expression systems contA; n~ on vectors which can be transfected into stAn~d recombinant host cells. As described below, a variety of such host cells may be used; for efficient processing, however, mAmmAlian cells are preferred. Typical mAmmAlian cell lines useful for this purpose include CHO cells, 293 cells, or NSO-GS cells.
The production of the antibody or analog is then undertaken by culturing the modified recombinant host under culture conditions appropriate for the growth of the host cells - and the expression of the coding sequences. The antibodies are then recovered from the culture. The expression systems are preferably designed to include signal peptides so that the resulting antibodies are secreted into the medium; however, intracellular production is also possible.
In addition to deliberate design of modified forms of the immunoglobulin genes to produce analogs, advantage can be CA 022l9486 l997-l0-27 W 096/34096 ' PCTrUS9~/05500 taken of phage display techniques to provide libraries cont~;n;ng a repertoire o~ antibodies with varying a~inities ~or the desired antigen. For production o~ such repertoires, it is unnecessary to immortalize the B cells ~rom the ~mmlln;zed ~n;m~l; rather the primary B cells can be used directly as a source o~ DNA. The mixture o~ cDNAs obt~;ne~ ~rom B cells, e.g., derived ~rom spleens, is used to prepare an expression library, for example, a phage display library trans~ected into E. col i . The resulting cells are tested ~or immunoreactivity to the desired antigen. Techniques ~or the identi~ication o~ high a~inity hllm~n antibodies ~rom such libraries are described by Gri~iths, A.D., et al., EMBO J (1994) 13:3245-3260; by Nissim, A., et al. ibid, 692-698, and by Gri~fiths, A.D., et al., ibid, 725-734. Ultimately, clones ~rom the library are identi~ied which produce binding a~inities o~ a desired magnitude ~or the antigen, and the DNA encoding the product responsible ~or such binding is recovered and manipulated ~or st~n~rd recombinant expression. Phage display libraries may also be constructed using previously manipuiated nuclaoL~d~ se~u~l~s and screened in similar ~ashion. In general, the cDNAs encoding heavy and light chain are independently supplied or are linked to ~orm Fv analogs ~or production in the phage library.
The phage library is thus screened for the antibodies with highest a~inity ~or the antigen and the genetic material recovered ~rom the appropriate clone. Further rounds o~
screening can increase the a~inity o~ the original antibody isolated. The manipulations described above ~or recombinant production o~ the antibody or modi~ication to ~orm a desired analog can then be employed.
As above, the modi~ied or l~nmoA;~ied rearranged loci are manipulated using st~n~rd recombinant techniques by constructing expression systems operable in a desired host cell, such as, typically, a C'h;ne~e hamster ovary cell, and the desired ;mmllnoglobulin or analog is produced using st~n~rd recombinant expression techniques, and recovered and puri~ied using conventional methods.
The application o~ the ~oregoing processes to antibody production has enabled the preparation o~ human ;mmnnospeci~ic reagents with respect to antigens ~or which hnm~n antibodies have not hereto~ore been available. The ;mmllnoglobulins that result ~rom the above-described methods and the analogs m~de possible thereby, provide novel compositions ~or use in analysis, diagnosis, research, and therapy. The particular use will, of course, depend on the ;mmllnoglobulin or analog prepared. In general, the compositions o~ the invention will have utilities similar to those ascribable to no~hllmAn antibodies directed against the same antigen. Such utilities include, ~or example, use as a a~finity ligands ~or puri~ication, as reagents in immunoassays, as components of immunoconjugates, and as therapeutic agents for appropriate indications.
Particularly in the case o~ therapeutic agents or diagnostic agents for use in vivo, it is highly advantageous to employ antibodies or their analogs with ~ully h~lm~n characteristics. These reagents avoid the undesired ;mmlln~
responses engendered by antibodies or analogs which have characteristics marking them as originating ~rom non-h~lm~n species. Other attempts to "hllm~n;ze" antibodies do not result in reagents with ~ully hllm~n characteristics. For example, ~h;m~iC antibodies with murine variable regions and hl~m~n constant regions are easily prepared, but, o~ course, retain murine characteristics in the variable regions. Even the much more di~icult procedure o~ ~h~lm~n;zing" the variable regions by manipulating the genes encoding the amino acid sequences that form the ~ramework regions does not provide the desired result since the CDRs, typically of nonhllm~n origin, cannot be manipulated without destroying ;mmllnospeci~icity. Thus, the methods o~ the pre~ent invention provide, ~or the ~irst time, ;mm~lnoglobulins that are fully hnm~n or analogs which contain ;mmnnospecific regions with ~ully hllm~n characteristics.
There are large numbers of antigens for which hllm~n antibodies and their hllm~n analogs would be made available by the methods of the invention. These include the ~ollowing as a nonlimiting set:
leukocyte markers, such as CD2, CD3, CD4, CD5, CD6, CD7, CD8, CDlla,b,c, CD13, CD14, CD18, CDl9, CD20, CD22, CD23, CA 022l9486 l997-l0-27 W 096/34096 PCTrUS95/OSSOO

CD27 and its ligand, CD28 and its ligands B7.1, B7.2, B7.3, CD29 and its ligand, CD30 and its ligand, CD40 and its ligand gp39, CD44, CD45 and iso~orms, CDw52 (Campath antigen), CD56, CD58, CD69, CD72, CTLA-4, hFA-l and TCR
histocompatibility antigens, such as MHC class I or II, the Lewis Y antigens, SLex, Shey, SLea, and Sheb;
adhesion molecules, including the integrin~, such as VLA-l, VLA-2, VLA-3, VLA-4, VLA-5, VLA-6, LFA-l, Mac-l and pl50,95; and the selectins, such as L-selectin, E-selectin, and P-selectin and their counterreceptors VCAM-l, ICAM-l, ICAM-2, and LFA-3;
interleukins, such as IL-l, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, Ih-ll, IL-12, IL-13, IL-14, and~5 IL-15;
interleukin receptors, such as I~-lR, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9R, IL-lOR, IL-llR, IL-12R, IL-13R, IL-14R, and IL-15R;
ch~m~kines, such as PF4, RANTES, MIPl~, MCPl, NAP-2,~0 Gro~, Gro~, and IL-8;
growth ~actors, such as TNFalpha, TGFbeta, TSH, VEGF/VPF, PTHrP, EGF ~amily, FGF, PDGF ~amily, endothelin, and gastrin releasing peptide (GRP);
growth ~actor receptors, such as TNFalphaR, RGFbetaR,~5 TSHR, VEGFR/VPFR, FGFR, EGFR, PTHrPR, PDGFR ~amily, EPO-R, GCSF-R and other hematopoietic receptors;
inter~eron receptors, such as IFN~R, IFN~R, and IFN~R;
Igs and their receptors, such as IgE, FceRI, and FCeRII;
tumor antigens, such as her2-neu, mucin, CEA and endosialin;
allergens, such as house dust mite antigen, lol pl (grass) antigens, and urushiol;
viral proteins, such as CMV glycoproteins B, H, and gCIII, HIV-l envelope glycoproteins, RSV envelope glycoproteins, HSV envelope glycoproteins, EBV envelope glycoproteins, VZV
envelope glycoproteins, HPV envelope glycoproteins, Hepatitis ~amily sur~ace antigens;
-CA 022l9486 l997-l0-27 W 096/34096 PCTnUS95/05500 toxins, such as pseudnmo~ endotoxin and osteopontin/uropontin, snake venom, and bee venom;
blood ~actors, such as complement C3b, complement C5a, complement C5b-9, Rh factor, ~ibrinogen, ~ibrin, and myelin associated growth inhibitor;
enzymes, such as cholesterol ester transfer protein, membrane bound matrix metalloproteases, and glutamic acid decarboxylase (GAD); and miscellaneous antigens including ganglioside GD3, ganglioside GM2, hMP1, hMP2, eosinophil major basic protein, eosinophil cationic protein, pANCA, Amadori protein, Type IV
collagen, glycated lipids, ~-inter~eron, A7, P-glycoprotein and Fas (AFO-1) and oxidized-hDL.
Particularly preferred ;mmnnoglobulins and analogs are those ;mmllnospecific with respect to hnm~n Ih-6, hnm~n Ih-8, hllmAn TNF~, hllm~n CD4, hllm~n h-selectin, and hnm~n gp39. Human antibodies against Ih-8 are particularly useful in preventing tumor metastasis and inflammatory states such as asthma and reper~usion injury. Antibodies and analogs ;mmllnoreactive with hnm~n TNF~ and hllm~n Ih-6 are useful in treating cachexia and septic shock as well as auto;mmlln~ disease. Antibodies and analogs ;mmllnoreactive with gp39 or with h-selectin are also effective in treating or preventing auto;mmnne disease. In addition, anti-gp39 is helpful in treating gra~t versus host disease, in preventing organ transplant rejection, and in treating glomerulonephritis. Antibodies and analogs against h-selectin are useful in treating isch~m;~ associated with reper~usion injury.
Typical auto;mmlln~ diseases which can be treated using the above-mentioned antibodies and analogs include systemic lupus erythematosus, rheumatoid arthritis, psoriasis, Sjogren~s, ~ scleroderma, m;~e~ connective tissue disease, dermatomyositis, polymyositis, Reiter's syndrome, Behcet's disease, Type 1 - diabetes, ~h;mnto's thyroiditis, Grave's disease, multiple sclerosis, myasth~n;~ gravis and pemphigus.
The examples below are intended to illustrate but not to limit the invention.

CA 022l9486 l997-l0-27 In these examples, mice, designated ~xennm;ce", are used ~or initial ;mmlln;zations. A detailed description o~ such x~nnm;ce is ~ound in the above re~erenced PCT application WO
94/02602, Tmmnn; zation protocols appropriate to each antigen are described in the speci~ic examples below. The sera o~ the ;mmlln;zed x~nnm;ce (or the supernatants ~rom immortalized B
cells) were titrated ~or antigen speci~ic human antibodies in each case using a st~n~rd ELISA format. In this ~ormat, the antigen used ~or ;mmlln;zation was immobilized onto wells of microtiter plates. The plates were washed and blocked and the sera (or supernatants) were added as serial dilutions ~or 1- 2 hours o~ incubation. A~ter washing, bound antibody having human characteristics was detected by adding the appropriate antispecies Ig (typically ant; hnmAn K chain antibody or ant;hllmAn ~ chain antibody) conjugated to horseradish peroxidase (HRP) ~or one hour. In some cases, the bound antibodies were tested ~or murine characteristics using antimurine antibodies, typically antimurine ~ chain antibody. A~ter again w~h; n~, the chromogenic reagent o-phenylene ~; Am; n~ (OPD) substrate and 2 0 hydrogen peroxide were added and the plates were read 30 minutes later at 492 nm using a microplate reader.
Unless otherwise noted, the antigen was coated using plate coating buf~er (O.1 M carbonate bu~er, pH 9 . 6); the assay blocking bu~i~er used was 0. 5% BSA, 0.1~ Tween 20 and 0.01 Thimerosal in PBS; the substrate bu~er used in color development was citric acid 7.14 g/l: dibasic sodium phosphate 17.96 g/l; the developing solution (made ;mm~ tely be~ore use) was 10 ml substrate bui~i~er, 10 mg OPD, plus 5 ml hydrogen peroxide; the stop solution (used to stop color development) was 2 M suli~uric acid. The wash solution was 0. 05~ Tween 20 in PBS.

Example 1 ~llmAn Antibodies Against Human IL- 6 Three to 5 x~nom; ce aged 8-20 weeks were age-matched and ;mmnn;zed intraperiton~Ally with 50 ~g hnm~n IL-6 emulsi~ied in complete Freund~s adjuvant ~or primary ;mmlln;zation and in ;ncnmrlete Freund's adjuvant ~or subse~uent injections. The mice received 6 injections 2 - 3 weeks apart. Serum titers were CA 022l9486 l997-l0-27 WO 96/34096 PCTrUS95/05500 det~rm;ne~ after the second dose and following each dose thereafter. Bleeds were performed 6-7 days after injections from the retrobulbar plexus. The blood was allowed to clot at room temperature for about 2 hours and then incubated at 4~C for at least 2 hours before separating and collecting the sera.
ELISAs were conducted as described above by applying 100 ~l/well of recombinant hnm~n IL-6 at 2 mg/ml in coating buffer. Plates were then incubated at 4~C overnight or at 37~C
for 2 hours and then washed three times in washing buffer.
Addition of 100 ~l/well blocking buffer was followed by incubation at room temperature for 2 hours, and an additional 3 washes.
Then, 50 ~l/well of diluted serum samples (and positive and negative controls) were ~ to the plates.
Plates were then incubated at room temperature for 2 hours and again washed 3 times.
After washing, 100 ~l/well of either mouse antihuman chain antibody conjugated to HRP at 1/2,000 or mouse antihu-man K
chain antibody conjugated to HRP at 1/2,000, diluted in blocking buffer were ~e~. After a 1 hour incubation at room temperature, the plates were washed 3 times and developed with OPD substrate for 10-25 minutes. 50 ~l/well of stop solution were then added and the results read on an ELISA plate reader at 492 nm. The dilution curves resulting from the titration of serum from ~Cenomouse~y A40- 7 after 6 injections are shown in Figure 1. The data in Figure 1 show production of anti-IL- 6 ;mmllnoreactive with ant;hl~m~n ~ and ant;h-lm~n ~ detectable at ~erum dilutions above 1:1,000.

Example 2 3 o ~llm~n Antibodies Aqainst Human I~-8 - Tmmlln;zation and serum preparation were as described in Example 1 as except that hllm~n recombinant Ih-8 was used as - an ;mm~lnogen.
RrT~ assays were performed with respect to the recovered serurn, also exactly as described in R~C~mple 1, except that the ELISA plates were initially coated using 100 ~l/well of recombinant hllm~n IL-8 at 0.5 mg/ml in the coating buffer. The CA 022l9486 l997-l0-27 W 096/34096 PCT~US95/05500 results obt~;ne~ ~or various serum dilutions ~rom ~nomouse~
A260-5 a~ter 6 injections are shown in Figure 2. Human anti-IL-8 binding was again shown at serum dilutions having concentrations higher than that represented by a 1:1,000 dilution.

Example 3 Human Antibodies Aqainst Human TNF~
Tmmlln;zation and serum preparation were conducted as described in Example 1 except that hllm~n recombinant TNF~ was substituted ~or hllm~n IL-6. ELISAs were conducted as described in Example 1 except that the initial coating of the ELISA plate employed 100 ~l/well recombinant human TNFa at 1 mg/ml in coating bu~er.
The dilution curves ~or serum ~rom X~nnmouse~ A210-8 a~ter 6 injections obt~;n~ are shown in Figure 3. Again signi~icant titers of hllm~n anti-TNF~ binding were shown.

Example 4 Euman Antibodies Aqainst Human CD4 The human CD4 antigen was prepared as a sur~ace protein using human CD4 ~ on trans~ected recombinant cells as ~ollows. Human CD4 ~ consists o~ the extracellular ~nm~; n o~
CD4, the tr~n~m~mhrane ~nm~; n o~ CD4, and the cytoplasmic ~nm~;n of residues 31-142 o~ the mature ~ chain. Human CD4 zeta (F15 LTR) as described in Roberts, et al., Blood (1994) 84:2878 was introduced into the rat basophil leukemic cell line RBL-2H3, described by Callan, M., et al., Proc Natl Acad Sci USA (1993) 9Q:10454 using the kat high e~iciency transduction system described by Finer, et al., Blood (1994) 83:43. Brie~ly, RBL-2H3 cells at 106 cells per well were cultured in 750 ml DMEMl~W +
20~ FBS (Gibco) and 16 ~g/ml polybrene with an equal volume o~
proviral supernatant ~or 2 hours at 37~C, 5~ CO2. One ml o~
medium was removed and 750 ~l o~ in~ection medium and retroviral supernatant were added to each well and the cultures incubated overnight. The cells were washed and expanded in DMEMl~W + 10~
FBS until su~icient cells were available ~or sorting. The CD4-zeta transduced RBL-2H3 cells were sorted using the FACSTAR plus W 096/34096 PCTrUS9J/05SOO

(Becton Dickinson). The cells were st~; neA ~or hllm~n CD4 with a mouse ant;hllm~n CD4- PE antibody and the top 2-3~ expressing cells were selected.
T~mlln;zationS were conducted as described in Example 1 using 10 x 106 cells per mouse except that the primary injection was subcutaneous at the base o$ the neck. The mice received ~
injections 2-3 weeks apart. Serum was prepared and analyzed by ELISA as described in Example 1 except that the initial coating o~ the ELISA plate utilized 100 ~l per well o~ recombinant soluble CD4 at 2 mg/ml of coating bu~fer. The titration curve for serum ~rom Xenomouse~ A207-1 after 6 injections is shown in Figure 4. Titers o~ hllm~n anti-CD4 reactivity were shown at concentrations representing greater than those at 1:1,000 dilution.

Example 5 Human Antibodies Aqainst ~llm~n L-selectin The antigen was prepared as a surface displayed protein in C51 cells, a high expressing clone derived by transfecting the mouse pre-B cell 300.19 with LAM-1 cDNA (hAM-1 is the gene encoding L-selectin) (Tedder, et al., J Tmmllnol (1990) 144:532) or with similarly transfected CHO cells. The trans~ected cells were sorted using ~luorescent activated cell sorting using anti-Leu-8 antibody as label.
The C51 and the trans~ected CHO cells were grown in DME 4.5 g/l glucose with 10~ FCS and 1 mg/ml G418 in 100 mm ~;~hec. Negative control cells, 3T3-P317 (trans~ected with gag/pol/env genes o~ Moloney virus) were grown in the same medium without G418.
Primary ;mmlln;zation was done by injection subcutaneously at the base o~ the neck; subsequent injections - were intraperitoneal. 70-100 million C51 or trans~ected CHO
cells were used per injection ~or a total o~ ~ive injections 2-3 weeks apart.
Sera were collected as described in Example 1 and analyzed by ELISA in a protocol s;m; 1~ to that set ~orth in Example 1.

W 096/34096 PCTrUS9~/05500 For the ELISA, the trans~ected cells were plated into 96 well plates and cell monolayers grown ~or 1-2 days depending on cell number and used ~or ELISA when con~luent. The cells were ~ixed by ~irst washing with cold 1 x PBS and then ~ixing solution (5~ glacial acetic acid, 95~ ethanol) was added. The plates were incubated at -25~C ~or 5 minutes and can be stored at this temperature i~ sealed with plate sealers.
The EhISA is begun by bringing the plates to room temperature, ~licking to remove ~ixing solution and w~h;ng 5 times with DMEM medium cont~;n;ng 10~ FCS at 200 ~l per well.
The wells were treated with various serum dilutions or with positive or negative controls. Positive control wells cont~;n~ murine IgG1 monoclonal antibody to human L-selectin.
The wells were incubated ~or 45 minutes and monolayer integrity was checked under a microscope. The wells were then incubated with either antimouse IgG (1/1000) or with ant;hllm;1n K
chain antibody or ant;hllm~n ~ chain antibody conjugates with HRP
described in Example 1. The plates were then washed with 1~
BSA/PBS and again with PBS and monolayer integrity was checked.
The plates were developed, stopped, and read as described above.
The results ~or serum ~rom ~n~mouse~ A303-3 are shown in Figs.
5 and 6; human antibodies both to L-selectin and control 3T3 cells were obt~;n~. However, the serum titers are higher ~or the L-selectin-expressing cells as compared to parental 3T3 cells. These results show that ~nomouse~ A303-3 produces antibodies speci~ic ~or L-selectin with hllm~n ~ heavy chain regions and/or hllm~n ~ light ~h~3; nc, T~T.T.~ were also per~ormed using as the immobilized antigen a ~usion protein consisting o~ the extracellular ~om~;n o~ hllm~n h-selectin ~used to the constant ~om~;n o~ human IgG
(Guo, et al., Cell Immunol (1994) 154:202). The L-selectin ~usion protein was made by transient trans~ection o~ hllm~n 293 cells using calcium phosphate trans~ection (Wigler, M., Cell (1979) 16:777). Serum preparation was per~ormed as described in Example 1. ELISAs were conducted essentially as in Example 1, except that the initial coating o~ the ELISA plate employed 100 ~l trans~ected 293 cell culture supernatant co~t~;n~ng the CA 022l9486 l997-l0-27 W 096/34096 PCTrUS95tO5500 L-selectin-Ig ~usion protein. Detection employed HRP-mouse ant; htlm~n K and HRP-goat antimouse IgG.
Figure 7 shows the results from ~r~nomouse~ A195-2;
antibodies speciEic ~or h-selectin having hnm~n K light ~h~;nc:
and/or h~lm~n variable regions with murine heavy chain ~ regions are present in the serum.
The antisera obtained ~rom the ;mmlln;zed x~nnm;ce were also tested for St~; n;ng of hllmAn neutrophils which express L-selectin. ~llm~n neutrophils were prepared as follows:
peripheral blood was collected from normal volunteers with 100 units/ml heparin. About 3.5 ml blood was layered over an e~ual volume o~ One-step Polymorph Gradient (Accurate Chemical, Westbury, NY) and spun for 30 minutes at 450 x g at 20~C. The neutrophil fraction was removed and w~h~i twice in DPBS/2~ FBS.
The neutrophils were then StA; ne~l with either:
(1) antiserum from ~nnmouse~ A195-2 ;mmlln;zed with C51 cells (expressing L-selectin);
(2) as a positive control, mouse monoclonal antibody ~AM1-3 (against L-selectin); and (3) as negative control, antiserum from a X~nomouse ;mmlln;zed with cells expressing hllm~n gp39.
The st~;n~l, w~h~-l neutrophils were analyzed by FACS.
The results f~or antiserum from Xenomouse~ A195-2 are shown in Figures 8 and 9.
These results show the presence of antibodies in ;mmnn;zed ~nnmouse~ serum which contain f~ully hllm~n variable regions ;mmllnoreactive with L-selectin. The negative control antiserum from mice ;mmlln;zed with gp39 does not contain antibodies reactive against hllm~n neutrophils. Serum from A195-2 (;mmlln;zed with L-selectin-expressing cells) contains antibodies binding to hllm~n neutrophils detectable with a goat - antimouse IgG antibody (Figure 8), which binds with heavy chain protein composed o~ ~ully hnm~n variable regions and mouse y - constant regions. St~;n;ng with anti L-selectin X~nomousen' antisera detected with a mouse monoclonal antibody against hllm~3n K chain antibody is shown in Figure 9, showing the presence oE
~ully hllm~n K light chain.

W 096/34096 PCTrUS95/05500 As explained above, thege antibodies cont~;n;ng hllm~n variable regions are readily convertible to ~ully human antibodies. For example, using hybridomas secreting these antibodies, the cDNAs encoding them can be obt~;n~. By ampli~ying the genes encoding human V regions using primers cont~;n;ng restriction enzyme recognition sites and cloning them into plasmids cont~;n;ng the coding sequences ~or human constant regions as described by Queen, et al., Proc Natl Acad Sci (1989) 86:10029, genes encoding the ~ully human antibodies can be obt~;ne~ ~or recombinant production.

Example 6 Human Antibodies Against Human gp39 gp39 (the ligand ~or CD40) is expressed on activated hllm~n CD4+ T cells. The sera o~ ~n~m;ce ;mmlln;zed with recombinant gp39 according to this example cont~;n~ antibodies ;mmllnospeci~iC ~or gp39 with ~ully human variable regions; the sera contained ~ully hllm~n IgM antibodies and ~h;m~ic IgG
antibodies cont~;n;ng human variable regions and murine constant heavy chain ~ region.
The antigen consisted o~ stable trans~ectants o~
300.19 cells or o~ CHO cells expressing gp39 cDNA cloned into the m~mm~lian expression vector PlRl.HUgp39/IRES NEO as shown in Figure 10. CHO cells were split 1:10 prior to trans~ection in DMEM 4.5 g/l glucose, 10~ FBS, 2 mM glut~m;ne, MEM, NEAA
supplemented with additional glycine, hypoxanthine and thymidine. The cells were cotrans~ected with the gp39 vector at 9 ~g/10 cm plate (6 X 105 cells) and the DHFR expressing vector pSV2DHFRs (Subranani et al . Mol Cell Biol (1981) 9:854) at 1 ~g/10 cm plate using calcium phosphate trans~ection. 24 hours later the cells were split 1:10 into the original medium cont~;n;ng G418 at 0.6 mg/ml. Cells producing gp39 were sorted by FACS using an anti-gp39 antibody.
Mice grouped as described in Example 1 were ;mmlln;zed with 300.19 cells expressing gp39 using a primary ;mmlln;zation subcutaneously at the base o~ the neck and with secondary intraperitoneal injections every 2-3 weeks. Sera were harvested as described in Example 1 ~or the ELISA assay. The EhISA

CA 022l9486 l997-l0-27 W 096/34096 PCTnUS95/05500 procedure was conducted substantially as set forth in Example 1;
the microtiter plates were coated with CHO cells expressing gp39 grown in a 100 mm dish in DMEM, 4.5 g/l glucose, 10~ FCS, 4 mM
glut~m;ne, and nonessential amino acid (NEAA) solution ~or MEM
(lOOX). On the day preceding the EhISA assay, the cells were trypsinized and plated into 96-well filtration plates at 105 cells/200 ~l well and incubated at 37~C overnight. The positive controls were mouse ant;hllm~n gp39; negative controls were antisera from mice ;mmlln;zed with an antigen other than gp39.
50 ~l of sample were used for each assay. The r~m~;nA~r of the assay is as described in Example 1.
The dilution curves for the sera obt~;neA after 4 injections from mice ;mml~n;zed with gp39 expressed on CHO cells are shown in Figure 11. As shown, the sera cont~;neA ant;hllm~n gp39 ;mmnnospecificity which is detectable with hllm~n K and hnm~n ~ chain antibodies coupled to HRP.
In addition, the sera were tested for their ability to react with activated hllm~n T cells included in PBMC using FACS
analysis. To prepare the PBMC, hllm~n peripheral blood was collected from normal volunteers with the addition of 100 unit/ml heparin. PBMC were isolated over Ficoll gradient and activated with 3 ,ug/ml PHA, 1 ~Lg/ml PMA in IMDM plus 10~ FBS
plus 25 ~M 2-mercaptoethanol for 4 hours. A~ter washing, the PBMC were st~;n~A with mouse Mab against hnm~n CD4 labeled with FITC to permit separation of CD4+ and CD4- hnm~n T cells.
The activated CD4+ and CD4- T cells were then analyzed by FACS using st~;n;ng with either:
1) antiserum from a ~onnmouse~ ;mmlln;zed with 300.19 cells producing gp39;
2) a positive control mouse Mab directed against ~-CD40L (hllm~n gp39); and - 3) a negative control antiserum from a ~nomouse~
;mmnn;zed with TNF.
The detecting antibody in the FACS analysis was goat antimouse IgG (PE). The results are shown in Figure 12.
As shown in Figure 12A, CD4+ (R2) and CD4- (R3) cells were separated prior to FACS analysis. Panel B shows the results for CD4+ cells and shows that sera from mice ;mmlln;zed W 096/34096 PCTrUS95/05500 with gp39 (labeled A247-4 in the ~igure) reacted with these activated CD4+ T cells; panel C shows that these sera did not react with CD4- cells. These antibodies carried murine heavy chain ~ constant regions. The results o~ panels B and C also con~irm that the TNF-injected ~nomouse~ did not make antibodies against gp39.

Example 7 Preparation o~ Hiqh-A~inity Human Mabs Against Tetanus Toxin The antibodies prepared in this example were secreted by hybridomas obtained by immortalizing B cells ~rom x~nnm; ce ;mmlln;zed with tetanus toxin. The ;mmlln;zation protocol was similar to that set ~orth in Example 1 using 50 ~g tetanus toxin emulsi~ied in complete Freund's adjuvant ~or intraperitoneal primary ;mmlln;zation ~ollowed by subsequent intraperitoneal injections with antigen incorporated into incomplete Freund's adjuvant. The mice received a total o~ 4 injections 2-3 weeks apart.
A~ter acceptable serum titers o~ antitetanus toxinC
(anti-TTC) were obt~;ne~, a ~inal ;mmlln;zation dose o~ antigen in PBS was given 4 days before the ~n;m~l S were sacri~iced and the spleens were harvested ~or ~usion.
The spleen cells were ~used with myeloma cells P3X63-Ag8.653 as described by Gal~re, G. and Milstein, C. Methods in Enzymoloqy (1981) 73:3-46.
A~ter ~usion the cells were resuspended in DMEM, 15~
FCS, cont~;n;ng HAT supplemented with glut~m;n~, pen/strep ~or culture at 37~C and 10~ C02. The cells were plated in microtiter trays and maint~; n~ in HAT-supplemented medium ~or two weeks be~ore trans~er to HAT-supplemented medium.
Supernatants from wells cont~;n;ng hybridomas were collected ~or a primary screen using an Ti~T.T.C~
The ELISA was conducted as described in Example 1 wherein the antigen coating consisted o~ 100 ~l/well o~ tetanus toxin C (TTC) protein at 2 mg/ml in coating bu~er, ~ollowed by ;ncllh~tion at 4~C overnight or at 37~C ~or two hours. In the primary F~T-T-C~, HRP-conjugated goat antimouse IgG at 1/2000 was W 096/34096 PCTnUS9510~500 used in addition to HRP mouse ant;hllm~n IgM as described in Example 1. Two hybridomas that secreted anti-TTC according to the ELISA assay, clone D5.1 and clone K4.1 were used for further analysis.
As shown in Figure 13, clone D5.1 secretes fully hllm~n anti-TTC which is detectable using HRP-conjugated ant;hllm~n Ghain antibody and HRP-conjugated antihllm~n ~ Gha~n antibody.
This is confirmed in Figures 18 and 19. Figure 14 shows that clone K4.1 secretes anti-TTC which is ;mmllnoreactive with antimurine ~ and ant;hllm~n ~ HRP-conjugated antibodies. Thus, clone K4.1 provides anti-TTC fully with hllm~n variable region as confirmed in Figures 16 and 17 and a murine constant heavy chain region.
The antibodies secreted by D5.1 and K4.1 did not ;mmllnoreact in ELISAs using TNF~, IL-6, or IL-8 as immobilized antigen under conditions where positive controls (sera from xenom;ce ;mmlln;zed with TNF~, IL-6 and IL-8 respectively) showed positive ELISA results.
The affinity of the monoclonal antibodies secreted by K4.1 for TTC antigen was determ;ned using commercially available reagents and instrumentation. BIAcore Instrument, CM5 sensor chips, sur~actant P20 and the amine coupling kit were purchased from phA~m~cia Biosensor (Piscataway, NJ). TTC was immobilized at two levels of antigen density on the surface of the sensor chips according to the manufacturer's instructions. Briefly, after washing and equilibrating the instrument with buf~er contA;n;ng surfactant, the surfaces were activated and the TCC
was immobilized.
For high antigen density, the surface was activated with 35 ~1 of equal volumes 0.1 M NHS and 0.1 M EDC injected across the sur~ace followed by 30 ~1 of TTC fragment at 100 ~g/ml in 10 mM sodium acetate buffer pH 5Ø The sur~ace was blocked by injecting 35 ~l 1 M ethanol~m;n~ and washed to e~--~ve noncovalently bound TCC using 5 ~l 0.1 M HCl. The entire immobilization procedure was conducted with a continuous flow of buffer at 5 ~l/min. This results in about 7500-8500 response units (RU) of TTC per chip. (1000 RU corresponds to about 1 ng o~ protein per mm2.) CA 022l9486 l997-l0-27 W 096/34096 PCTrUS95/05500 For chips with low antigen density, the procedure utilizes 15 ~l rather than 30 ~l o~ TTC, resulting in chips cont~;n;ng 550-950 RU.
Chips could be regenerated a~ter use in single det~rm;n~tions by injecting 10 ~l ~ormal or MgC12.
The chips are used to det~rm; n~ binding a~inities by determ; n; ng ka and kb (the association and dissociation rate constants) ~or the antibody with respect to the immobilized TTC.
The association rate constant is measured over six minutes at a flow rate of 5 ~l/min. at di~erent concentrations o~ K4.1 Mab in the range o~ 2.16 nm-69.33 nm. The dissociation rate constant is measured at a constant bu~er ~low rate o~ 5 ~l/min after completion o~ the antibody injection. The raw data are graphed in Figure 15 and the calculated results are shown in Table 1.

W 096/34096 PCTrUS9S/05S00 ~ o o ,C X
X 'I 'I
~ X
a U ~ o N
~ ~ a o O
~,, ~y o O
-- ~ X
a m, ~o g V g _ N .1 ~ v m o g S~ _ N N
- ~ ~ ~

~ t7-~ .~
P ~ n 0 ~ 'm ~ ~I

a.~ ~ ~ o t~ a~
r~

O O
m O ~1 rr~
~! ~ ~I) I
- ,d ~J
_, p pP
' m ,i 0 H a~

W 096/34096 PCTrUS95/05500 As shown, the K4.1 antibody has a binding constant (Ka) ~or TTC somewhat larger than 10l~ M-1.
The complete nucleotide sequence o~ the cDNAs encoding the heavy and light t-h~; n~ o~ the K4.1 and D5.1 monoclonals were det~rm;ne~ as shown in Figures 16-19. PolyA mRNA was isolated ~rom about 106 hybridoma cells and used to generate cDNA using r~n~om h~m~rs as primers. Portions o~ the product were ampli~ied by PCR using the appropriate primers.
Both cell lines were known to provide human K light ch~l; n~; ~or PCR ampli~ication oi~ light chain encoding cDNA, the primers used were HKP1 (5'-CTCTGTGACACTCTCCTGGGAGTT-3') for priming ~rom the constant region term;nll~ and two oligos, used in equal amounts to prime ~rom the variable segments: B3 (5'-CCACCATCAACTGCAAGTCCAGCCA-3') and B2/B1 (5'-GAAACGACACTCACGCAGTCTCCAGC-3').
For ampli~ication o~ the heavy chain ~rom K4.1 (which contains the murine ~1 constant region), the primers were MG-24Vi ~or the human variable regions:
5'-CAGGTGCAGCTGGAGCAGTCiGG-3' which, with inosine as shown recognizes the hllm~n variable regions VH1_2~ VH1_3' VH4 and VH6' and ~rom the constant region MG-25 i.e., 5'-GCACACCGCTGGACAGGGATCCAiAGTTTC-3~, which, cont~;n;ng inosine as shown recognizes murine ~ 2A, ~2B, and ~3.
For ampli~ication o~ the heavy chain o~ the antibody derived ~rom D5.1 (which contains the human ~ constant region), MG-24VI was used to prime ~rom the variable and ~P1 (5'-TTTT~ll"l~l-lGCCGTTGGGGTGC-3') was used to prime from the constant region t~rm;nllc.
Turning ~irst to the results shown in Figure 16 representing the heavy chain o~ the Mab secreted by K4.1, the sequence shows the presence o~ the human variable segment VH6, the hllm~n diversity region DN1, and the human joining segment JH4 linked to the murine ~1 constant region. Nine base-pair mutations ~rom the published germline sequence were present in the variable region, two o~ them within CDR2. One mutation was observed in the D segment. Three nongermline nucleotide additions were present in the DH-JH junction.

W 096/34096 PCTrUS95/05500 Referring to Figure 17 which shows the light chain of the K4.1 antibody, analysis shows the presence of the hnmAn K
variable region B3 and joining region JK4. Eight nucleotides are missing from B3 at the VR-JK junction and four mutations were found in the variable region. Five nongermline nucleotide additions were present at the VK-JK junction.
Referring now to Figure 18 which sets forth the sequence for the heavy chain of the antibody secreted by clone D5.1, this shows the heavy chain is comprised of the hnmAn variable fragment VH6, the h~lmAn diversity region DN1 and the hnmAn joining segment JH4 linked to the hnmAn ~ constant region.
There were two base-pair mutations from the germline sequence in the variable region, neither within the CDRs. Two additional mutations were in the D segment and six nongermline nucleotide additions were present at the DH-JH junction.
Finally, referring to Figure 19 which presents the light chain of the antibody secreted by D5.1, the hllmAn K
variable region B3 and hllmAn K joining region JK3 are shown.
There are nine base-pair differences from the germline sequences, three falling within CDR1.

Example 8 Production of Human Antibodies to IgE
A. Tmmlln;zation of Mice Germline ~h;me~iC mice contA;n;ng integrated hllmAn DNA
from the ;mmllnoglobulin loci were ;mmlln;zed by injection of 15-20 ~g of hllmAn IgE/~ in adjuvant. The mice were boosted with 15-20 ~g of hllmAn IgE/~ every 14 days after the primary ;mmlln;zation~ A bleed was done on the ;mmun;zed An;mAls to test the titer of serum antibodies against hllmAn IgE/~. The mice with the highest titers were sacrificed and the spleen removed.

B. Fusion of Splenocytes Myeloma cells, line P3X63-Ag8.653, used as the fusion partner for the spleen cells, were thawed 6 days prior to the fusion and grown in tissue culture. One day before the fusion, cells were split into fresh medium contA;n;ng 10~ fetal calf serum (FCS) at a ratio of 1:3.

. --CA 022l9486 l997-l0-27 W 096134096 PCTrUS9S/05S00 After sacri~icing the mouse, the spleen was aseptically removed and placed in a culture dish with serum-~ree culture medium. A single cell suspension was created by gently grinding the spleen between two ~rosted microscope slides. The cells were washed in f~resh serum-~ree medium red blood cells were lysed and debris ~iltered away.
The splenocytes were ~urther washed twice by centri~ugation in serum-~ree medium. Myeloma cells were also washed in serum-~ree medium at this time. Each cell type was 10 counted and co-mbined at a ratio of~ 1:3 (myeloma to splenocyte), m;~ gently and centri~uged once together.
A solution o~ 40~ polyethylene glycol (PEG) was slowly added to the cell pellet while the cells were gently resuspended over a period o~ one minute. Cells were incubated at room 15 temperature for one minute in the PEG solution and then slowly diluted into 5 ml serum-i~ree medium over 5 minutes. Five ml more were added over the next 90 seconds. Cells were incubated at room temperature f~or 5 minutes. The cells were centrifuged at low speed and the supernatant removed. The cells were 20 resuspended slowly and very gently in 5 ml o~ hybridoma medium cont~;n;ng 10~ FCS, lX OPI, lX NE amino acids and 10 mM HEPES.
Cells were ~urther diluted to 100 ml ~inal volume in hybridoma medium with lX HAT solution (hypoxanthine, aminopterin and thymidine). The ~used cells were aliquoted 100 ~l/well o~ 96-25 2311 plates and cultured at 37~C and 10~ CO2. Cells were fed at 10 days post-~usion with 100 ~l/well o~ hybridoma medium with lX
HT (hypoxanthine and thym;~;n~) and allowed to grow close to confluence be~ore screening.
Supernatant was aseptically taken ~rom each growing 30 well and tested ~or the presence oE ~ully hnm~3n antibodies.
Positive wells were ~urther tested ~or human IgE/~ speci~icity.
When a positive well was identi~ied, the cells were trans~erred i~rom the 96-well plate to 0 .5 ml o~ hybridoma medium with lX HT
in a 48-well plate. At this stage the cells were subcloned by 35 limiting dilution into 96-well plates so that a single antibody producing cell was in culture. As the culture became con~luent, the cells were ~n~ l to 1 ml, 3 ml, 5 ml, etc. and frozen CA 022l9486 l997-l0-27 W 096/34096 PCTrUS95/05500 aliquots were stored in liquid nitrogen to preserve the cell stocks.
Using the ~oregoing procedures, antibodies speci~ic ~or the antigens described above are prepared.
In accordance with the above procedure, mouse hybridomas producing h~m~n antibody against hllm~n IgE/~ were obtained.
In accordance with the above procedures, a ~h;m~ric nonhllm~n host, particularly a murine host, may be produced which can be ;mmlln;zed to produce hllm~n antibodies or analogs speci~ic ~or an ;mmllnQgen. In this m~nner, the problems associated with obt~;n;ng hllm~n monoclonal antibodies are avoided, because the transgenic host can be ;mmnn;zed with ;mmnnogens which could not be used with a hnm~n host. Furthermore~ one can provide ~or booster injections and adjuvants which would not be permitted with a hllm~n host. The resulting B cells may then be used ~or immortalization for the continuous production o~ the desired antibody. The immortalized cells may be used ~or isolation o~
the genes encoding the ;mmllnoglobulin or analog and be subjected to i~urther molecular modi~ication by methods such as in YitrO
mutagenesis or other techniques to modify the properties of the antibodies. These modi~ied genes may then be returned to the immortalized cells by trans~ection to provide ~or a continuous m~mm~lian cellular source o~ the desired antibodies. The subject invention provides ~or a convenient source o~ human antibodies, where the hllm~n antibodies are produced in analogous m~nn~r to the production o~ antibodies in a hnm~n host. The ~n;m~l host cells conveniently provide for the activation and rearrangement o~ hllmAn DNA in the host cells ~or production of hllm~n antibodies.
In accordance with the subject invention, hllm~n antibodies can be produced to hllm~n ;mm~lnogens, e.g., proteins, by ;mmlln;zation o~ the subject host m~mm~l with hllm~n ;mmnnogens~ The resulting antisera will be speci~ic ~or the hllm~ ;mmllnogen and may be harvested ~rom the serum o~ the host.
The ;mmlln;zed host B cells may be used for im-m--ortalization~
e.g., myeloma cell ~usion, trans~ection, etc. to provide immortal cells, e.g., hybridomas, to produce monoclonal antibodies. The antibodies, antiserum and monoclonal antibodies will be glycosylated in accordance with the species o~ the cell producing the antibodies. Rare variable regions o~ the Ig locus may be recruited in producing the antibodies, so that antibodies having rare variable regions may be obt~;ne~.
All productions and patent applications cited in this speci~ication are herein incorporated by re~erence as i~ each individual publication or patent application were speci~ically and individually indicated to be incorporated by re~erence.

Claims (49)

1. A method to produce an immunoglobulin having fully human variable region or an analog thereof, specific for a desired antigen, which method comprises:
administering said antigen or an immunogenic portion thereof to a nonhuman animal under conditions to stimulate an immune response, whereby said animal produces B cells that secrete immunoglobulin specific for said antigen; wherein said nonhuman animal is characterized by being substantially incapable of producing endogenous heavy and light immunoglobulin chain variable regions, but capable of producing human immunoglobulin variable regions; and recovering said immunoglobulin or analog.
2. The method of claim 1 wherein said recovering step comprises recovering polyclonal immunoglobulin or analog from said animal.
3. The method of claim 1 wherein said recovering step comprises immortalizing B cells from said animal immunized with said antigen, screening the resulting immortalized cells for the secretion of said immunoglobulin specific for said antigen, and 1) recovering immunoglobulin secreted by said immortalized B cells, or 2) recovering the genes encoding at least the variable region of said immunoglobulin from the immortalized B
cells, and optionally modifying said genes;
expressing said genes or modified forms thereof to produce immunoglobulin or analog; and recovering said immunoglobulin or analog.
4. The method of claim 1 wherein said recovering step comprises recovering genes encoding at least the variable region of immunoglobulins from the primary B cells of the animal immunized with said antigen;

generating a library of said genes expressing the variable regions;
screening the library for a variable region with desired affinity for the antigen;
recovering the genes encoding said variable regions and optionally modifying said genes;
expressing said recovered genes to produce an immunoglobulin or analog containing said variable region and recovering said immunoglobulin or analog.
5. The method of claim 1 wherein said immunoglobulin is fully human.
6. A recombinant DNA molecule comprising a nucleotide sequence encoding the immunoglobulin or analog produced by the method of claim 1.
7. A recombinant DNA molecule comprising an encoding nucleotide sequence corresponding to a gene prepared by a method comprising administering a desired antigen or an immunogenic portion thereof to a nonhuman animal under conditions to stimulate an immune response, whereby said animal produces B
cells that secrete immunoglobulin specific for said antigen;
wherein said nonhuman animal is characterized by being substantially incapable of producing endogenous heavy and light immunoglobulin chain variable regions, but capable of producing human immunoglobulin variable regions;
immortalizing B cells from said animal immunized with said antigen, screening the resulting immortalized cells for the secretion of said immunoglobulin specific for said antigen, and recovering the genes encoding at least the variable region of said immunoglobulin from the immortalized B cells, and optionally modifying said genes.
8. A recombinant DNA molecule comprising an encoding nucleotide sequence corresponding to a gene prepared by a method comprising administering a desired antigen or an immunogenic portion thereof to a nonhuman animal under conditions to stimulate an immune response, whereby said animal produces B
cells that secrete immunoglobulin specific for said antigen;
wherein said nonhuman animal is characterized by being substantially incapable of producing endogenous heavy and light immunoglobulin chain variable regions, but capable of producing human immunoglobulin variable regions;
recovering genes encoding at least the variable region of immunoglobulins from the primary B cells of the animal immunized with said antigen;
generating a library of said genes expressing the variable regions;
screening the library for a variable region with desired affinity for the antigen; and recovering the genes encoding said variable regions and optionally modifying said genes.
9. The DNA molecule of claim 6, 7 or 8 wherein said encoding nucleotide sequence is operably linked to control sequences capable of effecting its expression.
10. A cell or cell line modified to contain the DNA
molecule of claim 9.
11. A method to produce an immunoglobulin with fully human variable region or an analog thereof which method comprises culturing the cells of claim 10 under conditions whereby said encoding nucleotide sequence is expressed to produce said immunoglobulin or analog; and recovering said immunoglobulin or analog.
12. An immortalized B cell which secretes an immunoglobulin with a fully human variable region to a desired antigen prepared by a method which comprises administering said antigen or an immunogenic portion thereof to a nonhuman animal under conditions to stimulate an immune response, whereby said animal produces B cells that secrete immunoglobulin specific for said antigen; wherein said nonhuman animal is characterized by being substantially incapable of producing endogenous heavy and light immunoglobulin chain variable regions, but capable of producing human immunoglobulin variable regions;
immortalizing B cells from said animal immunized with said antigen, screening the resulting immortalized cells for the secretion of said immunoglobulin specific for said antigen; and recovering said immortalized B cell.
13. A method to produce an immunoglobulin or analog which comprises culturing the recovered cells of claim 12 and recovering said immunoglobulin or analog.
14. An immunoglobulin with fully human variable region or analog thereof produced by the method of claim 1.
15. The immunoglobulin or analog of claim 14 which is fully human.
16. The immunoglobulin or analog of claim 14 which is an agonist or a catalyst or wherein the immunoglobulin is chimeric.
17. The immunoglobulin or analog of claim 14 wherein the desired antigen is selected from the group consisting of transition state mimics; leukocyte markers; histocompatibility antigens; adhesion molecules; interleukins; interleukin receptors; chemokines; growth factors; growth factor receptors;
interferon receptors; Igs and their receptors; tumor antigens;
allergens; viral proteins; toxins; blood factors; enzymes; and the miscellaneous antigens ganglioside GD3, ganglioside GM2, LMP1, LMP2, eosinophil major basic protein, eosinophil cationic protein, pANCA, Amadori protein, Type IV collagen, glycated lipids, .gamma.-interferon, A7, P-glycoprotein, Fas (AFO-1) and oxidized-LDL.
18. The immunoglobulin or analog of claim 17 wherein the leukocyte marker is selected from the group consisting of CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD11a,b,c, CD13, CD14, CD18, CD19, CD20, CD22, CD23, CD27 and its ligand, CD28 and its ligands B7.1, B7.2, B7.3, CD29 and its ligand, CD30 and its ligand, CD40 and its ligand gp39, CD44, CD45 and isoforms, CDw52 (Campath antigen), CD56, CD58, CD69, CD72, CTLA-4, LFA-1 and TCR;
the histocompatibility antigen is selected from the group consisting of MHC class I or II, the Lewis Y antigens, SLex, SLey, SLea, and SLeb;
the adhesion molecule is selected from the group consisting of VLA-1, VLA-2, VLA-3, VLA-4, VLA-5, VLA-6, LFA-1, L-selectin, P-selectin, and E-selectin and their counterreceptors VCAM-1, ICAM-1, ICAM-2, LFA-3; Mac-1 and p150,95;
the interleukin is selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, and IL-15;
the interleukin receptor is selected from the group consisting of IL-1R, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9R, IL-10R, IL-11R, IL-12R, IL-13R, IL-14R, and IL-15R;
the chemokine is selected from the group consisting of PF4, RANTES, MIP1.alpha., MCP1, NAP-2, Gro.alpha., Gro.beta., and IL-8;
the growth factor is selected from the group consisting of TNFalpha, TGFbeta, TSH, VEGF/VPF, PTHrP, EGF
family, FGF, PDGF family, endothelin, and gastrin releasing peptide (GRP);
the growth factor receptor is selected from the group consisting of TNFalphaR, RGFbetaR, TSHR, VEGFR/VPFR, FGFR, EGFR, PTHrPR, PDGFR family, EPO-R, GCSF-R and other hematopoietic receptors;
the interferon receptor is selected from the group consisting of IFN.alpha.R, IFN.beta.R, and IFN.gamma.R;
the Ig and its receptor is selected from the group consisting of IgE, FceRI, and FCeRII;

the tumor antigen is selected from the group consisting of her2-neu, mucin, CEA and endosialin;
the allergen is selected from the group consisting of house dust mite antigen, lol p1 (grass) antigens, and urushiol;
the viral protein is selected from the group consisting of CMV glycoproteins B, H, and gCIII, HIV-1 envelope glycoproteins, RSV envelope glycoproteins, HSV envelope glycoproteins, EBV envelope glycoproteins, VZV envelope glycoproteins, HPV envelope glycoproteins, Hepatitis family surface antigens;
the toxin is selected from the group consisting of pseudomonas endotoxin and osteopontin/uropontin, snake venom, and bee venom;
the blood factor is selected from the group consisting of complement C3b, complement C5a, complement C5b-9, Rh factor, fibrinogen, fibrin, and myelin associated growth inhibitor; and the enzyme is selected from the group consisting of cholesterol ester transfer protein, membrane bound matrix metalloproteases, and glutamic acid decarboxylase (GAD).
19. The immunoglobulin or analog of claim 14 wherein said desired antigen is selected from the group consisting of human IL-6, human IL-8, human TNF.alpha., human CD4, human L-selectin, human gp39, human IgE and tetanus toxin C(TTC).
20. A recombinant DNA molecule comprising a nucleotide sequence that encodes the immunoglobulin or analog of any of claims 15-19.
21. The DNA molecule of claim 20 wherein said encoding nucleotide sequence is operably linked to control sequences capable of effecting its expression.
22. A cell or cell line modified to contain the DNA
molecule of claim 21.
23. A method to produce an immunoglobulin or analog specific for a desired antigen which method comprises culturing the cell or cell line of claim 22 under conditions wherein said nucleotide sequence is expressed to produce said immunoglobulin or analog; and recovering the immunoglobulin or analog.
24. An antibody containing a fully human variable region or analog thereof which is specifically immunoreactive with an antigen selected from the group consisting of transition state mimics; leukocyte markers; histocompatibility antigens;
adhesion molecules; interleukins; interleukin receptors;
chemokines; growth factors; growth factor receptors; interferon receptors; Igs and their receptors; tumor antigens; allergens;
viral proteins; toxins; blood factors; enzymes; and the miscellaneous antigens ganglioside GD3, ganglioside GM2, LMP1, LMP2, eosinophil major basic protein, eosinophil cationic protein, pANCA, Amadori protein, Type IV collagen, glycated lipids, .gamma.-interferon, A7, P-glycoprotein, Fas (AFO-1) and oxidized-LDL.
25. The antibody or analog of claim 24 wherein the leukocyte marker is selected from the group consisting of CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD11a,b,c, CD13, CD14, CD18, CD19, CD20, CD22, CD23, CD27 and its ligand, CD28 and its ligands B7.1, B7.2, B7.3, CD29 and its ligand, CD30 and its ligand, CD40 and its ligand gp39, CD44, CD45 and isoforms, CDw52 (Campath antigen), CD56, CD58, CD69, CD72, CTLA-4, LFA-1 and TCR;
the histocompatibility antigen is selected from the group consisting of MHC class I or II, the Lewis Y antigens, SLex, SLey, SLea, and SLeb;
the adhesion molecule is selected from the group consisting of VLA-1, VLA-2, VLA-3, VLA-4, VLA-5, VLA-6, LFA-1, L-selectin, P-selectin, and E-selectin and their counterreceptors VCAM-1, ICAM-1, ICAM-2, LFA-3; Mac-1 and p150,95;
the interleukin is selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, and IL-15;

the interleukin receptor is selected from the group consisting of IL-2R, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9R, IL-10R, IL-11R, IL-12R, IL-13R, IL-14R, and IL-15R;
the chemokine is selected from the group consisting of PF4, RANTES, MIP1.alpha., MCP1, NAP-2, Gro.alpha., Gro.beta., and IL-8;
the growth factor is selected from the group consisting of TNFalpha, TGFbeta, TSH, VEGF/VPF, PTHrP, EGF
family, FGF, PDGF family, endothelin, and gastrin releasing peptide (GRP);
the growth factor receptor is selected from the group consisting of TNFalphaR, RGFbetaR, TSHR, VEGFR/VPFR, FGFR, EGFR, PTHrPR, PDGFR family, EPO-R, GCSF-R and other hematopoietic receptors;
the interferon receptor is selected from the group consisting of IFN.alpha.R, IFN.beta.R, and IFN.gamma.R;
the Ig and its receptor is selected from the group consisting of IgE, FceRI, and FCeRII;
the tumor antigen is selected from the group consisting of her2-neu, mucin, CEA and endosialin;
the allergen is selected from the group consisting of house dust mite antigen, lol p1 (grass) antigens, and urushiol;
the viral protein is selected from the group consisting of CMV glycoproteins B, H, and gCIII, HIV-1 envelope glycoproteins, RSV envelope glycoproteins, HSV envelope glycoproteins, EBV envelope glycoproteins, VZV envelope glycoproteins, HPV envelope glycoproteins, Hepatitis family surface antigens;
the toxin is selected from the group consisting of pseudomonas endotoxin and osteopontin/uropontin, snake venom, and bee venom;
the blood factor is selected from the group consisting of complement C3b, complement C5a, complement C5b-9, Rh factor, fibrinogen, fibrin, and myelin associated growth inhibitor; and the enzyme is selected from the group consisting of cholesterol ester transfer protein, membrane bound matrix metalloproteases, and glutamic acid decarboxylase (GAD).
26. The antibody or analog of claim 24 wherein the desired antigen is selected from the group consisting of human IL-6, human IL-8, human TNF.alpha., human CD4, human L-selectin, human gp39, human IgE and tetanus toxin C(TTC).
27. The antibody or analog of claim 19 or 26 wherein the desired antigen is human IL-6.
28. The antibody or analog of claim 19 or 26 wherein the desired antigen is human IL-8.
29. The antibody or analog of claim 19 or 26 wherein the desired antigen is human TNF.alpha..
30. The antibody or analog of claim 19 or 26 wherein the desired antigen is human CD4.
31. The antibody or analog of claim 19 or 26 wherein the desired antigen is human L-selectin.
32. The antibody or analog of claim 19 or 26 wherein the desired antigen is human gp39.
33. The antibody or analog of claim 19 or 26 wherein the desired antigen is tetanus toxin C(TTC).
34. The antibody or analog of claim 19 or 26 wherein the desired antigen is human IgE.
35. The analog of claim 19 or 26 which is a single chain Fv.
36. The antibody or analog of claim 24 which is fully human,
37. The antibody or analog of claim 24 which is an agonist or is a catalyst or wherein the immunoglobulin is chimeric.
38. A recombinant DNA molecule encoding the antibody or analog of any of claims 26-37.
39. A recombinant DNA molecule which comprises an expression system for the production of the antibody or analog of any of claims 26-37 which expression system comprises a nucleotide sequence encoding said antibody or analog operably linked to control sequences capable of effecting its expression.
40. A recombinant host cell which is modified to contain the DNA molecule of claim 39.
41. A method to produce an antibody or analog which method comprises culturing the cells of claim 40 under conditions wherein said coding sequence is expressed; and recovering the antibody or analog produced.
42. Use of the antibody or analog of claim 36 for in vivo prophylaxis, therapy or diagnosis in humans.
43. Use of the antibody or analog of claim 27, 29, 30, 31 or 32 for treating an autoimmune disease in a mammal.
44. The use of claim 43 wherein the autoimmune disease is systemic lupus erythrematosus, rheumatoid arthritis, psoriasis, Sjogren's syndrome, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, Reiter's syndrome, Behcet's disease, Type I diabetes, Hashimoto's thyroiditis, Graves' disease, multiple sclerosis, myasthenia gravis, or pemphigus.
45. Use of the antibody of claim 32 for preventing graft versus host disease, for preventing rejection of an organ transplant, or for treating glomerular nephritis in a mammal.
46. Use of the antibody of claim 31 for treating reperfusion ischemia in a mammal.
47. Use of the antibody of claim 27 for treating cachexia, septic shock, myeloma, renal cell carcinoma, osteoporosis, or Paget disease in a mammal.
48. Use of the antibody of claim 29 for treating septic shock, cachexia, osteoporosis, or systemic sclerosis in a mammal.
49. Use of the antibody of claim 28 for preventing tumor metastasis, and for treating asthma, rheumatoid arthritis, glomerulonephritis, reperfusion injury, adult respiratory distress syndrome, or systemic sclerosis in a mammal.
CA 2219486 1995-04-28 1995-04-28 Human antibodies derived from immunized xenomice Abandoned CA2219486A1 (en)

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