BG98287A - Intercellular adhesion molecule-3 and its binding ligands - Google Patents

Abstract

The intercellular adhesion molecule-3 (ICAM-3) is included in the process when the leukocytes identify the places of inflammation and migrate to them in order to stick to the cellular substrates during the inflammation. The invention is related to those molecules, to screening tests for their identification and to antibodies capable of binding them, as well as to therapeutical and diagnostic applications of the adhesion molecules and the antibodies capable of binding them.

Description

FIELD OF THE INVENTION

The present invention relates to the discovery of a new intercellular adhesion molecule referred to as GC3.3 _KO which is involved in the process in which a population of leukocytes recognizes and adheres to cellular substrates, 1AM-3 melts cellular interactions with, other lymphocytes, macrophages and neutroyls in inflammatory and immune response sites,

The present invention further relates to the use of ICAM-3 alone or in combination with ICAM-1 _and / or ICAM-β to inhibit intercellular adhesion of cells of granulocyte, lymphocyte or macrophage origin. The use of such molecules provides a method for the treatment of specific and non-spenic inflammations.

The invention also relates to a therapeutic and pro-prophylaxis method for suppressing H1U ' s limpoplasty infection, _and more specifically to HIV-ι in an individual who is available for HIV _{or is} infected with HIV, ιτρ _θ3 administration of 1 _{AM-3 g} alone goes in combination with ICAM-1 and / or ICAM-3, Therefore, therapy is provided for diseases such as AIDS / Acquired Immunodeficiency Syndrome caused by the HIV virus,

The invention also relates to a therapeutic method for inhibiting the migration of HIV-infected cells from the bloodstream using ICAM-3, alone or in combination with ΙθΑΜ and / or ICAIvI-2, thereby providing therapy for diseases such as AIDS caused by the HIV-1 virus,

The invention also relates to a therapeutic method for podti * Cane destruction of T cells and fordaraneto of syncytium "in an individual infected with HIV _using ICAM1-H. _Seven alone or in combination with ICAM-ι and / or 1SH-2, This provides rapeseed for diseases such as AIDS caused by HIV-ί virus

The present invention also relates to the use of ICAM alone or in combination with ICAM-1 and / or ICAM-g for the treatment of asthma.

In addition, the present invention relates to molecules capable ^of binding to GAMC-3 (hereinafter referred to as anti-TCA-3). an anti-ICAM-3 molecule to ICAM-3 _ο θ is expected to modulate the biological functions associated with ICAM-3 _{4 The} binding molecules of the present invention may be an antibody, peptide or carbohydrate capable of binding to ICAM-3 H,. Such binding molecules can be used to modulate the biological functions of ICAM-3,

The present invention also relates to the use of anti-ICAM * -3, alone or in combination with anti-ICAM-1 and / or anti-ICAM-g, for inhibiting cellulose intercellular / intercellular / cell adhesion with granulocyte, lymphocyte or macrophage The use of such molecules provides a method of treating specific and non-specific inflammations.

The invention also relates to therapeutic and prophylactic methods for. suppression of leukocyte infection is HIV, _and in particular with HIV-ι, in individuals who are available for HIV _or infected with HIV _{Ch is the} introduction of anti-TCAM-3, _{c8Mostly or in} combination with anti-TCAM -1 and / or anti-ICAM-g, IJq _{T03, and a} method of providing treatment for diseases such as AIDS caused by HIV virus. In addition, the invention relates to a therapeutic method for inhibiting the migration of HIV-infected cells from the bloodstream by means of anti-TCAM-3 agent, alone or in combination with anti-YuAM-1 and / or 8 anti-CAM-2 agent, thus providing treatment and diseases such as AIDS, which ggoichinyavat of the HIV virus.

The present invention further relates to the use of an anti-YuAM-3 agent, alone or in combination with anti-ICAM-1 and / or anti-ICC-M-2, for the treatment of asthma

A description of. related to isopethenia ect. pb.pdsh.

A, Levopopic adhesion and function.

Leukocytes should be able to adhere to cellular substrates in order to protect the host from invasion,

for an overview of these features. The leukocytes must be able to adhere to the endothelial cells so that they can migrate from the circulatory system to the inflammatory sites Jb further, they must adhere to the antigen presenting cells so that they can. Normally, a specific and nonsignificant response occurred, and finally, they should adhere to a suitable cellular target so that lysis of the virus-infected cell or the tumor cell was performed.

The leukocyte surface molecules involved in the mediation of the above, related to adhesion Functions have been identified using a hybridoma technique. In short, monoclonal antibodies directed against human T cells (1 ' 1 '). ef aL,? roc Naif.Acad, Sei. TlSA 784535-4539 (1981) and murine splenocytes were found to bind to the leukocyte surface and inhibit the adhesion-related functions described above / $ pg1 poeg, T. et al, fecL.Proc. 44: 2660-2663 / 1985 //.

The molecules identified by such antibodies are called Wic-1 and Lymphocyte-Functionally Associated Antigen-1 / f, Mass-1 is a heterodimer found in macrophages, granulocytes and large granular lymphocytes. 1FA-1 θ heterodimer found in most lymphocytes

molecules, plus a third molecule, p! 50.95, which has a tissue distribution similar to Mas-1 /, plays fields in cellular adhesion / cell adhesion / / Keeg, 0'et, a1., H1g.0'Lmmipo /. 1541421147/1985 //.

The leukocyte molecules described above are found to be members of the glycoproteins / Sanches-Madrid family. , Ret. (Med., 158: 1785-1803 / 1983 /} ^ ', _2eg> &, Ώ et!., ^ IgL. ^ MIPO.C 154142-1147 / 1985 /, referred to as the glycoprotein family, in a glycoprotein family is composed of heterodimers having one alpha chain and one beta chain. Although the alpha chain of each of the antigens is different, the beta chain is

Med. 1584785-1803 / 1983 //, The beta chain of the glycoprotein family, once referred to as Cpts, has a molecular weight of 95 κοί, while the alpha chains have been found to range from 150'Ko to 180 κώ /£yr1po, .Proc. 44: 2660-2663 / 1985 //. Although the alpha subunits of the membrane proteins do not share the extensive homology shared by the beta subunits, cynics, analysis of the alpha subunits of the glycoproteins has shown that there is a substantial similarity between them. A review of the analogy between alpha and beta subunits of IFA-1 linked glycoproteins is made by ffanc / ieS

-Madrid / et.a!., I 'P ₍ .Exper, M _e d, 158: 586-602 / 1983 / «Ί.ΕχρβΓ.

Med. 1584785-1803 / 1983 / /.

A group of individuals were identified who were unable to

- 6 express normal amounts of any member of this family of adhesion proteins on the cell surface of their leukocytes / Anderson, DS, 1 hour {., Fed. Proc.44 ^ 2671-2677 / 1985 / j Anderson, D.Sde ^ .a!., I.Inject.AlS, 152 ^ 668-689 / 1985 /. / ,.¾ such individuals are said to suffer from Eolest's leukocyte adherence 'insufficiency' / YAD / / Anderson, DS, ed ¹ .aL, Fed.Roskh 44 ^; 26712677/1985 / j Anderson, DS, et. af. DD2 ^ est. Yes .152 ^ 668-689 /1985/.- Characteristic features of patients suffering from MD include necrotic soft tissue damage, pus formation and poor wound healing, as well as abnormality of adhesion-dependent leukocyte functions in vitro, and susceptibility to chronic and recurrent bacterial infections. The granulocytes from these ID patients are fried in a more efficient way in vitro, as their cutaneous normal relatives do in an anti-CD18 monoclonal antibody. Ie they are not able to present adhesion-related functions such as napimer aggregation or adhesion to endothelial cells, but it is important to observe that these patients are incapable of producing a normal inflammatory response due to the inability of their granudopaths to attach to cell substrates The most important observation is that the granulocytes from these WJ patients are unable to reach the sites of inflammation - such as skin infections, for example, because of their inability to attach to endothelial cells in the blood vessels. bring near inflammatory lesions. Such attachment is a necessary step for extravasapia.

The lymphocytes of these patients show in vitro defects similar to their normal counterparts, whose CD-18 family of molecules is antagonized with antibodies .-- Moreover, these individuals are unable to attain a normal immune response due to the inability of their cells to adhere to the cellular substrates / Anderson, DS. ei.at., £ es1.Goss.44: 2671-2677 / 1985 / · Anderson, D.S., ei.ai., Ί.Ιπ ^ θοτ.ΛΗ.1 52: 668-689 / 1985 / /. These data indicate that immune responses are upset when lymphocytes are unable to adhere normally due to the absence of functional adhesion molecules from the CD-18 family.

Thus, in general, the ability of leukocytes to subdue, maintain a healthy veto, and the vitality of animals requires that they be able to adhere to other cells (such as endothelial cells). Such adherence has been found to require cell-cell contact, which includes specific receptor molecules on the surface of the leukocytes. These receptors allow the leukonites to adhere; to other leukocytes, to endothelial cells, and to other non-vascular, cellular, receptor cells of the cellular. n < + &gt; surface, AFA-1, Me.c-1, and p150,95, are strongly bound to the second one. People whose leukocytes do not have these surface molecular receptors exhibit chronic and recurrent infections, as well as other clinical symptoms, including defective antibody responses

In addition, to what extent is leukocyte adhesion involved in the process by which foreign tissue is identified and rejected, of course? the net of this process is significant in the field of organ transplantation, for example, kidney, bone marrow, tissue grafting, allergy and oncology.

^c . L ... NP

HIV infection is the cause of. AIDS, M _H ow variants of HIV have been described: the big two are HIV-ί and HIV-2, HIV-ί _is prevalent in Northern Ireland and Europe, and HlV-p is prevalent only in Africa. Viruses have similar structures and encode proteins that have similar functions. Non-HIV injection is assumed to occur upon binding of the viral protein (designated as the receptor molecule) labeled CD1'7 present on the surface of the Ί4 (T helper) pimphocytes / SdftniJmapp, S.M. et.a {., Ί. 1mm. {. 141 * 4181-4186 /1988/.After connecting this peptide, the virus enters the socket and replicates, and during this process kills the T cell. Destruction of the T4 population of indava) is a direct result of HIV infection.

T cell destruction leads to impaired ability of infected patients to respond to accidental infections. ^{i; j} anar individuals affected by AIDS pesto develop cancer, the link between this cancer and HIV infection is in most cases in doubt.

Although actual HIV virus infection is lethal to infected cells, such replication is only detected in a small fraction of the Ϊ4 cells of an infected individual. Recently supported results suggest that more visions are obtained than received, and the frequency of its T-cell injections is about 1 ^.

Several lines of research have elucidated other mechanisms by which the HIV virus mediates the destruction of the T4 population. · Apart from HIV replication, H1U infected cells can. be destructed by the effects of pytotoxic killer cells. These killer cells are normally present in humans;

'ι and serve to register the functions of the hospitable ©, destroying any foreign cells (such as transfusion or organ transplantation) that wish not to be beaten -

- 9 In HIV infection, Td cells show a jplSO molecule on their cell surface. Killer cells recognize Ί4 cells as foreign (relative to their own organisms) and mediate their destruction.

HIV infection can also lead to the destruction of uninfected healthy cells. Infected cells can secrete | p! 20 protein into the bloodstream. Free gp.1.20 molecules can then bind to SDD receptors of healthy, uninfected cells Lakova binding causes ^the cells to take on the appearance of HIV infected kletki.Tsitotoksichnite, killer cells recognize watt with | P120 binding to uninfected cells 14, concluding that these are foreign to organism cells and mediate their destruction.

Another mechanism, and of particular relevance to the present invention in which HIV can cause 14 cell death, is through the formation of syncytium. Syncytium is a multi-nuclear giant cell formed by the fusion of more than a few hundred T4 cells, HIV infection θ the cause of this cell's fusion with 14 other cells, both infected with H1 and healthy ones, Syncytium cannot function and soon dies Death causes destruction of both HIV-infected and uninfected cells. This process is of particular importance to the present invention insofar as it involves direct cell-cell contact. The ability of ηθ HIV-infected cells to form syncytium indicates that such cells acquire you to fuse with healthy cells.

HIV infection, and in particular HIV infection, appears to affect the reaction of the skin and, in particular, the pooling and adhesion reactions mediated by these hetero, dimers / EDD A, J., ei, al., lC {innnKest. 79 = 188 (1987); Η1 ^ _Γβ ^, J, E, K,

- 10 e4 ?. aL, Science 244 · 1075/1989 /} ^ alenl ^ n, ξ, efc.af., ^ Dminolocjy 144: 934-937 / 1990 /} Kossen, H.D., eKa {., I'ranS .Asfoc. American Physician 102: 117-130 (1989), Following the injection c

HIV-1 homotypic aggregation of b1937 cells increased, as did the expression of CD18 and CD11b on the cell surface / Peiii, A.D., ^ eKal. 'I.cIln.InVeS'b, 79: 188/1987 / /. HIV-1 injected H937 cells adhere to 1 ^ 1, stimulate the endothelium at a higher frequency than uninfected 37937 cells ^ this behavior can be suppressed by treating injected cells with anti-CD18 or anti-CDIA monoclonal antibodies, or by treating endothelial substrates with anti-IC? Mt antibodies / -kjo $$ ep, ?, e., θτ. aL, 'l'ran .Assoc. American Pfcsiclan 102: 1.17-130 (1989) /. Monoclonal antibodies against 0D18 or CD1.1a have also been shown to be capable of inhibiting syncytium formation, including phytohaemagglutinin (FHA) -stimulated lymphoblastic cells and constitutively infected, CD-4 negative T cells / Mol ge Μ, ¹ .®. al. Science 244: 1075 (1989). Treatment of only virus-infected cells with anti-CD18 or anti-CD11a monoclonal antibodies has been shown to have only a small effect on normalization

C ' ^- ·

V of syncytium, suggesting that these antibodies, in principle, protect uninfected target cells from the infection J ^ geJ ^ .- ED ,, et a {«, Science 244: 1075 (1989); ^ aieniln, A,, el.aL ·, ^ ^ m ^ nolofe jy 144: 934-937 / 1990 / /, Vg / jenlln e1? af, have recently confirmed these observations by demonstrating the fact of B inhibition

Is the monoclonal antibody specific for CD18 and syncytium formed in

Si; 'δρ upon re-cultivation of permanent T cell lines with HIV-infected infected I937 cells.

However, the mechanisms by which monoclonal antibodies specific for CD13 or CD11 protect susceptible "

- 11.

fusion cells infected with HIV infected cells remain unknown, not necessary within the meaning of the present invention, or 9 radiolabeled labeled assays are performed (jpl.20 suggest that heterodimers containing · CD18 do not provide a binding site for the virus / Vafeniln, A., ec, al., A1mmipo £ o £ y 144: 934-937 / 199θΛ Thus, HIV infection involves kletachnokletachni interactions, and / or viral-cell interactions which mimic such interactions kletachnokletachni T _hese kletachnokletachni interactions can lead to cell transport, c virus-free, or virus-infected cells through endothelial barriers.Viral cell interactions that mimic cell-cell interactions may facilitate or enable the free virus to attach to / or infect healthy cells.

According to the invention, this beverage stems, gradually, from the observation that HIV infection, and in particular MTV-1 infection, leads to increased expression of the CD11a / CD18 heterodamers and their binding ligandThis increased expression is of particular importance T because it increases the ability of HIV-infektipanite cells to adhere or aggregate with one ^'n other / ie. to undergo homotypic aggregation / .. Insofar as such homotypic aggregation was not observed among normal leukocytes, this finding indicates that the expression of the CD / 1 / CD18 receptors and / or ligand, such as 1AM-1 _{> is} required for such aggregation. 1 must bind to ICAM-1 _in order to exhibit homotypic aggregation .. As shown here, 1AM-3 is the only captive of the family of ICAM molecules that are expressed at high levels in dormant cells / resting 1 ' -cells /, Only anti-YuAM-3 antibodies are capable of blocking T-cell adhesion Kittel to the TF / Lj _9K0 T cells not sa''aktivirani *; Well, yes. anti-1Cl3 antibodies

- 12 (f can be used to inhibit aggregation of 1'-cells In addition, anti-1CAM-3 antibodies can be used to block the adhesion processes of infected клетки'-cells, allowing HIV-ί to be able to is transmitted from an infected k cell to healthy cells of an infected individual, and also allows or facilitates the infection of healthy free cell viruses.

C. Migration of infected persons. .C ... HIV cells

Migration and the spread of leukocytes is important in preventing the individual from the effects of injection.1 These processes, however, are responsible for the migration and spread of virus-infected leukocytes. ^υ τ Of particular interest is the migration and proliferation of leukocytes infected with NAP ^ gating such cells leads to the formation of extravascular foci, and may cause tumors and other neoplasms.

Histological studies have shown that the affected organs have extravascular mononuclear cell infiltrates. Attempts to identify such virus-infected cells in our inferior central nervous system infiltrates revealed the presence of HIV-infected cells Desi studies have shown that PVG_1 viruses exist primarily in monocytes and acrophages, as well as in other cells of this type / ^ .TMonnson, el.af 1'ASEB I, 242970/1988 / j Μ.Η, ζτοίθΓ et ai, J. Omeg.Med, Assn.256'2360 / 1986 / S .Garin el.al. Science 233: 215 (1986).

The mechanisms that stimulate the formation of extravascular infiltrates of HIV-1-infected monocytoid cells have not been well defined previously. Mechanisms may include both the transport of virus-free cells and the transport of h

- 13 viruses through the endoshelial barium inside the cytoplasm. of infected mononuclear cells.

To the extent that HIV-1 infection stimulates cell surface expression of molecules, which facilitates the adhesion of leukocytes to vascular endothelial cells and the trans locus α <;

of leukocytes from the blood to the extravascular sites of the tissues t SL no. QmUIi et (a,. 'L.cfci, Ini (esl. 82 ^ 1746/1988); included in the literature reference ./, it has been proposed to use antibodies that inhibit cell migration in order to prevent the spread of HIV infected cells (^ 90/13316).

E, -. Asthma 'Clinical characteristics

Asthma is a heterogeneous family of diseases, characterized by hyperactivity of the tracheobronchus of stinging ./^ ay ^ .B, J A] .1gou and 1pulashiyop, Asadem1c Pge99, / 1987 /. manifests with extensive narrowing of the tracheobronchus, sticky * thick secretions, spasms, coughing and suffocation. Although contributing to the reasons why are unknown, the end result is.

air ductility, hypersensitivity not tonsils and thorax ^ and hdashtzhzhi irregular distribution of ventilation and pulmonary blood flow. The disease is manifested. in episodic periods of acute symptoms, distributed between periods. free from the symptom periods, acute episodes lead to hypoxia and may be at the waist. Approximately?% Of the total human population in the world is suffering from (asthma, - - |

Two types of asthma have been described * allergic asthma and idaoxin- | acute asthma. Allergic asthma is usually associated with congenital allergic diseases such as rhinitis, tracheitis, urticaria, enzyme, etc. |

The condition is characterized by a positive reaction / inflammation of |

W &

- 14 »ί worn on indi- vidual skin (in mitra ter mul injection of air-borne antigens / such as pollen, environmental or occupational contaminants, etc.) and increased levels of serum IgE. The development of allergic asthma appears to be causally related to the presence of IgE antibodies in many patients. Patients with asthma who do not show the characteristic reactions described above are considered to suffer from idiosyncratic asthma.

Allergic, asthma, is thought to be IgE dependent, conjoined by T and B lymphocytes, and airborne antigens activated by germ of pre-normalized IgE molecules. Antigenic collision can occur at concentrations sufficient lead to produpirane ^pi and for a prolonged period of time to make sensitive the species - Once sensitized, an asthma patient can vet ί appeared symptoms in response to extremely low levels of antigen. 1 ί Asthma symptoms can be exacerbated by the presence of-;

key antigens, environmental factors, occupational factors, physical exertion or emotional distress.

Asthma can be treated with methylxanthines (such as theoin or beta-adrenergic competitors) such as catecholamines, resorcinol, saligens and ephedrine, glucocorticoids (such as hydrocortisone), fat inhibitors, cellular degranulation, such as chromones. sodium chromolin / and anticholinergics (such as atropine).

Asthma is thought to involve the inflow of eosinophils / eosinophilia / into the tissues of the tonsils / Y1 to 5, E. ei.a {. Aceguu with {u _P • ^ mimipo, 77 * 527-537 / 1986 /, included in the literature reference, appendix 1 '1 ι;

woman to the description of the invention.

I

- 15 The conception of the immunological basis of asthma is based on the results of bronchoalveolar studies 1 Godard, H.ei a {.

rotor smooth muscle tissue devoid of epithelium / ^ LaVanan, N

A.el.aL, J-.AppLHrysiof.58 * 834/1985 / j Barnes, HJ et a1., Io. RAagmasso !, 86: 685 /.1985//, Although these studies did not • clarify the mechanism underlying the asthma immunology, they led to the development of the basic hypothesis pertained to ¹ , but to the immunological etiology of the disease / see ^ r1 (ja $, E, et, a:

The fco mark of asthma pathology is the massive injection of pancreatic parenchyma from eosinophils and the destruction of mucociliary haikihaws.

The eosinophilic hypothesis we assume eosinophils are attracted to the bronchi in order to neutralize the void mediators released from the tonsils fat cells. , such as, for example, histamine, arisulsatase and chaosolipase A, which enzymatically neutralize the harmful mediators of fat cells, however, these molecules also carry out the destruction of mucociliary cells. apparatus, thereby preventing the clearing of the bronchial secretion and facilitate characte ristics damage tonsils in asthma,

Insofar as asthma involves the migration of cells, it has been suggested to use antibodies to inhibit this migration and to modify the effect of the allergens in the subject (WO 90/10453).

TOTAL INVENTION

The present invention is based on the discovery of a new cell adhesion molecule referred to as the Intracellular Adhesion Molecule -3 (1CAM-3). In addition, the invention relates to functional derivatives of ICAli / Lg ^ aHTH-1CAM-β antibodies, Fragments of these antibodies humanized anti-YuAM-3 antibodies and other molecules capable of binding IL- ¹ inhibiting the functions of ICAM-3,

The invention further relates to the diagnostic and therapeutic applications of all the molecules described above.

In particular, the invention includes. Yuam-h. or functional derivatives thereof, essentially free from natural contaminants,

The invention provides a method for obtaining a recombinant or synthetic DNA molecule capable to encode or expressing ICAM1 _3> or functional derivatives thereof.

The invention further provides an antibody, in particular a monoclonal antibody, capable of binding to a molecule selected from the group consisting of ICAM-3 and ICAT-3 functional derivatives.

The invention further provides a hybrid.domain cell capable of producing the monoclonal antibody described above.

The invention includes a method of producing the desired hybridoma cell that produces an antibody capable of binding YAM <or> its functional derivatives, which comprises the steps of ^: a) immunizing an animal with an immunogen selected from a group consisting of essentially pure YAM- 3 _} cell expressing ICAM-3 ^ cell membrane from a cell expressing ICAM-3, ICAM-3 * attached to a carrier, peptides, day Fragment of 1AM-3 _m or peptides 17 days Fragments of 1CG-3 _? connected to a carrier.

fusion of splenotypes isolated from the animal in a myeloma c / cell line,

I f ί)

I r

I r

I cells enabling fusion of splenocytes and lmelomas Form hybridoma cells secreting an antibody, and screening hybridoma cells for such a hybridoma cell capable of engrafting anti-1CAM-3 antibody.

see this

The invention further provides a method for 'judging IUu.i-3-mediated biological cell functions. Where sub-provision is not an object in need of treatment with eFecalcity, ICAM-3 modulates an agent selected from rovna comprising: an antibody capable of: with this antibody, and this fragment is capable of attaching to a functional derivative of ICAM-3: ICAM-3: _{and a non-} small bulin antagonist other than ICAM-1, ICAM- g _or deer of the CD-18 family of molecules.

is from

The invention further provides a method of treating sun-specific inflammation in humans and mammals, which method includes providing for the subject in need thereof, the treatment of such an amount of anti-inflammatory inflammation, including ^: a non-inflammatory agent, a sufficiently suppressing agent is selected from the group co-adaptable. capable .tse ^ bind to _{1SZh.z) r} ^ nt _P9gme of said antibody, said fragment being capable of binding to neimunoglobinov antagonist of ICAM-3, wherein said inflammation is a result of an organ. trans plantation (solid organs such as kidney) or transplantation of non-solid organs such as bone marrow or tissue grafting *.

In addition, the invention provides a method of treating non-specific inflammation in humans as well as in other mammals where this

/.· i? l · 'k

- 18 method involves securing the object which is to be treated | ι of such an amount of anti-inflammatory agent, sufficient to prevent inflammation <where this anti-inflammatory agent is selected) from the group consisting of an antibody capable of binding to 1CAM- | The 3 j fragment of the antibody, this fragment being capable of binding to / t is YuAM-3} substantially pure 1AM-3 j functionally arbitrary

ICAM-3} I or non-immunoglobulin antagonist of ICAIvLs, |

The invention further incl ^d ? the above-described method for treating inflammation wherein the inflammation is associated with cheloviya selected from the group consisting of · vazoastov CDS ^ MSM in natdlpeno breathing zhltiplen syndrome opganovo chvoezhdane, vtopi ^mm ene to septitseshyata, kshr chultiplen syndrome organ no yes no secondary k for septicemia, haemorrhage or trauma reperfusion damage, · j 'chocardial or other tissue acute glomeruloneuritis · reactive [arthritis dermatosis with acutely inflammatory components · acute purulent ί meningitis or other lesions system like! ' e.g. stroke, temperature damage, hemodialysis, ulcerative colitis, disease) * I of Cj * ohn, necrotizing enterocolitis, syndrome of chr ^ nucleocyte) associated transfusion and cytokine-in, duc.toxicity. '/

The invention furthermore includes a method for suppressing β metastases from haematopoietic tumor cells, the cell using a member of CD-18 (in particular LPA-1) for migraine, where this method | includes the provision of. a patient in need of treatment with such an amount of agent sufficiently to suppress metastasis, wherein the agent is selected from the group consisting of an antibody capable of binding to a 1CAGL-3 toxin crosslinker. this antibody;

a fragment of this antibody, such fragment being able to bind to -lCAivu3f produced. the toxin of this fragment's abode,

- 1.9 substantially pure -LCAld3} progenitor toxin of this Fragment · functional derivative of. 1AM-3 is a potent toxin of this derivative. GCA-3: or non-immunoglobulin antagonist of 1AM-3, other than a member of the BD-18 molecule family.

The invention further includes cetol for growth inhibition of HSS-3-expressing tumor cells, according to which an amount of agent is provided to a patient in need of treatment sufficient to inhibit growth, and according to which method the agent is selected from the group consisting of: an antibody capable of binding to ICAM-h: a toxin-derivatization of said antibody "fragment of said antibody, said fragment being capable of binding with 1SAM_z: a toxin-derivatization of said fragment" toxin-derivatized, ^mp linen of TD18 family of molecules » or tox a new derivative of the Functional derivative of. member of the CD-18 family of molecules.

The invention also provides a method for. detecting the presence of cells depressing ICAM-3, which includes · a) incubating a cell or cell extract in the presence of a nucleic acid molecule capable of hybridization with 1CG-3 MPNA, _and b) determining whether the nucleic acid molecule is ketogenic hybridizing to a complementary nucleic acid molecule present in the same cell or in the seventh extract of a given cell

The invention further provides a method for detecting the presence of ICA1U.3 _{in a} biological fluid. Which includes ^: a / incubioa. the sample, with an antibody or Fragment thereof capable of binding to ICAM-β, _and / or whether the antibody binds the sample.

The invention further provides a pharmaceutical composition comprising:

-? 0 GI / _a / Agent, selected from the group consisting of ^: antibody, g

.... p capable of binding to ICAM-3 j fragment roll antibody such as this fragment is capable of binding with ICAM.3: _P o substantially pure. / 101-3 j functional derivative of ICAM-.3 j or Nei '! Unoglobulinov antagonist of ICAM-3 other than ^bw flax family SD-18 rrunosupresoren agent

BRIEF DESCRIPTION OF THE FIGURES feypa. ,,, 1. Adhesion of T-Folds to the Braided BFA-1.

Adhesion of cell lines (A) and lymphocytes (B) to purified

EPA-1 counts for ICAI-1, ICAM-2 and labeled cells on 1FA-1 coated

ICAM-3, Binding of IRRM

I microtiter donuts in PRI.

the presence of C1A _B blocking agents ₍ specific for AHA-1 _# ICAM-β _and ICAM-3,

Control plates are coated without ^ PA-1,

Figure 2 Low cell count analysis. ICAM-1 _m <ICAIvLp and ICAM-3 expression p

(A) Dymphoblastoid cell lines are labeled with saturated β amount or MAg ^ R1 / 1 / anti-ICAM-1 _? MA CB-ICp / 1 / _enT and-1Cike p 2 /, MA _in CB ^ -1C3 / 1 / anti-KAM-3 / or unconnected control MA _{B x} 6 / _ / thin line /, and then followed by FlTC anti-mouse immunoglobulin, lin, (B) The remaining human lymphocytes and 3-day activated lymphocytes were analyzed for ICAM expression as indicated above.

Y'Gur8 3,

Immunoprecipitation of BCAM-3 (A) - labeled lysates, junoprecipitated with a non-binding control. ^ 63 of Mav CB-IC3 / 1 (yant ~ 1CAM_3), / B / ^^^ 1- labeled $ KW3 cell lysates treated with / + / or without / - / M ~ glycanase, and shun precipitated or non-conjugated control Mav CbZ, b! av W6 / 32 / anti-NM-A, B, C /, MAD ^ ξΐΛ / anti-CA1'j-.1_/, MA _C CBR-ICg / l / anti-ICAM-g /, _And MA _in CB.IC3 / 1 / anti-1CAM-3 /,

Figure 4. Immunopregnated thymus of DSAM-3 from soldering rats

ICAIvi-3 _is immunoprecipitated by labeled lymphocytes and neutrophil lysates using mAv double Sepharose. The ICAIvl_3 _C immunoprecipitates were redissolved by polyacrylamide gel electrophoresis. Other mAv were used for. transcription of other cell surface molecules. Human

Sepharose (control pine), CB4-ICg (-) (ICAM-g), CB4-ICg (i) (ICAM3), T4g (4I iFA-1), IMg (1 l MAC-1),

Figure 5. Effect of MMA on SKW3 binding, to

ICA1M _and ICALL3.

The ability of / hK ^ 3 cells to bind to purified ones

ICAM-1 and -LCAiL-3, _{and the} effects of -PMA stimulation on

F'F · ^: this coupling is tested as described previously (ibid. Al. 3414619 I 1989): Meg ^ et al, C _is {{5 {· 813-819 / 1987 /. .

one representative experiment is shown and the wrong bars show a standard deviation / ^ y.

Figure 6.

An antibody

Various antibodies have been tested with respect to their ability to block 1AM stimulated cell lines for binding to purified ICAM-1 or ICAM-3 as described previously / DiNr et al. , Matigue 3415619/1989 / | Merlin et al, Cell 51 ί 813-819 / 1987 / /. An elegant representative experiment is shown in the Figure, with the standard error bars denoting one St).

Figure 7.

Binding, of CQS cell transpectants to purified ICAM co3 cells were transected with APA and expression vector as described previously. / cleFocjero {{es et a /. D. Ehrles (.175 ^; 185-190 / 1992 //. The transfected cells were tested for their ability to bind to immobilized ICAM-1 and ICM-3 _{in the} presence and absence of anti-AFA-1 antibody / TS1 /. 2.2 / A proven representative experiment and the lines representing the standard error o denote Sb.

Figure 8.

Temperature dependence of 5 bMA stimulus ttypachd SkWs, binding to 10 AM

The ability of NMA stimulated No. cells to bind to purified ICAM-1 _and YuAM-3 _C was tested at I-J 1.6,22 and 37 ° C as previously described (Marfin et al. / Dec 515813-819). 1987 / /.

Tests were performed in the presence or absence of 1FA ~ mAv (T51 / 22). One representative experiment is shown, with lines representing the standard error indicating ·

- 23 Figure 9, Antibody, blocking, RCA, sty ^ / lyano. ^t ~

Various antibodies have been tested with respect to their cnocophilicity to block PPA-stimulated T-cell division, as described previously / Kegp et al. D. 1mmip 1.1: 314611-61.6 / 1983 / /.

Figure 1Ό. Waadaisce.,. -snsted ,. a _________ mixed lymphocyte response

Various antibodies have been tested with respect to their ability to block mixed lymphopathy, as described above. (Kgeppku et at., ^ Lmipo), 1.31 * 611-616 / ^and 983 / /.

'dirypa 11. .¾¾ ^ ¾ ..

YuAM-3.

ICAM-3 is purified and degraded with -Ο.Πθ _{π the} fragments are separated by high-performance liquid chromatography.

Intrure 1.2, Presentation in the form of Piagra branch 11.2,

On. the diagram representing clone 11.2, the position of the Н10 and NK-17 peptides, the resin DNA sequences that were obtained, as well as the transmembrane regions, are indicated.

Figure 1.3. Sequential comparison of the NK-yo sequence name with human ICAM-1,

The Phare _C program was used to identify the sequential LMW homology of the ΚΚ-γα primed subsequently, additionally, human ICAM-1 protein.

14. Sequentially, Wed.No-, of. 1-shod sequence - .. e human

The GAP _C program is used to identify the sequence homology of the X.3 primer sequence with human ICAM-1.,

Figure 15. Sequential comparison of the III13 sequence. with, human. 1 ^CO M-2.

The GAP θ program used to identify the sequence homology of the * W3 primer sequence and human 1AM-2.

Figure 16. Sequential. Comparison of 17 cytochrome sequences with human ICAM-1.

The GAP program _is used to identify the sequential ocular homology of the 17 primers. sequence and of. human ICAiv'i-i ₄

Figure 17. Sequential comparison of the '17 primer sequence is human. ICAKL. ^ ?.

The GAP program was used to identify the sequence homology of the '17 primer sequence and human 1AM-2,

Figure 18, 4g, ethical agreement of ICA1 / L2.

1 (NC sequence of clone 11.2 was determined using standard method.

A, Sequences obtained from the δ'-end of ICAM-3 De were obtained by clone 11.2 with 17 primers.

B. Sequences obtained from the interior of the 1AM-3 gene. These sequences were obtained by acting on clone 11.2 with the KK-10 probe.

8. Sequences obtained from the 3 - end of ICAM-3, Sequences were obtained by exposure to clone 11.2 with the reversed - ^ 13 primer,

DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The present invention is based on the discovery of previously unidentifiable ligand ids for APA-1, vesicles such as these! of the CD-18 family, which are involved in the cell adhesion process, are referred to as adhesion molecules.

I. & Ά - 1

The AFA ~ J adhesion molecule mediates a wide range of leukocytes but quotes, natural killer cells, and gaanulocyte interactions with other cells in immunity and inflammation / Springer, 7.A. ei, at., Ann. νθν.ίΜΜΗποί. 5: 293-252 (1989) _{is the} receptor for ICAM-III, ICAM-3, and the newly identified ICAM-3 (disclosed herein) / Desy surface molecules are constitutively expressed in some tissues and induced in others by inflammation / Marlin, S , D, et. at., Cell 51: 813-819 / 1,987/· feiin, Μ, Κ el.al., J-MMnno ?, ^T o (iay 9: 213-215 / 1988 / j US · Patent Appt. $ er.6 - 07/019 440,26,02.1987 and MS, Paf.Appt ζθΓ. ^ 07 / • 26 250446, stated 28.09.198614

XGA functions simultaneously as antigen-independent and antigen-binding cytotoxic, T helper, naturally absorbing, granulosa cell and monocytic interactions with other cell types / crgpeegL.A. et.a ( _o AiLLHHmmipo .58223-252 / 198? / | ^ Ι ^ ίιΙ, Μοτο, ^. Α 9t.a1., M ^ Lshipo! ./1^88, under seal /.

1SG-1 is a single-mass glycoprotein, varying massively in pas * personal cell types of 76 * 114 kD, and is captured on a superfamily with five C-band regions / fetis, Mleb.al., Mipo. 9 * 213-215 / 1988 / | SiannioB, DX _D d.aL & ii 58: 925-933 / 19 88 / | $ Spc Λ e.at, Netide 331 8624-627 / 1988 /. ICG is a highly inductive cytokine. including XFKUa, ΤΗΓ _and J & 4., - '''j)' «* β 'I in a wide variety of cell types / D ^ 41n L.H.a.a., hmipo1Looyau 98213-215 / 1988 / /. south 1SJ.1 on epithelial cells endothelial cells and fibrous glitter, medaiga HCA-i dependent adhevia of gmphocytes / DPJm j.a! l. Hugh Inno /. 1378245-254 / 19 ^ 6 /? Dichlrr al. , 1078321-331 / 1988 / J Dg41h e * el., A Ap.

Meo, 167J 1323 * 1340/1988 /. Adheia is blocked by re-treating GH01HITI with 1 H -M-Av_ or re-treating. the other cells o KAM-1 / E / 41n, ^ .1. ^. 31., ^. ^. ^ 0 ^ 6781323- ^ 340/1938 / /, Identical results are the recipes »YuABM in artificial membranes or on Petri dishes indicate that both ICM.1 are receptors for LRU ^D / Marlin, '.D. er.al ,, ^ θχ! 518813-819 / 1W / j

Mandala, A ^ .et.a1., X ^ attige 331886-86 A988 / /.¾ clarity, they are referred to herein as '' receptors or * siphon ^it , e ^ answer..C) * a further description of ICAM-ι _is given in I. \ 8a4.AppT. 07/045963,

07/115 798, 07/155943 07/189 815 fig. 07/750 446.

ΙΠ. W2.

Accepted OA and other »guds other than 1H-1, give edajrvm» are _not IM. / Mc? · ®r.al '? I ^ mli 17701274 H9

86 / | Maneva, MW et.a1., & Rd. * Niip! · 181637-640 / 19Я8 /, Λτζт1я е ^ .а1 _m ^ А11 « ^в ^ ъ 1071321-331 / 1888 /. The second imidifert im ligand is designated “1SG2 *.

1S.? ee different from ICAM to cellular daetribupia and lack of cytokidan induction, ICA & L? is a complete sbtdannone of totei with yields i ^ -like regions, whereas ICAM possesses 5 ^ -subcode regions / taipdap, DD. et. a., ce / {531925-933 / 1988 / | ^ IwonS, Det. A1., ^ Atigue 3311624-627 (1988) /. In short, ICAM-? is a little more related is you give end-regions of ICAM / 34 ^ idantically new »/ than 1CAM-1 from XAMAMv to the other members of ^ hev © tmLvtwe, damonet | shr®j1® sub-suture of ^ -sound ligands, which bind davda »® integrin family retyateriL * natatmyayu description of ICMLp _is give in IL Patent» 7 / 454,294.

P »iCAaua

The present invention relates to the detection of a third

W * 1 ligand, designated ^w WJ8L 3 *.

The development of W dam ICAM-2 allows me to be a girder »

HM-dadaimm, the 1AMAM-schadasid phenomenon, and to say that there is a third ligand for 1 * M. Binding to nkalda cell types such as hedgehogs and endothelial cells will give purification®! $ M,

- 28 can be yaaggllo blocking with a combination of 1SJ1 and KJo MDv, where 1AM-1,1SAM-? - the non-pygmy adhesion pathway to “exists in many cell lines and cells”. K $$ / ^ frypa 1 L

Do you characterize that at: a ^, i, os khtlzhpat to; K $ 3 and, in conjunction with antch-XAVMM and eggs-1CA> C? MA®, if they are exposed to aaagra, have the ability to immerse with the "fast" (this cell line to the staggered 1A-1. Selection of dapaty is, yes, MA).

<

CBP-IC3 / 1, which completely inhibits this new pathway of addition DgLLD pandesis to venerated ΙΓΑ-1 alone? it is gently squeezed. from the combination of anti-A & M blocking agents and anti-ACAashr MA®, Kwaro anti-1CAM-3 MA®, CB-N3 / 1 are delayed alone, the eddecai is slowly injected, and this mhibshdaya is complete. , Dogan is in a blocking anti-KZH2 MA® ^d AZka, gdyaeziyata of -Ή «um purified ^ * a" 1 shdaira yo longer than ICAKU3 «also shstichno from 1SZH

2. In adaisation to H * A ~ i _t, each of the four cellular data utilizes the three KAM ® different degrees, as shown by different inversions of the inhibited a. In lymphoblastoid cell line, it flows primarily through the ICAM1 pathway with the assistance of ICAM-2 and ICMU3 pathways. Other In the limbostoid cell line, - * M _t uses the 1SJ1 and ICABL3 ventricle. dodoyavoto adhesion was not shosibira duty of 1SZH1 tsiv® _of ICM.3 yA® alone and almost completely by MAb together. ^ cellular da? nya, -gggkat, use © dshv $> emieyao acA! M and 1iAE-h the pie for ah! with the assistance of ialsh Ada® screw zhzt »_ -4¾ * b ν \\, £ χ> ν ι E *> 2a / IB1-5? aPG21aoshzi, y ^ Idar q $ ooshmaglutinin * / f X _January m> / flAlso examined / db *. l atrocities have submerged πο-'ρβΗΟ, π® they bind tightly is purified ©! ® ίΡΑ-ι / Drt1p by »! ♦, liaseiw 341 * 619-624 / 1989 /, f tops superstition, as found, is strong yAM -aviscis, Qi activation is IR, XCAIM expression is induction, and adhesion to HCM occurs mainly by intestinal XLM, and partly through HCG, the 1JG2 component of "dhwad", as in the skin cells, cells and cells are detected, although and weighed down by the presence of hell. XACA1 and XACAM. Skhad is a comparative surplus in the use of ma ^ SAM hell of each cell, like hodo ·? are yadyahadad Shi brainstem antibodies hell. shne two ^ ush «

We except that the adhesion of the resting gmPhottites to the XFM, which occurs widely, iodinated gikv voichiai occurs, the combination of all three extrinsic adhesions narrows the binding of 1GM. comparable to those observed in the presence of aryl-MH. JV *

The comparative affinity of the three XAMCs with respect to XMG adherence by comparing their afferents for the binding of XGA * 1 as measured above x5x their cell surface expression as determined by immunofluorispentad Stemgia / <H% 2 of XAM% their oh! you for the XX * M adhesion shows.w has a greater aiadtet for

1GM and that 1СЖ-2 and ХСМ-3 have atoms »but lower affinity. For example, does гίζβτι® express ICBL? * XACs at similar levels, and each promotes IGAM-rich binding? the expression is greater than that HLS ad.,% as in & shad kits. The HSG pathway of adhesion dominates this hell. HCAM, in contrast, SMnSKtf® express three times more adVV M than ICAM and, surprisingly, the 1JJ pathway of athesia dominates over ICMLg m, resting T limbocytes WM-3 are well expressed, m 1CAM-1 are absent, nucleated X ^ M is mainly transmitted via ICAS-3. If XAI1M is well expressed, as is the case for, 1U and HiA-ectranslants, this is the primary adhesion pathway.

The manner of distribution of ICAM-3 differs from that of ICAM-1 and ICAM-2 in several ways. Unlike YuAM-1, _its ICA * Lo _f ICAM-g is not expressed in those present in either stimulated endothelial cells / data not shown / Dova does not agree with the established, heard iPA-1-dependent binding of cells to resting or activated endothelial thaiva is an ICAM-I and ICAM-2-dependent phenomenon. YuAM-3 is restricted to the hematopoietic lineage, and is highly expressed in lymphoid and monopitic cell lines, with few exceptions. In all cases, however, the expression of ICAM-3 in the cell lines is coordinated by Yu-1 ~, l 'ICAM-2-independent adhesion mode, Friday lines (H LIVED Dar), binding ΙΓΑ-1 solely through ICAM-1 and ICAM-Pn © show YuAM-3 expression, whereas cell lines / ζ 33ζ Χϊ9®7. Beer T (which showed poor binding through these three modes, had correspondingly low ICAM-3 surface expression (data not shown).

ICAM-3a are significantly different from ICA1M and JI * 2 in their expression in leukocytes (II <gura 2B). ICAM-3 _is expressed at high levels in resting cells-gmphOErti, myocytes and petrophils, while ICA-1 ~ _and ICAM-β _C is expressed slightly less or lacking. For comparison, DSAM-1 and ICAM-2 are weakly expressed in monocytes, and only 1SG.2 is present in the resting K5G1 cells, and 1SAB.2 is expressed in neutrophils. When lymphocytes are activated, NDDSJ is increased by 2-3 fold until XCA & L-1 expression is strong induction / Aj $$ 1n is | .a £ .D. 1mm (1371245-254 / 1986 / Z ^ iype 2B).

Immunoprecipitates of 1CAM-3 _O m different ^1S6 X labeled cell lines show a sharp band of 124,000 when reduced

- 31 conditions with slightly increased mobility under non-reducing conditions (Fura 3 A). Treatment with Lb-glycanase water reduced the ICAM-3 band to 87000, indicating that KAM-3, similar to ICAM-1 and ICAM-2, is a highly glycosylated protein (Fura 3®). The biochemical characteristics, mode of expression, and functional properties of ICAM-3 differentiate them from previously described adhesion molecules, including the human HOM receptor W1 / Tedder 1, 3Hm, 1.14 * 532-540 / 1990 /, the inducible endothelial adhesion molecule / Moe et al., ^. ¾) .Med. 171 * 1369-13 / 1990 / I Carlos ei al, BloocL In press / 1990 / | / et.at.,

Cell 59 * 1203-1211 / 1989 / / and the VIA family of matrix receptors / Ish1g, M.®, at {.8 * 365-400 / 1990 /, with no MA »with similar cellular spread l / Ci Iks LH, ya !. Hoikosut® Typing Dai Base W, Oxford. Uni / er ^ iTy Moss, Oxford, Inland, / 1990 / /.

The existence of three ΙΣΆ-1 ligands transmitted a specialization in various aspects of the HCM-less interactions. 1CAM ~ 1 is mainly expressed in the endothelium and in many epithelial cellular tigures and is highly induction in inflammation and adduction, where it regulates cellular localization and facilitates specific antigen recognition. / W ^ tsuk er.aL, Ummipo!. ^ EV. 108 * 135161/1989 /. Since ICAM-2 _{is a} predominant receptor, this adhesion may have significant consequences for the standard of recycling of α-1-bearing lymphocytes through the woven endothelium / Nammap JA1.,., Myo1 140 * 639-099 / 1988 / | Waskau f * .a!., • «· —_ ** - · · - *

J.Exp.M. 171 "810-817 / 1990 /} rc th." F., J. Wasf 140 « _d -» <- t ί -

1851-1853 / 1988 / | and / Shu1 eya (., $ shL &. 19 * 753-759 / 1988;

Currently, ICA1M frictions on neutrophils remain unclear, since homotoxic neutrophil aggregation is primarily

- 32 Je-1- dependent, thanks to the presence of ΙΓΑ »! / Eyegbep JA1., Χ.Χμμηπο 1.137> 15-27 / 1986 / | et al., Scand.

^ .jpvnv !. 22> 619 -631 / 1985 / /. The finding that adhesion of TEM lymphocytes to IFM occurs directly through the ICAM-3 _t B combination is the fact that SJ3 is better expressed than other IPM ligands on monocytes and its resting lymphocytes plays an important role in the initiation and the immune responses. In fact, T cell adhesion is an antigen providing cells requires XP-1 t XAMAM interactions / Aran ^ yle ^ oi e4 al., Hmmsh ^ .Ve <114 * 29-44 / 1990 / * Maj ^ oia ei aL, Xwiemol.Today 10 «417-422 / 1989 /, and wat © such, ^IC AM3 can play a genus, especially in those finding it in the T -« lymphocyte and, where the rivet © ICC4, PC © ICAM-2 are well expressed. Indeed, this kind of protein is supposed to be ligands other than hCL4 both in allogeny and in autologous mixed lymphocyte reactions / BagnaSeo j.a., Cell Ep. 128 * 326-369 / 1990 /. Moreover, IBA & L3 can be assumed to be important in the antigen-specific interactions between T and B dymphocytes, where these cells have not yet been activated. The YuAM-3 mode also should be important for the lysis of important targets by T cells, depending on the ICAM-1 / MADO ^ a y al. . 18 * 637-640 / 1988 /.

The existence of multiple ICAMs named important applications ea • clinical treatment with MAV versus ICAM or XSAM analogues »MLv is an effective species in prolonged renal / Co51m1 d it, Dmipo !. 144 * 4604-4612 / 1990 / and heart / ^ a ^ and y.a {., ^M Gat> 1 Proc. 235533-534 / 1991 / allografts. Southeast of IDv inhibits different and overlapping immune responses,

- 33 to what extent it inhibits the γGM-dependent interactions of distinguished subsystems! cell types.

Mm »any of the known methods should be used. . .... and in order to clone ICAM-3 rem. such netod Veda after photo analyzing a library of shuttle vectors insertm / golucheda of 1SZH-3 vkspresirashti cells / on the presence of inmrt.zhovto sadarga ICAM-3 _df of. % pv ansh »« x »de la» vrvmdga ora »tdnfed to the cell about the vector« olvd yam devmudvanie aa 1CAI-3 exprvoya.

ICAJU3 "DNA m preferably identifies the location of the malfdoi <ayad of bnff · and & J / 5.JIL n" C ^ where. AcaJ. % 1. USA 3413366 - 3369/1997 / aa identifying the np> bag of adhesion molecules. In this method, cDVK (library is made from cells that express ICAM-3 / such as 5 ^ 4 mSgkat or ^ K ^ lufblastoid cell lines. /. Preferably, the © DOS library is made of T cells.This library is used for transfection of cells that normally express ICM3 / such as Cb * or Η®1 <cells / The infectious cells are introduced into petri dishes that are pre-infected have been coated with or o anti-QoL-3 antibodies. The transfected cells containing ICAM-3 codes other sequences, and which express these ligands on their cell surface, will adhere to the I * M or anti-ICAJM antibodies from the surface of the petri dishes. Even the glued / non-adherent / cells are washed, and those adhered are removed and cultured. ICG-3 expression sequences in cells and cells

- 34 are then removed and reconciled

If used to cover the Sodium pan, Yankee-1CAM-1 _and anti-1CAM-2 specific antibodies are added to prevent the adherence of HCA1m or ICAM-2 expression cells. Adhesion of ICAM * or ICAM-2 * tranefectant to The XGA * 4 coated plates can be inhibited in this way is antibodies such as LL, anti-KAM-1 MDv and SVP-Yu / 2, anti- CAM 2 W binding of ICAM-3 transfected cells to X? M coated deleted inhibited it with HA _and anti-III * 1 MAb _$ , did not inhibit anti-ICAM-1 or aiti-1CAM-2 MAb _s . The ICABUj or ICAM-expressing cells are incapable of adhering to the sodium trays and are therefore eroded to all other non-adherent cells. Hunting enriches cells expressing the 1CAM, 3-fold sequence. the gene encoding YuAM-3 are well known to those of skill in the art and may be adapted to produce the desired gene.

Such a method of obtaining a gene sequence that is iodinated by CMM * 3 is that using an oligonucleotide probe for the curvature of cG or gay DNA. ⁱⁿ this method the ICAM-3 protein is purified by the known immuno-purifying method and the terminal amino acid sequences are determined by one of the method known in the art. In contrast, the ICAJLq enzyme is purified by (zhk with trypsin, ipei or c-C) ~ you tidy purify it, and the aminotasselin sequence of the oda from the intragastric fragments is determined.

Once a partial amino acid sequence is formed oligonucleotide is generated. probe based on iodone preferences shown by the body, degenerate probe is inserted, yes

- 35 for all possible codon combinations or codename combinations preferred. ICAM-1 or iCAJLp DNA sequences are known homologous, and codon degeneration is used to construct a probe. This probe is then used to screen both the genomic and cDNA libraries for sequences that hybridize to the probe.

Methods such as, or analogous to, those described above are capable of substantially cloning the genes alpha human aldehyde dehydrogenase /% i, 1.0. and. a {., Duce. ^ at1. Acad. £ c1. ^^ A 82 * - «i—« * mm. »· 4»

3771-3775 (1985), fibronectin, S. and al., $ o ».M.

^eL Ogrid. 4 * 2519-2524 (1985), human estrogen receptor gene / Waiter R.al., Duss.Jatf. Acad.Sei. ESA 82 <7889-7893 (1985), human tissue-activator tissue ( ^p epp1 with D. a. AE, ^ ip 301 * 214-221 (1983)).

In yet another alternative method of cloning the ICAM-3 gene, an expression library is prepared by cloning genomic DNA or, preferably, cDNA from a cell that expresses YuAM-3. The library is then screened for members capable of expressing protein. that binds is an anti-YAM-3 antibody.

The knockdown ICAM-3 gene, obtained by any of the methods is 1Jean above, can be operatively attached to an expression vector and introduced into a bacterial or eukaryotic cell to extend the ICAM-3 protein. are disclosed by Map1l1 $ L. »efc.ai., dirga, and are well known in the art.

In an alternative method using BCB to clone the YuAM-3 gene, the assumption was made that ICAM-3 _is capable of YuAL »! and / or iCAM »I used Degenerate oligotsukleetida® primers axis justified sequences sahreneni between CSI-1 and ICAM.p _t amplifadrani polymerase chain reaction" DNA Izh mRNA cells »known cat © expressing ICAM-3 protein, for example S ^K W3 or tonnage (SeGoi ^ eHe ei al., J.Etp.Mod., 1755185-190 / 1992). The clones are matched and those different from ICAM and ICAM-2 are used to obtain full-length columns.

The authenticity of clones obtained by any of the methods can be confirmed by expression of full-length clones, e.g. bc © $ cells and tested aa reactivity with ICAlLg m ..

VI _r factors of this invention t ICAIL3 _January

ITS FUNCTIONAL PRODUCTS ~ AGGUST AND ANTAGONTY

The present invention is further directed to XCM ^ j its functional derivatives, "its agonists and" antagonists.

A. Functionality of ICAM-3 Derivatives The functional derivative of YAMAM3 _is such a compound having biological activity (both functionally, thaia, and structural) that is substantially analogous to the biological activity of XAMAM-3. fragments, variants and chemical derivatives of the parent HCAS3 molecule.,

The ICAM fragment * is used to denote any 0 subsystem of the molecule. The fragments of the ICAM3 possess the activity of ICAM-3 and which are soluble / i.e. not bound is membrane / are particularly preferred. Soluble fragment is

- 37 is preferably taught by separating the regions connected to the membrane bridges by the parent molecule or by substituting hydrophilic amino acid residues to be hydrophobic residues. · Identification of such residues is known in the art. and is a number from the entire H ^ -state region, such as. areas 1, / F /, F and F, F-3, F-4 and F-B,

Variant * n & ICML3 means that it refers to a molecule of the same logical structure and function with both the whole molecule and its fragment.

One molecule is said to be substantially analogous to another molecule if you give molecules have substantially similar structures or if you give molecules reach a similar biological asset! host Yes, if two cells achieve similar activity, they are considered variants as used in this text, even if one of the molecules adopts a structure that is not found in the other molecule, or if the sequence is acidic. residues is not identical.

As used in the text, one molecule is said to be a chemical derivative * of another molecule when it contains additional amounts that are not normally part of a naturally occurring molecule. Such quantities can improve molecular solubility, adeption, biological sex Life, etc. Quantity may also counteract the toxicity of the molecule, or eliminate or attenuate any of the undesirable side effects. Quantities that are capable of mediating such effects are disclosed in <RTI ID = 0.0> e. </RTI> ^ op NvmaseiIs & 1 ξ'οίοποβ / 1980 /.

Toxin derivatives are a special class of chemical derivatives, toxin derivatives are molecules (such as 1CJ · 3 or anti-1CAM-3 antibody) that are covalently attached

- 38 to any amount of toxin. The procedures for the * coupling of tamgwa amounts to a molecule are well known in the art.

The binding of such a molecule to the cell, the beef-guided toxin in close proximity is the cell, affecting the resulting lr xyodine division. Loda can be used to supply any todaine amount; promised, readily such as ripin.cholera, daFeritin toxin toxin, or bzadarada dripped toxins into the membrane.

Native derivatives of ^ CA> M, having up to about 100 residues can be prepared, can be prepared by the method known in the art in the reaction of amino acid residues from purified The crude protein with an organic derivative that is capable of reacting is a side chain selected, and is terminal residues. The resulting covalent reactions can be used aa idenfluoride to remain important for biological activity.

% PRODUCTION AND ISOLATION OF FRAGMENTS TO KAKLg CAN BE USED VERY DIFFERENT TOTALS. the irradiation of avian functional factors may be used for cross-linking and coupling to 1C3 to a water-soluble matrix. fast, reactive, water-insoluble matrices such as e.g. niashgei-bromine-activator carbbdshrsh and reactive substrates, ojisda in ^ 16 patent »3969287, 3691016, 4195128, 4247842 4229537 and 4330440»

are used for immobilization of protein.

Fictitious products that have 1 amino acid sequence having the same amino acid sequence can be (W to be produced by mutation of the C 1 -C &lt; 1 &gt; C) Such fundaudal poultices include, for example, delda from, or inertia, or substitution within 39 residues the amino acid sequences of IC50.

3. I will use any combination to project the final structure possessing the desired activity. It is imperative that the mutations that will be carried out in the DNA encoding the functional derivatives do not place the additions beyond the reading frame and for it is preferable not to create complementary regions that produce a secondary mRNA structure (see patent description published below 75,444).

genetically IDA _d functional derivatives ask to be created by site-directed mutagenesis of DJ, kodireshta HSAM in · yielding DNA encoding the functional derivative, and thereafter expressing the DNA _into pekombinantna cell culture.

As long as the insertion site of the amino acid sequence variant is predetermined, the horn structure does not need to be predetermined. % example, to optimize a site mutation, random mutagenesis, such as linker * can be carried out at a target codon or target region to create a large amount of derivatives that can then be expressed and screened for the optimal combination with the desired activity. Such techniques as may allow mutations at predetermined genesis.

familiar, e.g. site directed mutaPoluchavaneto functional derivatives QoL-3 in accordance with what is already achieved by site-iasochenata tsutagenezg DNA that encodes KSHM _And there odats earlier prepared functional derivative of, 1SZhz, technique of such site-specific mutageieza well known in the art, as evidenced by T's publications.

(1982), site-directed mutagenesis allows the production of ICAJL3 functional derivatives by using specific ligand nucleotide sequences that encode a DIC sequence with a shania mutation.

Someone can generate amino-deletion weights, insertions or substitutions using site-directed mutagenesis. Acino acid foci generally range from about 1 to 30 residues, preferably 10 to 1 residues, and are usually adjacent. generating a soluble form, i.e. ICASL3, soluble forms of ICAM-h _sv generated mostly by deleting either the membrane spanning from ICAM-h ^ aka and hidroFobzhte residue within 1SZH-3

4 Acid inserts include insertions of single or multiple amino acid residues within the Southeastern coding sequences, such as terminal fusions with polypeptides being substantially unlimited in length, intrasevenous insertions. insertions within the complete ICAM-3 molecular sequence / may range from about 1 to 10 residues, preferably from 1 to 5. An example of a terminal insertion involves a signal sequence duplication, whether heterologous or homologous to the host cell, is the end of the molecule to facilitate the secretion of recombinant host derivatives.

The third group of Functional Derivatives are those? which at one or more amino acid mols in the ICAM.3 molecule are removed residues and in their place insert other various residues. Such substituents are preferably carried out in accordance with the following Table when it is desirable to modify the characteristic of the ICAM.3 molecule.

TABLE 1

Original acid residue Sample substitutions Ala o (y »$« · iys A $ n ofn t ₅ 0G ^A SP Cfs a $ d with | and CR ^G fy afat pre nn a _£ n * ofn H · (e «t ^ a ( Hey U.S V.t rf * # And * (f * »sad Ffe measures: (ei * £ yy Sir yfcr ψτ Trp -mouth Tyr * rp 'jf » v4 * 4®t | «t

Substantial functional or functional identities are accomplished by selecting substitutions which are *, * they are less canned than those of Table 1, i. E. lumbered residual residues that are more marked in impact

- 42 for storing the α / structure of the polypeptide skeleton in the displacement region, such as the broad band or hecoid structure, в the charge or the hydrophobicity of the molecule at the target site, or α / the bulk of the side chain.

The substitutions that are generally less conservative are those? Vito? / Glycine and / or diarrhea are substituted by another amino acid or are deleted or inserted.

c / xi, profile strand is replaced by hydrophobia is / cysteine residue is substituted by any other residue </ residue having electropositive suffering chain is substituted is a residue having electronegative charge and is a residue having a volumetric side with one that does not have such a side chain.

Gb-preferred are substitutions that affect the solubility of ICAM-3De _C a generated by substitution of hydrophilic is hydrophobic amino acid.

The mutations constructed to enhance the affinity of TCAM-3 mutations can be guided by introducing the amino residues present at homologous positions in ICAM-1 or ICAM-2.However, such mutant ICAM-3 molecules can be b; are created but lack the C-linked CHO in homologous movements in ICAM-1 or

It is difficult to predict what effect a given substitution would have, 4-4, deletion, or insertion, on the biological activity of HOAs, so that DV would be achieved. But a person skilled in the art would be able to evaluate the effect by routine testing methods For example, a derivative is usually obtained by site-directed mutant * 43 'independent of DNA, encoding the native ICAM-3. The derivative is then expressed in recombinant host, and can be purified from cellular yaunur, for example by immunoassay chromatography.

The activity of the cell lysate or of the purified derivative is then screened for in appropriate screening studies for the desired characteristics. For example, the change in the nsunate nature of functional derivatives, such as e.g. affinity for a given antibody is measured by competitive immunoassay type. Changes in immunostimulatory activity are measured by appropriate methods. Modifications of such protein properties as regular or teru stability, biological degree of tulle-life, hydrophilicity, warming-up of protein degradation, or tendency to agitate or tendency ltimers, is tested with well-versed methods for the ordinary person skilled in the art.

C. HCAM-3 agonists and antagonists The ICAM-3 agonist * is a compound that enhances or enhances the ability of ICAM.3 to perform * any of its biological functions. An example of such an agonist is one factor that enhances the ability of ICG-3 to bind to cellular receptors.

* An ICAM-3 antagonist is a compound that attenuates or impedes the ability of QoL.3 to perform any of its biological functions. The gagonist includes GSAM1 and 1C.AMc _> functional derivatives of ICAM-1 and ICAM-g, _aH. you are the SAMZ-antibody, the yant-pm antibody, etc.

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Antibodies that are capable of inhibiting thiog aggregation further are then tested for yes. to determine whether they inhibit aggregation by cleavage by 1CG3, or intestine by joining any of the members of the BD ·! 8 family * ® of molecules. In this study, they used * * * * ® all the means used to distinguish YuAM-3 from DM. Thus, by the example, the antibody antigen from the antibody can be analyzed by daudoprevodov 1 G, by means of polyacrylated electrodorrhea. It is possible to distinguish between those rust members that bind to members. the CD-13 family of those that bind XCAi-3 through the SCR screen obnostta of the antibody to bind to cells that eispreskryat HRM.no not 1SZH.Z / but w v ^ s? ι / ehz / The ability of an antibody to bind to an oath.expressing XP-1, or not 1CAM ~ 3 'may. the medium used. The nodules used by those skilled in the art will nullify the samples, in particular those using the immunosuppressant / wt. agtinade, antibody yarn drink, and yes,

In a preferred method, the antibody is selected by the ability of Judas to bind cells expressing 1CMM, but not cells that do not express HCl3.

In addition to the agogasters and antagonists described above, the inventors invented, treated and treated for inflammation, infections, asthma, and the like. include anti-isotypic antibodies against anti-hCG.1 antibodies and antibodies or their antibodies. The "fragments" that are able to bind are AI,

The 4g-dyotinic antibodies according to which it was intended to bind in competing portions or to the leakage of / ILM bodies may be mimicked, for example, by culturing a single antibody against anti-YAM antibodies. The ability to erode is the hedgehog of ICAM-3's natural binding ligand.

Insofar as the molecules of the CD family are ea bound to bind it to ICAM-3, the introduction of such molecules f, for example, as heterodamers having both alpha and beta subdomains or cat molecules consisting only of alpha or beta subunits, such as molecules that have fragments of any one, drink or subdue конку will compete with the cells to bind to them is 1CJ3 glowing on their surface.

The anti-aggregation antibodies of the present invention can be identified and titrated in many ways by measuring the ability of the antibodies to differentially bind to cells that express ICAM-3 (such as T cells) and their ability to be differentiated. bind to cells that are unable to express ICAM-3. Dzdhodyashti izgitaniya of cellular aggregation are those encircled in I.b.Patentno description 07/045963, 07/115798, 07 / 115,943 07/189815 or OB / ZbOUb.Obratno, the capacity of the antibodies to bind is ICMup _{yyai m} Thiede fragment 1AM * 3 may be measured. As may be determined by one of skill in the art, the methods described above may be modified or presented in a different sequence to provide a variety of screening methodologies, each capable of identifying and deletes individual antibodies capable of binding ICAM-3 to members is a family molecules, referred to as CD-18.

E.g. extraction of agents according to the present invention

The factors according to the present invention wm to be obtained by the nature of bees / eg by the participation of animals, plants, fungi, bacteria, etc. in the sale of non-immune

- 47.

globin antagonist 1AMAM, or by exerting on the side of cells and polyclonal antibodies capable of binding to ICAM.S / | by synthetic method / instance, ^pi Res synthesizing ICAM1 * h _is fushtsionalni derivatives m ICAM-h, Izh protein »antagonists of ICAM.

/ as immunoglobulin, thia and neim * ® globulin / by the hybrid technique / e.g. for the production of snoonal antibodies capable of binding is ICAM-3 / or by means of rheumbinatization techniques such as e.g. for the preparation of the agents of the present invention in various host species such as yeast, bacteria, funnels, cultured mammalian cells, etc. (using recombinant plasmids or viral vectors). Choice of methodology used -. · «- will depend on factors such as convenience, desired yield, etc. But it is not necessary to use only one of the methods, processes, and technologies described above for the preparation of a special anti-inflammatory agent. The processes, methods, and techniques described above may be combined to provide a specific agent.

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PYUZVDNIN, AGONISTS AND ANTAGONIA

Agents of the present invention can be used to mitigate the various biological activities that are mediated by ICAM-3.

A. Suppression of inflammation

One aspect of the present invention stems from the ability of ICAE-3 and its functional derivatives to interact with CD receptors. 18 mviecular family of gliooprinses, and g-clamp alns # 1,

It interacts with the members up to the CD-18 by means of the QoH moiety. Ea suppression can be used. to prevent the going from weakening / inflammatory processes.

The term "inflammation" as used herein means that it involves the reactions of both the specific and the non-specific defense system.

The term "Manto" is used here, the term "specific defense system is the intention to refer to those yomguyant nv,"_; . the immune system that responds not to the presence of specific dysarthritis of the crucibles. Inflammation is considered to be a response to the specific defense system, if the inflammation is a hot spell. It is associated with the © sublingual defense system. Idemers of inflammation, which are the result of a response to a specific defender system, include the response of antigens such as rubella virus, autoimmune diseases, and delayed type and. the hypersensitive response mediated by T cells / as seen e.g. in Indavites who respond positively to the Medtech test h. Chronic inflammatory diseases and rejection of shunted tubes

Organs such as the kidneys and bone marrow, and other examples of inflammatory reactions to a specific defense system.

As used herein, the term -reaktsiya ca "nespedefichtta defense system" ee otyaaeya December reaction »medairana by leukocytes which are nesposobzh of immunological memory La ^m Cmax cells include granulocytes and macrophages Littell ee used herein, it is believed that ee inflammation resulting from a response of multifunctional defense system, if the inflammation is caused by a mediation of a reaction to a non-specific defense system. Jimede of inflammation, which lead, albeit partially, from a reaction to a non-specific

- 49 defense system include inflammation, conditions associated with respiratory imbalance © / W RUB / or multiple organ damage », secondary to septicemia, threesomes or hemorrhage | reperfusion injury of the myocardial mJ other tissues __ acute gdameruiephrosis | reactive arthritis Acute inflammatory dermatoses Epoch components | Acute purulent meningitis or other central nervous system disorders such as stroke, thermal damage, hemodialysis, ulcerative colitis, Qfolm disease, necrotizing enterocolitis; dcdoovondzhhjr ^^ »associated granulorite syndrome and tditokin-induced severe toxicity.

As discussed above, the binding of ICML3 to the members of the D-18 molecular family is central to cell adhesion. Through the process of adaasia. The yapfds are capable of continuous observation and, more precisely, of controlling an animal for the presence of foreign antigens. Therefore, if these processes are normally desired, they are the vessels so, and the reason for the rejection of organs is transplantation. / such as kidneys, bone marrow / and tissue transplants, as well as many autoimmune diseases of Dzhev., any agent that is able to slow or inhibit cell adhesion. would be very desirable for recipients of dense organs / and -specially kidney rub eplantaiti / meme ki organs / a spepialno bone marrow / tissue trensplantenti or patients with autoimmune diseases.

^ onclonal antibodies against members of the CD-18 family inhibit many adhesion-dependent leukocyte functions; Dmmysh 137: 2901 * 2906 (1986), homotypically adhesive /. β ^ .θί., ^. Ηκρ. ^ Μ. 163 * 1132-1149 /1986/.antigen and mastin-inducing lymphocyte proliferation / I 1u sha, A. eb. aL »^ nose. «I d., U ζ K 78 * 4535 • 4539 (1981), the forch antibody band is £.

13613196/1985 / and effect all lymphadata *. · As a dysfunction of cytotoxic T cells / hepatocytes *. al., £, mmy £ w 12100-2182 / 1084 /, m8cfatt / £ ego $$ mapDe # .a {.

Mmun !. 136t4328-4333 (1G), and all cells involved in antibody-dependent cytotoxic reactions (Ui X x X ^ 1D "ide1L2Y2-J? 8 /1984/"). In all of the above functions, ANJ '' W · inhibitors the ability of leukocytes to adhere to a suitable cell substrates that, in turn, inhibit the histologic function associated with binding. gives functions, in addition to including 1CG-3 / II * M interactions, can be suppressed by anti- SW-3 antibodies.

In this way, monoclonal antibodies capable of binding to YuAM-3 can be used as mammalian mammalian anemia. It is remarkable that these agents differ significantly from the essential agents in this respect. they are capable of selective inhibitory adhesion and do not exhibit the many effects, such as nephrotoxicity, that have been found with conventional agents.

Satisfied KAM-3, in particular in solutions (R), is capable of acting in a judgmental manner as an antibody against members of the CD-18 family, it can be used to suppress inflammation. Moreover, functional derivatives and antagonists of ICM-3 may also be used to suppress inflammation.

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E. Tumor Oppressors

The agents of the present invention can also be used to inhibit the stasis of haemothiotic tumor cells, which requires the migration of functional members and members of the SD ~ 1.8 family. In accordance with the present embodiment of the invention, a patient in need of such treatment is provided with the appropriate amount of agent / antibody, the means to bind is iCM-3; toxia derivative of this antibody is an antibody fragment, the fifth of which is capable of splicing about 1C.UU3 f that is, a new derivative of this fragment i being substantially pure ICAM-3 | an additional ICAfrLg ί derivative, or an ICAM-3 non-globulin antagonist other than ICAM-J, or YA ^ p / * sufficiently to suppress the meta-tag.

In the embodiment of the present invention, there is provided a method for inhibiting the growth of 1AM-.3-extgress1 thirsting tumors of 1years.This way, the grandfather! S method encompasses supplying the needy cadmium® sputum from the agent which is the prime. not to suppress the corresponding growth. Suitable agents are * an antibody. It may bind to the 1 SABr ^ opto-derivative of a given antibody # antibody fragment by probing the Fragment to be able to bind to the ICAM-3 # toxin derivative of this Frypnea toxium derivative, which is of the SD-18 schulk family or toxia product ©, the 2unl derivative of member C 5-13 of the molecular family.

In a further embodiment of the invention there is provided a method for preventing the growth of -expressing tumor cells. Specifically, this method involves providing the patient with, because it needs such treatment, a flush of toxin, which is sufficient to suppress the growth given. Soothing toxins. 57 *

K Sdestestene and »OT of infectious» preventing MIV scattering

The present invention in the present invention is a burdensome method of extinguishing OT. the yedafoat of that "you are * it *" in that it inculcates the introduction of poisons from the "offendid zhajtmid n" *

effective moaning np NP oftadgt agent _t *% tr you * re * wthhho to relate to the method they dadaistede and »otyavedavd _t track to understand,» ® tow tow is a viable gene vete variant m HIT / veto te1f. NGr / .which totho infect the thoths in aug, w> iodine to be pedaed by ^ modao according to the test * * ntion. ote a variant of the OTi eitaly of »cheli * ♦

they are not the burden, «► <·« a given aspect then the present disobedience npowBwnw of mtj | .hh · pda you smell you murmur the expression not ** l * 7 and, in some elves, ending the legend of M -1, descending from OT yanfeda ^ nta, zero * on the torus gives you the dasho-tehta reactions they a.ltereidaya »the same toto yes

you have to cut the weight of the tear gas, you know * «this is the transfer of an earthquake from the hammer» oh the clutched clutter »» this nedane the agents of nostegia and ghetto / ghetto were able to slim it * B »1 / to panty but capable of suppressing the infection and, in particular, NOT the Indo-Indigenous.

ΙΓΜ and you claim, you also submit FROM «ifeidia is the impairment of the capacity of ΣΓΜ you are giving a true HIV transmission« h ^ H * tbp »

..— ^ .. l * Mm fT> w .ΤΛί 1mM WkiA · ** AMMkJkidKtikJfc ΒΛΛΛ jtk 4MN ^ bmSh * M

NMT® SHELL! DV o1Pv | Zh8h? wMitirwilO tearRtM1 IV 8d | wm * IC ^ WPJBI>

i «1 ^ a> *« mM ^ k * m <~ u ~ - -ίι <· τη am. £ · - _ w j mn <1k ** M1 »A * mj shmλλ øjjk1kMv« 0well, molecule RUB which eng * * ** ·! / zhdotoshetetet1®n1 may impair the ability of the 3D1 / 3D8 to retrieve the NP from the impederade and if it sows it *

ABOUT LM * A1 * OMkMVKPZh - * ** le ft W -, mk «M. Wft-TWM »η ιΠ W rftft ft *

KLSTdv * ^v VIEW vv / zhv® SiOOOgKMZTT NV OJJghl CLiTi® LV CO *. . the geimucl is the CD1 / SDS receptor, or to the HEM © srdidae cortex,

Ewes »is to be num» »ICA1M, Fragment by HOJ ^ ftnddeio * *

muddy derivative w wam mj adai-hcmz awwtel.

The inventors of the invention have intended to be used in the appropriate amount, w mw ® yes. will be achieved »daži® on NP ijafdeop. _e ,%. two w · h «tz © a © rent for zhdazhzh to * eat '/ swadtda J nifoedit» a1 »» the dose is zhizh w sa * W mzh to ttddetvtdeda tazh YAP izfeyadeyaLed factors oe give m padeende.da.

- <

have come out ya »yaz have come from NP gift.

Walk / agayat · This is the present invention shayag de serve w »» the gift of the sun, give also for the prefizmtzh «in the evening. Hmmm is for. nroFmdegitde targets, its agent is jaredas giving the ndieriyte "even though" devt © and be a symptom of ia g <rdaia mefetoya / datdadar yarn, when "it comes soon sj / time de" gave yaefekdeya, yav before giving any symptoms of such indakli. * The introduction of the agent for the treatment of urinary tract infections added to the subsequent infusion. When ego is used, it is necessary to use the agent to make sure that the agent is able to absorb all the nutrients. ΗΙΪ yifeshi.

Agents from destodo go on to get a "dyadag infectious" infection or give a pidigy to the intended infection number / ej deiovitoldetto ^^ "shmaalmaaA. »Ll - ·» ΜΛι «mk ** aHm« wi EL * «th« Dg «Mj | 11G» HI ^ 1E tlftt 4IN1mm * SHMM »<hmm ll ll. WM1111MM "MM detection of such viral ectacid cells * to trigger further infection /" the invention improved dodo? <N

SJ _a * good means for the iodisadne w jp in ^ kpiata.po · * spedevlgo ΗΓ7 · ι iwberw. co-administered with ⁵ / X / XGAm * »3 _# or soluble HCLM.3 transients, ZD1 / date 0G1a, C $ 1c, ZDIS /, soluble CDs in the form of edible, CD! 8, solutions» ® ZD .8 iroiavid? ", See CD | 1. / bd18 hsterodimer, or soluble padiDo of CDi / ODb heterodgtra and / or / XI / antibody, at a later time to bind to HXJ3 © / XD / cell or partially associate OR or rejuvenate jarenyavidis H8. and / or (XV) a molecule (preferably an antibody or antibody and a &quot; titer) &lt; / RTI &gt;

Under the r MsaZe Mr. provides -there .from initiating the migration of the IP ^ n ^ cell counts Ltffg ^ dodo is, «and w ^ uw includes introduced ^ the effective state of the o * anti-wrretWHeH agarad in the YPchgaFetran indavid"

UW -.,. ** ** A ^ ww.T ^^ 'O'W'f' © gnat ^ touch twwb © <

1SLM * 3, freg «.4ent and» XSA ^ Z.fnipiioad ^ o? r ^ r * eiadnn of HSSl ^ .Antn-1CSH. With antibodies »rondo is in a state up to a quarter oun

of H1U ^ nb ^! tto * thu quarter be connected with HEM I want. Alpdoids, which are aberrant with 1CS-3, suppressed myrrh beetle to the ability of TGC3.3, 'to' ~ dos; ngtp of NTT ^ n3 ^ yygdo ^ -η-α ^ κτι »

ds o they connect de glet * and, lvprlspdo ^ and SlM / ZDj dotgotdor »^ pdov deoI1 * but not the affinity of ad ldooido to is weighed o, SDm / SHBa • adte ** tor, tet '* · *' · ^!: hell is to se mpodoad t-doi ^ fir-dope ^ to w «p • n ^ pdo a

HZZHZ.

Shvtdate o »nestoyashtet® idabpdanie is obeepechdada · ta Dada eyutte in nmeem _t 1»? Ut to the floor iyadadat of IH7 / ^ yak u * other shrueno <nzhektnrezh Cell »* g shyavchshdadage considered st, me ^ liC7S ^ №№9S Yes! JwfiJ ^ WCjW lflO * pSTwR * J41 NJ * LIFE ¹ ® # lc © JwJUWRB VIR le lm. shlk allA ^^ dak> «* MA iiuh i, ll. yam-amine · yam yam-yam a.zhm * mm. | Ma ^ shzh *. ^ The mlm agent is sufficient to west® or I pre-

The introduction of such supplements does not need to be sewn, even if it is a prophylactic need, because its infectious daftdad, the agents have egg-like isboetein® its datcd fcfc ^ fc. ^ IShkMMShM MMMY BRIDGE * K ** flLA ^ W ^ LKY ^ IN I MEMBER9 i ^ l.

ar®.ddarnteon In JIAW and W is a SYMPTOM SB NIRUS “WHY!” · * - * rter, pre _{s s} *, or given after / a nd a n d a n s * ♦

but you always have to keep it a symptom to tad wn $ ewn.W® $ «B» if * you enter that agents are crazy to give. <m »are issued terdatdanda», the agents are wmwiw to / in the "jusredven" ice / they burn you '' toektda perfection. Then enter the introduction of an eludag agent to don 'flOHbjewem' donate 'ta * m' T cells,

The agents of the "standing ittagethe way" they * are * to be sub-igure and give the © pre «the pallet you lend the l1 ^ e» si / so we to submit® the daidahidaya the waddings of the w> rrra «re t oww / lady and after Fedachshto ia tash www in ^ ktash ktash »j rlbw ^ ewMfciEHMMfcJih '.WHWH ALNSHMV • e * tadadage IW daTda

According to "you give igebgetzhe.edan arm * able to modulate ΣΓΑ * ι / ŠZZ hitMetvid her tune in the thirst for ast. * Honestly from the adatastate agent in mndaid, tai is® in need of treatment »'i» 4r sgentmte but in the present invention include xx-3, fralads? ka IC ^ M, ^ uzhtsionalno pryapvagm * of ICAJ. «3 _{t YLI} to ^ · CSI» h antibodies GERT ia sposob® to ^ zhpdat? ^1shso! It is not possible for them to coexist with the M ^ Htggg, which binds to XCLM _.. With the Jfm subtraction of the rides, eat the human quadruple ability ia 1CA - '* 3, express> fian on the cells. with the exiresravad SDI / CD1B receptors.

Anti-gst ^ a zents © t presently invent breakfasts are provided ^tji r pe'SHmfowrHT © in ^ε · ό. · Humanities, up to cm * dark w pazlpt to call οίΐ ^ το -me «I eat - ^ - t ^ ,

The agents of the present invention are to be administered as a non-toxic agent _, as well as more blemishes · textured anti-asthma agents / dasho-a-t-hetylcoadains - alto *, theophylline, bp-adrenergic compounds, wattage> danv, pvzor? rul, and edadan, gcacortivoid, or hidecortnzon. chromones - cat © sodium hdomoyagn and antoolivergip. when atropine, is a view of reducing the amount of agents required for the number of astdilate emntiaos.

Rav ^ danet © of arwwe from present * ?? When the profile may become a cap, the profile is used in a precise manner, the agent is washed in front of the cawTOM, CR> Filakti purely indicated. the agent serves as a © prevented delay and is always a delightful botmsww response. ”is treated therapeutically, the agent is © applied with / through the center! vein after / onset same asthmatic eimda ^ n.herepe ^^ dosho introduction * given: in agent edui »to slow every ytudonan ush & hd *

The agents of the present invented, well-to-be. t-r ^ oatash yak before the beginning n »yarn gamma astmvtvchep every year and after tosh. sorry.

- 62 C. Apply for Diagnosis and Pdg

Wmnjnm antibodies »able to bind to ICHLg can be used as a means of delivery and visualization of the sites of cChAM expression and inflammation in a patient * "- " and others. / fluorescents, see Darasgnetic atoms. The method of carrying out such a detection is known in the cabbage region. The labeled antibodies can then be used for deatistical assumptions. Key applications of antibodies in the field of administration are described by yoMapLA, Mmi.f / tn rd. 13M65-474 (1986), W ^ ej VSJa ^., HpJLa ^ o /.

20 * 693-700 / 1985 / and «OL% 1eme 2091295-29? LOO.

The expression of 1CG $ may cause the vessel to open by using hybridization probes, e.g. DNA or DNA or a probe that binds & XCW * 3 gene poadazelets »st ₉ 11L! with ICAM-3 m? NC by trace of the weights available in cell " ₉ expressing XM-3, Techniques for counterfeiting *". - · · i ни · - · Hybridazone trials have been drunk by L. vJmp., In * wfee. C & n1r | »a4c. Schwogg (1982) and by

Naume ^ .VD. a1. »c> X & ofeie J14 4r®r! ciisa | ton, a fyeciieef ir _G 4 <a ^ n | Aoi, F / 1985 /.

Detection »© of the focuses of Sh3 expression is nowiwa of a miscible antibody or nucleic acid probe, a bear used in the diagnosis of tumors. In a given aagetics experiment, tissue or blood samples were incubated in the patient in the presence of antibodies, which are or can be labeled. The preferred embodiment has been performed, these techniques are performed by irrelevance.

Such diagnostic toasts can be used to give recipients of the organizer tdadopdantdoifvpr. b & delirium, with ♦

'data are potentiad for rejection of ad opram, ^ Addition to the testing to be conducted in an effort to rest a long way against the position of some yipigids to advadoid? arthritis or other chronic inflammatory diseases ».

For example, in the j-ideo-active ardagenesis of Жnti-XIIIx3 antibodies or antibody - ^! teghts, the exhortation is to -stann Fdapnyiand antigen with a nd radoi ^ gnsh samples.D> bro description of gdaioulhni tests * pia / PIA / may be -measured in HavogCgu Ϊββ & πΐ ^ ιιος ODO Bloched flar in biology, ψοΓβ, Τ. , j a £, Shtp Βοίйй ibeihninij Somrayau, PW? Jt /, is a partial reference to the head called * Introduction to rhdmoimmune studies and related tegaea by C ^ J, T ,, Reverse », the doja antibody» to be fluorescently labeled compound, enzyme, and "other known markers, some of the agility in the field, β complemented the localization" of the aesthetic. of inflammation, antibodies able to bind P3 can be used to test non-biological fluids for the presence of pirvudartyas, 3 using any of the SFWWrH abusive media. response to inflammation from 1 &lt; 1 &gt; CMU3 median environmental fodder *, In addition, the presence of 1Cl in adchotic fluid is associated. is an urdu- nary of the "breadmnoet". Any Jo * logical sample can be used "for such a long distance," preferred geological fluids sa t blood, serum, pdasma "sciatic fluids, amniotic fluid, fluidity, fluid

-64.

INTRODUCTION of the smolder of the ice

Therapeutic Epheetes of 10-3 can be trouble? obtained by administering to the patient the halo molecule ^ C3 H3, whichever is the therapeutically active Fracture thereof. The therapeutically active fragments of <RTI ID = 0.0> 1l, </RTI> which are five-fold.

I> | CI ^R * - - YafChYag y * y

ICAM and its features are - they can be semi '*. Synthetic Peninsula Using Protein Protein Protein Protein Protein Protein Proteins Coverage of the kw on the carrier to achieve the activity of 1HL »Coverage of the present invention ere extends ** ® fuyaydayuyayut overcooked at 1C $ M.g> that show the absence of amino and aesthetic estates», which are found in the vessels and acids altered They necklace are arbitrary or wheat pdotedavat ^ Iologopshta. see the pharmacological activity of CMI,

The hired antibodies to the undigested, they «and the ICMM molecule described here are considered to be * are * in fact procured by nature» yetamans1 *, and »o the devotees. left »epw? in nature, • the flock was invented to probe into antibodies and biologically aesthetize their Foggins / independent polycaldic and live clones / mine are able to bind S. 3,% suture antibodies can ^: or with the means of editorial technology. go to WHM, go to milkman.com »from ΧΟΜθ,

HH yuyah to Oude accomplished © self-efficacy in the home of the ear is HSSH1 with the XCA & Up, Introducing aiti-XLM ayataya, 1g ww adleuiu, a way »to connect with HCG-3 or szhuzhite, semi» e «by ICMM'Uom to be carried out independently in the Embassy o *

anti * XQ # t antibodies and / or anti-XSHM antibodies. The life of the adjuvant, see Fragments of ad antibodies, mode of adherence with HLC, is administered to the patient for QoL (s), and their derivatives (). The dates of the agent introduced will vary depending on the such factors as the age of the patient, weight, gender, basics, half life, medical history, etc. Hat-offcto.It is desirable to have a roaddippie dose of the antibody that is fed within the range of odoao ДОρο / ι »TO W to L / body weight of the patient /,« that it may be administered more closely high dose. CVs are given to HJC. I molecules or topics Functional arbitrariness;

discuss, therapeutically effective until they would then be * reduced *, aia anti-HCLM antibody is either a * XX * or antibody, an * K * LM antibody and / or anti-HCl? antibody. Kat is here, for one sake, it can be tempered in addition to another when the administration of the give compounds is at the same time that the two sockets are driving g * h »at erititi to hedgehog and <sr time in patient's serum ·

And the antibody able to bind 1 € M $ and the ICMUn melee itself.Dogt to be inserted into the pate. ® HSZ4 becomes ngeadonda, introduces read mozo to go through the seller and afterlife, or through single singles and myoshevizh pricked ·

The avents of the present invention are predetermined by the hashtag in marriages, delivered, called to be treated physiologically effetely. But the date is sufficient to prevent or delay the survival of the child. why did you howl »you> imk vvrayaaie is 1SJ.2, Spde? <p, one of the agents we * toddeu azobretoaao is given ya the patient is aiming to gougev * not inflammation and aiao is r dose, sufficient. to give * this * in% a «to be given to him / her» is vvogogically oFavadno,

In detl ««, * * XAMAMZ3 agents' agents, its heavy Fragments give <1 * date to introduce "mw the status of a dawtaia and gambichmgya is a hedgehog" or to be a number of <a1 | Introduces taoyao / such / soyadjaya to be cwo »ptfilachy * hzh, tao and ya therapist cvzh ^ yuga c® uses pro ^ l®hiva, 1 shudavupreshi» it eudanen · / instant / beams are given »at me or the responders a symptom / depressor before, at the same time a day or so elv ^ time of horde «ova or sad * gattpdap» adam, at the forefront of dapman, and be a symptom of va odag Yielding the organ L ^ daFidantically you enter the saedevde / zyata / serve to prevent going to add m-ft it and to be the next inflammatory response / that yupgtmr, stingy not m organ izh Tarawa L ^ ready to give teadvvtdapu.edet / bolt / give away / go directly through the fuser / the reader is not a symptom of n acutely inflated® / that · dapr. give away? »to the organ or tudant / Therapeutic introduction» to sedepoeia serve to relieve all jejuodao inflammation / as ypres, reject the organ or tissue /.

Thus, anti-aging agents, according to the growing idolatry, can be pressed in front of the bee and the green hedgehog prefabricated after eating the fruit.

For a composition, it is healed, * they o farmecode »yoishish * a» its introduced ouzh® to be borne by the datsentL zhg aget is »080,40 ea given in a '' therapeutically effective amount *, hell that 'introduces' the lead is Physiological means, "a given agent is physiologically ours, and" his presence made us want to gain a distinguished presence in the physiology of accepting the sick.

Antibodies and X-AM ampoules according to the three percentages may be fourier in accordance with the inno vative method of obtaining a pharmacologically applicable composition. and it "Forms, solanderas in itself other human proteins" wto human serum albushn "are described, for example, in Rtp ^ op Science / 1bc ocL, OSof, A ₀ ^. _t Hfioiu ϋ ^ 4οπ ⁽ PA / 1980 / / »Pharmacodagic Supply Formulation is a view of administration to the naked. Such compositions will contain an efficacious nude of the agent of the present invention having the age of the nose.” In the present invention. can be humenized by chro zhrishzh izh SD? waxi »drink» to steadya-yoo.pada in Phar-, meioztich »relation for five flowers Medicinal methods are described in the Asst. Datasheets» 9009543,0, 9009549,8 and PCT will

PCT / I J / 02ZD2 and PCT / F 91 / 0P946, to report at 4Af the Ministry of Justice on April 27. 1991

- 68 control m pdpddl.u-zhtda ia action wrer le *

be the sorrows of the grandfather ^ weigh? > method method. You control the release of tpepezretm? L> get. · "% Yavg osposteeii with slop" to "polymers for absorbent, but only those from the frequent invention". The old age and the pro, the fierceness and the control delivery of "gray to be regimented" de fywa rzzdar popbor * gosha wider * molecular datriio, by trrrvne * w ^ wiepwe ny ^ iniarated molecules, albeit the method of idagrporeyre. of the duration of the action I eat intestine control release agents is, mturguring the agents of the present Beo6peTs »l4FIac« w at the delphi material, the dasher. Reverse the sixth tepodeshrt these agents on the gudamer parts, it is in rain to be in the range of ** in 4taptu, making, for example, the technique of interfacial flaking, _and worming, iedatin, _and tjug in dadeipalic smtmitters. albuminos 1 and crepes, cuttings, cutlets, and wound capsules,

In the present invention, the compositions of the present invention are composed of: a / gnti-extracellular agent / gacho, e.g. is a wwroe capable of binding HS a fusion of this antibody capable of 2CAM * | _t fuchtrunnally produces 1SJZ In addition, opioid opiates are not 1CLM, doses of 1CMl and KICs, and are a single-agent agent. Zhshri for tsevda MywcwRWHH agents «a. * daisa ^ gaaon, azathiogt1t and twwbchow A,

- eo After the ephemeral is already described in the text, it is the same as the agents and methods used to obtain them, then it is understood that the irkshrit will lead to a lack of focus. where his volume is barred ·

ha, KshHp .. «aa, ashjiyav, ^ ΜηΜ, .Μ.ΙΙΙιΧ,

The neo was described de-dere »you will condemn» adhege to ® * ® * l weave daida and zhfoiiti w covers is XHAi dash / & ς ^ ίπ il! Coiol Spring Ndeer Ghaf,% Jude »B1 © {. 54t 7S3-W5 Hunting / <^ uid by XU Lidants XFM Adaorbirte Iard 98-term maturing deiditer schist (X1 | Adi14egtei) at 1100 AoG sites. The maximum binder binding pathway is 0 BSA and f® pltestet is W / 0

MjCIg / 0.5 ^ HSA / medium for the testing of HCA »! is achieved by a tube of 30 min of birds And ¹ vitaotitheride of the kendenchata with 1/000 dilution of T 02? / ahti-HEM / esd ^ de The dying people in the TouSh T datates isolate the de date stitch on the shjstiaeovl surface and nylon Filter and ea 90 3 *, den

RIAn ^ daptas were generated during cultivation of de jeetdat® yadapsk in the presence of 10aJ / m! of the flux swallowing f Ϊ ^ Α /. G) with fluorochrome IL / Mo1e <<br * ¥ owr. inc./, nWWWlT CO Μ are re-certified in the medium aa of the product. MA »prstretzde de edetkit consists of incubation is 1 / S00 dilution aa epipytes de 45 min at 4 ° C» after you give in each put © is preyjrakt 10 ^ yutshLyat nit®shsh adhere to the solid Phase de XMM de ¹ not © he Y7 ®0, • the non-adherence cells ee remove is 6 aspirations (? 3 oooh needle), so that as w * phooges settle w Yu k gw for 5 days. de Ja7®b aa 30 pcs. Do not overlook Liorites, give it a shot away. t-hard to remove the tip their size * ^ oreceoLvR ^^ degas deroit © is the soda m Wopo®W «OK no.jjaetor MaxJe / * All MA» «· new» is in a raareded state / 1L »SJ dilution de asct. vkzhvzh * T 1/22 / aj * SD1a, 1®C! // Semfees * ^ oi4 Nwt, ^ aoLSoi L $ A 7917489 * 749® / 19® /, Wt / rn "-HSJ, 1, ^ et / st." {. Dj | * ®1. gchiru-rm Lchm /. cbp, .i &>.

/ anti «LSJ» 2, ioCW LJ Ih ^ erollo <4 aL, / 1991 / / in yw ^ /, and SJOD / 1 / anti- ^ C ^ M, X ^ Cl /. CBF-IQj / f is an oyster mum curry oath $ 3 X 534 ^ 0L5® with an opyoufpo of our • irritated Be / in / with w «w / 9 *» ^ j1 · l4.a /., Gom. C, J Sen. 3 »231-53β L <G7 /,» βί »hLpitzh is scrounged for their ability to de m & r * X 'In connecting cc you submit» »CB ^ * 1N / 1 do not reetrate with the preexisting b ^ M / where © o Ci $ h .student troisfeitants on, 1CAM-P or XFM cW / rain ^and ? i w.wt «they /. % 1n of the four representative experiments * deded *, with the guards showing standard eating.

(iHUiEP II

Aagyi ^ atyaoio ^

All utilized cell harvesters have been described previously / Blues equivalents. SB 1674-681 / 19Jl Jdefde *% mw * aeaw oaths by per ^ erzht kuv »creew deshgdean cojwmww» · to m * dorouggart ® Moctl *% de ^ ie / 4,077 / as oiled by DI »e4, aL» 'I.Ceil-BioL! G7t®l-Sl / 1 ,^/.^g RUBR0®Go

- 71 separate from «lnnets uteAzh and cent.tzgz n» nm * / o sp ^ hhtttg from * echo the chro haotoninon zzhio. ^ The ostia and tononite are separated by the SWiWW WmiA8 «WVW ježžz» WH. *

1k moizdiv and T iato spetzhitt, toioyayonal rontsyat F&W weave ^ owl ajl wash and promise not to. aMMfesptrm from YZh m tetzhda co ^ waiting for the iroto «ntouste to 10 ^ zhudno»! / F /. The ooo oimigrat yielded is imwa wa SKCS Hxkvo * M <| »y (» Shai iwis / Coalier / ^ ^ bjžne w 1 $ totting ^ 1feš * the same HJJ with wrh you are in shia jmfotsish is 7 * 3 gr.T1® more- from any of the GCs, and hh h _{t t} lotto mount · ». ojasproyrot 3 * 4 times nowo © hsz» as long as XCASM ogaprooia ayro neutroys is a boozy playful leitn sh ^{and you are} from Me © * 1 / CDIs / LLP / .To treated with 1shto with a foejage With dash »te * o f FUrsps

- 72 TABLE 2

Inorescence analysis for the correspondence between surface antigens and expression of 1CAM

^; ιSpecific intensity of. · Kinraunchch fluorescence Cell LineAip aICAM-1 (RR1 / 1) aICAM-2 (CBR-IC2 / 1) aICAM-3 (CBR-IC3 / 1) Lymphocytes at rest 4 22 106 1 - pans RNA-BLRSTI 22 18 78 2 _ ppe in our PH A- with you 85 25 42 45 205 223 5-day RNA -. <Lg _With you_ 13 39 224 ^ 0 'TTTTE 1 0 213 «Eutrophilies 1 'lymphoblasts SKW3 0 98 73 Jurkat 2 166 161 Sup T. 10 113 19 Molt 4 1 242 117 In the lymphoblastic Stoics JY 154 119 47 SLA 224 113 306 Ramos 132 136 112 Raji 266 88 0 Monocytes U937 HL60 62 17 67 43 37 203

. . Pineapnate specific intensity ' ν ___ / rn Flöpospenpia I-fly line / 1itt ' - '- - aICAM-1 aICAM-2 aICAM-3 (RR1 / 1) (CBR-IC2 / 1) (CBR-IC3 / 1) • Melanomas inc RPMI 7591 896 475 3 0 0 0 Brittany lion is chemical K562 293 143 0 Mixed \ HUVEC Hep G2 HeLa RD3 / 5 E51DZ A-172 31 1526 1082 0 409 0 494 41 9 0 0 0 0 0 0 0 0

+ Membrane expression opeepelena ^mm through the working i'p ^ ₀ 7tpg _P that _Ci echten cytometric analysis cho ^^ p ^ p ^ p ^ l ^ d ^ is echprp- ν methods meanings are ottoepelyachi for scratch RDP epopeimenta. The fluorescence xrw is and the peak is ^m -e ^ ^l <ww ·. υθ Tig that is meters. thus h Epic ^bw p .mu.m is CCI-tgipitelno 1 (d yluopespeinoni ekvilyalentya / _f FLjSmesenite klettpni lines ^sour: human is ^so -gpota ^π 'n ^g cells allantoic vena.krtlplcho'w κπρτκτζ mammary, Hep Avg. tgovetcha is pi te.pochina cell .piniya, not 1a, ^mp oveshch? sang ^ in ^ yusyapkoma.NTs ^Ό / 5 human fibrosarcoma and FS 1,7,2. .echeyki gpksZpastosh.

• 74 The squirrel beige in the η clamp is' ^ 1 ee realizes is ® W «of iodogen / Ž41 * й® w, at _M « *, Ж! »® ^ no» 384 ®3588 * 3595. <* '·, / 19® /, Kittens joi her with Triton X-100 Λ & ζ Her cages w * SttQHHI o bovine "Svarva, and consequently her tpdoI ** is a suitable paver e Sh® seferod ea 2 hours. The ovite layers are burned and are present in the Presence buffer, 50,

0S1S _in 10 2 * markepetol. ^ mW edits are boiled in buffer, in the quince is absent? * mercaptoethanol and © is treated is and # j®jgh «M, JfcjijLifclMMniaLŽMG MG IJMM. We mHmMM ^ MUMA * WE HGTM «mShmmmmMMMMM AND · ® · MNAA - IODOShZhshzh,« ^ it is enough »to be inflated and ® f ~. > Our 2271680-685 / 1WO /, and its protein zhouizhrat is aitrediography. It treats nv mW®o is $? · Usnmme / ^ Cn / yMO / as described by pm / ^ agopigo / ka, LAVavShig 24> 46654671 (1J), was performed with the ionceitrir deflection of the ® ® odate ahh, 37% 18 hours /, yielding an optimum yield to the warrior »N * associated oligoaccharide from the leyatid skeleton. No. X contains H-overlapped carbodate, less than 1CG-2! m 60 000,6 1X-overplaced sites, skeleton of Mp 28 383 / is highly bovine.

- 75 Rapprtlian © by XAL - s

... w »? Dm. ^. 4 »ammmmm ^ mmmmmml lym * ash * i№lmk4k« * K1 * k.lM1Shk <in * Ak ^ kISmk ^ s ^ m ^ шmMsh ^ k _ALk. cloister · ^ wvMh ^. LADI * ¹ * · * '® * ® YATYATRLVTV by fwWTOffiwT® etJgirvtvgYash <w ffSTRIw · **

ANJ * W MMtaMMIMki MMIkAMNMtk ^^ flk 4ShkYkM ^ * M * ISHMM * L ISH1 ILLvv ^ Jav mi »an Yar — adadayav © © irtdayap1 tadadato ra> cj © d®yada © vi **» l «i» (3 or® TJ8 «W ν OIKI ^ RYA JAV I | fSvWWfpiFy ®W SHOW * <« VpZhSh 3 TfSTSTYAMG Oumar · © kdeimaadad »thirsty #, hoist® peanut ® # lrz © © t t ® ® oyutfvvi» * '. Clothing ® e by ewwwrn w ll »3 her © grtzhchava w * - * hezhedzhajad« zhzh · Zhadad © twwwTpwwi?

------ _ ^, _,. ** ay --- —.y — yam n · & -Wifi “j — nor

ZDBZMMT © 1®M »DOGYA HR Art * ^ F © F? © THIS» JAVYaNN® OshvTYAV '"» r ya O? L »© You by womrt, wi»! »I» »sta W & c awwrem / daiad from © a adadaaad L Kwt and ©> tshte © t shtmetrtchnya aaja, then you need to see "aeladadada poadada.t that ICAM dejfmyat yavad © a otfeadch & ad to hamshpmshkjap days · awWWV ·, ψ * - ** W ΗΜΙ * ^ * W * ΗΜΙ * ΗΜΙ * W * ΗΜΙ *" ** *

- 76 TABLE 3

AND? GnoF.torescence iitometric analysis of surface antigen-related ICAM expression

Specific intensity of linear * Cell Lines / Type ----- Fluorescence aIGAM-3 (CBR-IC3 / 1) aICAM-1 (RR1 / 1) aICAM-2 (CBR-IC2 / 1) Lymphopathy at rest 4 22 106 1-day FHA glitter 22 18 78 3-day IAA blasts 85 42 205 5-day RNA blasts 25 45 223 Monopits 13 39 224 Neutrophiles 1 0 213 T lymphoblastoid SKW3 0 98 273 Jurkat 2 166 161 SupT 10 113 19 Molt 4 1 242 117 8 lymphoblastoids JY 154 119 47 SLA 224 113 308 Ramos 132 136 112 Raji 266 88 0 Monocytes U937 62 67 37 HL60 17 43 203

-π -

^! Linear specific intensity ' 1 Cell Lines / Type 1 Fluorescence aICAM-3 (CBR-IC3 / 1) a1AM-1 (RR1 / 1) aICAM-2 (CBR-IC2 / 1) Melanomas inc 896 3 0 RPMI 7591 475 0 ο Erythro leukemic K562 293 143 0 ι Mixed- " HUVEC 31 494 0 HepG2 1526 41 0 HeLa 1082 0 0 RD3 / 5 0 9 0 FS 1,2,3 409 0 0 A-172 0 0 0

⁺ Membrane ekspresiya.opcheledacha tgred rtpgtsoFshurpespent »f tan cytometers-ene analysis is as sweat ^m echtyacha in materi- I?

p Oh!

or methods. Values were determined in at least two experiments. ^The fluorescence droplets are used to calibrate the pythometer. Thus, the elec elicity is approximately ¹ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 0 0 0 1 itSiCkCjV-loS-k CS ₍ H ^ o / esx ^ ₍ PL /

Chu I.

Mixed cell lines include ^: allantoic allantoic vein enzyme cells. human epithelial carioinomas cell line. human mammary gland cells. Gg. human ryazzo-Fosariote. R, R h / b.tsovei z ka fibrosarkomai FS 1,2,3 '] mm _O veshk₽ gliobyaastoma

* «Σ ** li« mshmlmshshanlk. «Cl aaiiw Dmjtmg— | Imm -. * | Ma ~ mgsh1 ·

Ανηιβ ^ 5 C® fJJJo'iWC / TU 0 T! 00isirgYa I YaIu1vdv®N1IVD | URE JwpBMBffl © · rpa # » _t ! ^ O mew edao yu & mc antibody SJ1 <& / 1 © is immobilized rebellion. fcw mmw insurrection »and * iodination w BUM are the same and are different.

* .a * b oa * - ~ - »* LJk« M№Sh ^ b.> ^ lmM> mLm ** uk I / il. ft I ^ »* ml ^ .LMIML SHGMlNMMMJ * ** 'th *. ^ k4JkM1K * SHO-aHk MMfiirlCiWi— · **

I © 0 »®j ^ RJJAM ^ 4IV®Ch d $ ® · * * <5e ^ wW8®3wR fJ®JJ ^ JJ W wra oww cheerful. <bftnowo · e ^ .L. W ^ .¾. r W. 17SHMM90 / 1SH /. Been cut cwwtmw and pour "knows" press me for washing and peels / reagents "oderm ejb® / ea vesge zhmt and any antibodies for cleansing them are giro" *

yoswadhwade> chiadifferential chromatography.

Bt was bachelor, SJ was lacerated by & W jtj or et come ttjjari / ie. throat from squeezing / yuetde clearly gtsyatzhm · mexjrw teg from otzlo ISO w W «D, zhko VZh ^ yrvststoyak from neutrophid® lick mmsoee« lew »weight«

from 1 & 0 F 150 «D.

Be warned in this way, the BUM states that its ability to overexert itself with day-to-day antibodies and its -1 -1 ж

itiypt 6 and 7 L

SWR VI

% determine mechiyuzht © weight w B1I from the reel of the blades * our types oo uvpolzvet tjupretzhpitadeya and «zhzh e ^ dzhaidezhshdaa m agzhroffert. ! «Lymphotides» GHz isolated from and lyfvdam glandular glands eat as lying o f weight «from» 120 to W «dyaddaod weight of CMM, go lyre» from wr * rofida · a little da-jos of that m is expressioir ^ by W1id8 * ido !,! B1B8weid moydot from osdo 130 to 150 «DUFggurl 4 / ♦ tame variations ® r * w« w »is wneww to honey m XAMAM family from gj» «dotot, SO1 added tzre sz ^ zh va * »ntsh in the dalochuzkuto =: ®gl means rzdzdchnto xwww seeLvadito · the molecular tode», added to. VAM & yrtidav from variations in the range to glioailapit. ^ However, varying in the weight of the body to 1SWZ seems to be long overdue from the rea * sion at the glitheir radius, the Voada socialist in the field would viadju this, but » yes rvdaj gdakosdaaii and dr-ui eizishv tidak »dabVvddaaish išdaDstze imn <a zdo effect on daiaejuzhe weight · Zhdotsimta in the range pas glidadalashk jaa 1Sl a ramoam that appeals to dardo * ^ * 1 | Zhrayzh range you don't get it »KJd, is smibbb yes ** generate hsj $ passed, you are looking for a link to connect and "zhddo zhddo da X ^ AM.priner", laths from SDC / CD to the gioirotein family * psha ha

TOL-F lShMMZSM1Y ^ | pugiyayu *% n®m ea iizheidarot with doynegayadai from a.shoshi and xsm-3 τφ ^ »tesh«> give her .pr ^ tions from Khthish toyadazhi harvest, as long as scratched to * above. mw * 30 · * * from imnassreshto anthotz are so.thenn tshajivji awwwwu

Table 4 conveys about $ to «maiitito ah * XLI yantsh Yashmichno antibodies ea idaetftgt» g on the basis of the weight oio · h «*. W> g * zhio jelo.c this co sarizh rush different wwww come on gommo co knows w with «hsj.Z weights and elol toaa ee mw» rw m and ^ unopredayaytad sz rajobeliasash XC1M heavy? ®? M »w chew.MDv followed by" aa oe thug "for egy ^ Sheta to them to ri® 1Sh» zhuadzhnit SKW clone aggregate a szhezhetzeto ya anyai XS & H1 1 a ezh-1CYa antibodies · Obdita ^ aiz ^ AHM hedgehog · body nsh id »izhmfshkran on sodaobost« in w inhibit · ry syringe ia SK4® w »tsh tm yash ^ gzheidashte 'tadji 1SAM _# £ yes from zhkt dazaaaiada.cho third zdaizh ia XX * M Oirsgauiv and priyatzhet 4

1W coa ^ fwperai W waited for the ward. Chad yei »w® na. 6mwp®w this aareiriowe mwe about live ai-hsj ^ tjjaoyakyazh atheiorui »so it is shlniyni- at <* VR ♦ COVL and ~ X <& / &_# wro

Table 4 ICAM-3 mAbs mAb Isotype PMA. -indicated Aggregation * On my own + IC1 + 2 mAb + IC1 + 2 + IC3 / 1 mAb CBR-IC3 / 2 IgG2a, k 3 2 0 CBR-IC3 / 3 IgG2a, k 4 3 2 CBR-IC3 / 4 IgM, k 4 3 2-3 CBR-IC3 / 5 IgG2a, k 2 2 The scoreboard is now 0-1 CBR-IC3 / 6 N.D. 5 5 5 ICAM-3 antiserum 3 0 0 CBR-IC3 / 1 IgGl, k 5 4 - HP2 / 19 ** 1 ⁺ Refers to the scale of J. Exp. Med. 1991 paper j -. aggregation. , 0 = aggregation number Anvrfi ICAVLp mAr from mp Hp Hr · pptlp ^ apjieg Madrid). The stepping on the glass of the cup results, they have rested '' a m ^A in which they went crazy. but never oh, octa ^; 'ipa.11i <O1f _{T0T (!} TTE θ 1stum_d CBR-IC3 / 2, 3/3. 3/5 ^ munopretsipitiret 120 kD ivipa as CBR-IC3 / 1. ^L

• $ 8 *

oamuidide and decoyde dedeel ^ et. Appearances are HLL, HLL / WU>

WM * connectivity is established® is mwo tootur, here and there «

grandfather f jk Schwur 8 / / yes km it is acrrsr? /, fcyps 9 goes out total uddeiststde where. the raiyadis yaithed on the lhmdgdede of the ldto divide Ldeo noted de * rede / ^ geggdu e4. a £, hayloi1 · 131 1611 * 616 / 1.W /, J1A stimulates the pro-fierad to swear it is f * '«· -' 'apti-XMM, in antv-XC $ M. »™ here, yantes * XSM $ yantyatde, yag gombkzhtsim on adem * XSAM and tt? * XSMM antibodies» t »« e where de »mam» • WMefeit raw JA stiijrait goes anywhere de1dezde.devde (de »1dev / dem anty-Yu41, in * "you-hsl ^ and ^ yachda. hsjl ονρητομι,? / gives edem-hjl vtetol / AG3 / 1 and XQ1 / 2 / and 3 / shda-x ^^ M and food- hSml ejhthtde are efutizde Irdg & Irtsheto IJA1A stimulated © vdede dajedegns.

SHI »IX

^> the reaction of the mixed gmphocytes. used to assess that reactivity was coming. Mvtvaivo memo * basically debut on a fishtvde but hmtei yinh heard about anyone / there redder, sue | «« ^ G1 · ** from real individuals / answer tslezhi / and measure the level de from * warnsh, use «go deyandeste The test is the first step in identifying a composition that has been applied in the art of transgenic antibodies and Tochenium antibodies and Tochenium. antibody® to AND LR reaidite® is irodetten de% | Hooray 16 »Qi« oSh »« dei *

- t ·

XCAM Shuyatoyatye mtw.

m »six w on« fodadaoyoet zh bzhzhzh m # * oe utit.che her pat »at iw6H®er <from at-LSMM g w * F | ohttLew »juti regatat is ticked at teeteJamtaetgt by a? fw * XCMUi _t aFT» -XCA ^ * t m anti * 1 (F * 3 «Danish *

IBW X

J LAMA »K ~ 1 D poison .. Zm * CIJAV®DrY1v owwMBP ^ | is * lWKM | B№KWriBII IV» d-daamj · ^ - ~ T / ~.-1PG-C _L ... IITJUM..nj |||| UiailWlUIII> LllWll | IIOIIll ^ -J r ... ΊΙ uaill.il - C .. - LillllilllWlO 1111) 1 pg. '! .. lI1 | 1 | 11..II

1SJ.Z has been moved by him »« g tdaaygyaarni am® immat * »** vom is waitingMizhtyatyaa? Mwo is osh-elgo in% wp 5 * ^ kn wertwft ZHZZ && tj» t, dat eyashmgo is hue * € you eat tpwwf m mm ** Fretshjn her goytadag is HFW Achdarw. And prod »cww * i» w »a 1f ^ gotbo ya f4go> d1zh« those hot m m schn * »

since r *> w tkpkwto rearage® · Shggoao 10 and 17 ea. x, n »tNkaag * rdash wo ojh» F iwkw Frvishdaa with szvotolsh paowp and © truzhur »with osvd szdayuveia / by tu * yudayaz ^ Mo and IM? respectively / «

But the acidic mite »saddles the same 1G» 17 g Shio mnw ♦ child oo wfvdvlya on the astringent metsdazha.Sshzde ^ kogoztt® «g and» F »10 the potozh, as it was established, is OdatShNJ / £ GMD, P0d / Shrsht / K / © etched into the daisiness of her counts as wghttp®t® “, as long as * t *** tshthpzhtshthp hedgehog” remnant.

The PS-17 ®о® is a standstill if it is a MZHZHK / ZD. 1D. 1®L /% flock and mill IR-10 frpwmm.w * the harvested zhzhsh residue is pepalotda and more often the dashido is -W light-fed.

Sronolla ya totheteeteto m XSh10 and NK-yo you find more <5 pos »HSJ» 1 and 1SJ £ pvslvdavtltoti.toiase yayeei • melted m woawmo »· 11X17 ej t» »» zyjayimi .

XHU1O pepeid ejuvaavv-sb. znatgya a mcwow »* wew * · in the 4LS 1MM, ®№ tracing m ICAM

J bot n here davadavadayanet, 1 "zhvga1 po ^ goro, @ a pdaludagrviv voroda ozhso ^ glkleotnny voad *% slzhut w> ** shga * wk © e tdado ® o" id t «t on u! Da« vfinwrai nz * of jav * gave, tbdadasht in mshh aa IZh »1 and 1SH2 hwwoth days n» ®ad. date »Ear Plugs Railway» t «yaoe? n ia © ont» oe »yes.not those of IXX1O in XXXX17 proteins are sewn © lie ·

11X17 Probe * LRW -73 wp e 24-arethmand, "trv" | 211, / Knet K

OTHX de X1X11de ^ 1J »W11deJJ ^ XSh1i S / tDDDHo 4

IIX1G probe * 25 measures e 8 nretsch gerandano, yedda | 5 XX / igaiya /,

ΓΙ & Ό ** - where * where * 1 «where. * U.de ** deAg1Mde4 ^ s I & x · JKM'MMkMkl'jMMk deMdea iMMMM ·· *** grandfather, where,« MMQ4NMMK * YaMMM-M ^ MNIk r ^ tft car * euisprerenonsh snootozh oo gets at tonzhrt »***** that a mm tu-rshu / Wbb w» oU, lWe * llarU ^ ao · et * AND *

821 TS- ^ 18 / 1JV L Dglpdate the money w is wwwt w

11X17 probe "float, yo zhdvvv zhiizze ^ ya her krishrat with iwhrts at XXXW drilling * * schn shon» kzh »pc 11»? _t ce the knife w holds otherwise ohm !, in yes 1.8 nv in dmgshn. " Shutters * ® «

WTO «fe.detoshsh th zhyae» 11.2 and dedezhdedeyate w PK.in _January 1ZHL7 dapti.dato and d "th" of 12% rym.

Krutta de ideertote her agusht is the act ¹ ® nv of the methodw _t mi nati edea »hundred,« tv tv dtltv se ^ zhzhetit tzzhiktsde® «dezut © t © zhzhadal vector, the grandfather PK40 ezde»% © is the tempam child gigretka smmerde "A predetection? Aunt will * tedev © © and proyatet e®" o "dam * deris tosevto *" e "daoetLoeda © pdaadest in © blvstt®. there was no decapitation ^ scept-test node w & w to pass that * w to be a dextde de rrtind wm.

The total of half a dozen dozen is a ptstst-g? yes ^ here

18 ,. In the tetd pdetetetgzhzt szh .ja * & it stelglvž yes ** ». Htz grandfather Ydede, deslesdevatelest is rvcow teething on detolptpt * '· is aunty» · the marriage area ia XC - ^ * 13Where you go ww duw * re daztder »» Fragments of -FML ^ grandfather to pglttta r error dea * yaydeatelstest »after the easel iv child © n, tobettle?

on taypa 12. Ydere, desdeedel! you will give, oiost1hhh ^ inflated by 5 * crede m «days 11.2 is wto not bhdzda with 5 -« paradise de naturally met proud ww de her antecedent © ©du odaendeya demodeooD | delta eadestC -i ₁ 1JJ _and 1JJ.

PI »XII * 3Ν · ι®№ · Μ№ΜΐύΜϋΉ№ amammnmm 1Nma ^ a ^ M £ F * goes ^ m ^ a d. Sche.jh ®vdede№shdeam Vf« roH »4» vnrW ^ wWWww * iwvT J ^ WTVn'fwT © ******* 'weOTl ^ y ^ B ι | ιΙ »ΐΗΠ> ΐίιι1ι®ΐιΜ · .1> | · ίι.ι | ιι · Ι | ~ ITIW Πΐιιΐ ΐ: -L n .iM ^. j ^ i> 4iWiiii | i TOWniW lnWΐι · «jQllliι.ίΐί» 1¾ ΙΠ »W ir: I Ίί .1111 '. 1Γ HU · ΊΓΓ .Γ.ίίίΙΙρΗΙ— tynmoMi * «w» ^ ^ ^ де де ν ν ν IHM? 1tsh * t n «ukdeotizht tddemghey ^ st ^ fatness g» o * dere e®, compared® about devdeemt · deededetdelet de 1 SLIL and CMM 2! ^ gourne 18 de 17 l

I ^ ghetetote pm®odet, where X € Ž $ hegeda is about ten o'clock

GOAL as with HJC ^ te and is LJ?., Seoondoanda de «thirsty rain * 87

ICAM. to 1CAM “a stagnant and rhm” and the first Dora W / and to the fourth and fifth regions and »OM, as well as the trashbrusht to rf you were reaped from the stojamadamt area m OM / ituri 13 and 14 L depmgztelnc the dashiat © memo? * daiag tv5L »needle« iia1, | ® »n de oa ide®» ® or C5®z * on the tap, obtained by »XAM.Biachit. live * lifeMG is tbjjzh zzhdg ICA & 3 and last areas of 1AM / youra 1? L 11 »e la veshlevai aa pnvtatshyu" makeup not bib * zhitzhi. " / the article is that ml »at the same time prepare sJ ^ ixer * you from the oj © 7 de? _in 4 Lhette not toia »» ož <deuieazo is tzlatz and «divvt, the deltmt nmtso with deej ^ deemer not but izhk * fidaraio.

/ 1 / OAVD

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prluo'iF, T'wsmy A.

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Claims (48)

1 ICAIvL-3 or its Fuchppuchall 'π-χν -tu -, -, -ο er'oc' ^ r are free OT at Native -ΌΓίΤΑ? · ΗΉ ^Τ ! ^Γ 'Ή. 2. A recombinant mole is a pool capable of 1Ca or its functional arbitrary. 3. A reconbinant molecule DO- according to that of Essence 2, which is additionally capable of transmitting GS-An-3 into its Functional Derivatives into a cell. ** 4. An antibody or antibody fragment capable of binding to a molecule selected from the group consisting of K3-3 in non-functional functional derivatives. 5. An antibody according to p ^ is ~ et.uya 4 wherein svtpzl ⁰ -duo ^yy and eject the antibody bound to said molecule uvrelda ability of that molecule to bind to a receptor molecule. The antibody of claim 5, wherein said receptor is IPA- ₁ The antibody of claim 5, wherein said receptor is a MAC-1. The antibody of claim 5, wherein said receptor is p150.95. A hybridoma cell capable of producing a monoclocal antibody according to claim 4. A method for producing an> desired hybridoma cell to produce an antibody capable of binding to the Xcd-3 -differential derivatives thereof, which includes the following steps ^: -immunization of u with the purified - fusion of a splenic animal with a bee) nteuu * 90 - line, © / but allows fused splenocytes and malfunction cells to reinforce a hybrid cell, secretion antibody, and o / scrvffan® cells to produce the desired hybridoma cell capable of producing the desired hybridoma cell an antibody that folds a 3Z, 11. I. Mvtod va M $ D | ^ LIRVL® HBR KJWHFSW ΗΜΎ® ^ B & I & HCHIP ^ HE ^^ YAZhIv * that get shitty: tweet from HZDM, wtwm | providing aa. yeah, it needs treatment and it has an effective IC> Lp agent, which from its own guard is selected from the flu, consisting of> an antibody capable of binding to HCl | a fragment of this ayuttle, which is also capable of bonding to it 1JJ »3 | 1SJ4 | its funnadonal leads and monkey globulin w antagonists of 1SH »3, more than 1SJ» 1,1CM ^ or members of the mD »18 family. 12. The iodine according to m-etoadia 11, wherein said XAMA-mediated biological fradsch responds to inflammation and said ICAM modifying agent is provided to the foam subject in an amount sufficiently supplemented by inflammation. and. ^& w © e as claimed in claim vc, wherein the inflammatory response to the specific inflammation in response w. conditional, selected by the group, including * an immediate type of cognitive impairment, a symptom of a contractual illness, an organism weaving rejection after a traumatist. 14. » ^; etode according to claim 13, wherein said organ is a paid owbhob trisplant. 15d yetod »weighly weighed 14, but ergenic transeguntant is a kidney * 16. Ytsd, according to claim 1, wherein the tracer is 91 * tai is a soft-wobbly traonplant. 17. The method of claim 18, wherein the graft «KOSTOV Yu8UL, 18. The method of claim 13, wherein said azoimmune disease is selected from rhinosodium, an ectopus erythrocyte syndrome, autoimmune thyroiditis.VD, ultrasound sclerosis, rheumatoid arthritis, and lupoid epithedosis. 18, Mtod claimed in claim 13, wherein the response to the inflame of our disciples ignited in response w to a selected "from a group illuminating ee from t syndrome of disturbed infant age" (Dbb), multiple orchestral lesions, secondary to fir , trauma iz hahoragnl, ruf »rfudao« to damage the bladder and other d & d, acute gdrmerulonephrosis, reactive arthritis, dermatode with acute vapazhezhya k <zpoyent, a.kutsu tsurulentzh yav · vyadvayut the other systema e.g. blow /, thermal damage, let's get ₉ dafeferezh, platoon of colitis, Zoleet ia Sgo ^ unbearable entoroiozhzh, aoo There are three cases of GFR syndrome and CNV toxicity. 20. '' iodine, according to pretester 11, raw® XSMM non-essential Fuyadshta are meta-methas to give da tatic tumors 'cells, these cells requiring a functional member of their DM * 18 molecular seed and a specified agent to be provided' for the subcold entity in the body. .a sufficient effect on these metastases. 21 · A method according to example 11, wherein the W2M mediated biodegradable &quot; grad * of infection &quot; with leukocyte pyrus and indicated &quot; ICM-3 modifying agent is introduced into the subject having the same name in a &quot; • 92 · sufficient to suppress migration then The method of claim 21, wherein said viral and erythrocyte cells are infected with 23, M®tode according to Pg. 1L, wherein the biological funnel is a building block with an asthmatic etgogor, and said ICAM moduder agent is provided with up to eleven subjects in a child. 1 «that city. Method. * suppresses »the infection of yatdet by which this method involves introducing &quot; subject exposed to HIV &apos; s infection to an effective growth from an NGM and a fekionic suppressing agent selected from a group that is capable of. © is too high for 1SJ3, then who de pendetao s this antitodeTergent of the antibody capable of binding to the .mu. Toxidate derivative of this fragment! 1 ^^ M | fungus where produced © w ICAM-3 | deu-uno ^ deve antvdedeot ma G »M3, other than LSM _t ICAM goes to a member of the SD * 18 delenulde family, • a toideide derivative of that member and ® SDIZ of the milk family · 25. The method of claim 24. wherein said NP _& NF! 26. the development decadent decoder ICAM is a tuderde cell that vyuadade provides »de subject needs treatment of an amount of said.dastadayu to be said • is a development, this being selected from the group consisting of * antibody capable of binding to 1SCL | togeide derivative of this antibody frepende de this antibody, wo this '^ region' is capable of g eder® is ICAM | todeidesh tshmsh) de toS an · yapsh fragm®nt | toxi? y? de member of the C / M8 moduvulito titular union and the "active production.sh® tefutashosh" at the same time as a member of the ShM8 gluteal family. 27, Step aa suppress the restriction of P * A »1 * hedgehogs» breakthroughs and tmshorsh daughter, have a secured provision for the subject in need of similar treatment for the growth, want to feed growth, want mw is selected from lute. you are composed of ICAM-3 tenogranium and the totein arbitrary ICAM ratio. 28, Method according to any one of 11 to 27, w which method additionally introduces a hedgehog? eat press agents, yudrebi from the group, consist of · 1JW1 | 9JAMI> but to connect is OM, frat to this piece? liu, because this Frag ment is capable of maturing »is IFM, nvg ^ n & global antagonit aa% »1 _t antibody capable of being transfected with -WM-g * Fragment to tov ^ w * heavy, then this Fragment is capable of eud it» »e & G <4, act ,. able to bind O & AM-2 is not that enthase, "this Fragment is capable of ever with 1SDM" 2. 29, The method according to howl ν pa is from the third-order 11 * 27, lmto G. 3 master agent is introduced entorate. 30, according to any one of the preceding 11 *? 7, as well as ^ic AM • 3 the oodularate agent introduces prophylaxis. 31d A method according to any one of heavy 11 to 27, wherein the IOU3 breastmilk is ascending idamite, 32, A method according to claim 29, wherein the precursor medium is in the first instance condemned by interventions. 33, a composition, an intake agent, selected from labor, with- • V. is from * an antibody capable of contracting »is ^^ 3, F» gm to tone® antibody that this Fragment is capable of doing is ΙΟΑΚ / ς 1СЖЗ. functionally cultivated on HCSL * non-glutinous anta * - 94 * gonadal shk ^ elongated by 1SJ »1,1SJ2 and mm mm» SD * 18 family * 34. pharmaceutical composition according to P3, taiga sartar additionally and are emotionally suppressive. 35 »Schradevtic composition, see 1C $ M modradradelt agent from» «© and * is from theteads 11,24,26,27 mj 28, in the« Shomdeya about the grandfather in pharmvdezhzhsh »carrier. 36 &lt; 1 &gt; heparinyl composition according to spherolin 35, in deibibration with at least children other iunosuprolene aheite. 37. An X &lt; RTI ID = 0.0 &gt; rhepatic &lt; / RTI &gt; composition comprising a antibody and a fibrin thereof congests a pregandel 4 in a germicidal solvent in a carrier. 38 »Tea composition comprising a antibody to a antibody against the antibody according to Example 4 in the antioxidant protein 39. M utering the presence of a plethora, depreperating 1GAM, secrete the t a / myWfi of the identified cells between the null and viable sulfur in a nucleic acid molecule whose molecule is capable of clotting with 1 gAM. In this case, the said moleyou toide acid was hibshdderal and ish dmjtadaadaaa nyyyalamchode gsejia, a pststde in the given rhizome, and stripped of these deutsch. 40. Stod de devgdeetmder of hCG3-edet? Ssirvate tugariya oaths in bodeidec, which has seen a / introduction into the thirsty subject of a composition containing detectable hetichi, with a deg fragment, after which the conjunct is 1C3 and de / bind the deotone antibody to the targeted 10 * 3.. 95 A method for diagnosing mammalian inflammation, goiter includes t / a prbba containing a drunk of a given owt with a composition comprising an antibody coming from its fragment. It is able to bind a cleavage.expressing ICAM, and c / detecting the associated antibody dem specified cell. 42. Method for Deagdecirculating the Presence of g ICAM-3 ₈ Liquid Poultry. Taken from a Mammal.which includes biological and precision harvesting of a poultice taken by the subject with an antibody-containing composition capable of being coupled. to ICAM, _x in / detecting binding of said antibody to said fluid. The method of claim 42, wherein said fluid is selected from the group consisting of * blood, serum, plzma, sitsuvial fluid, aioutic fluid is urine. 44. A derivative according to claim 1, wherein the derivative is a fragment of Southeastern, A fragment according to claim 44, which is selected from the group consisting of * 2.4b, The functional derivative of claim 2, wherein the derivative is a fragment of said LC molecule capable of de vedpalCAMi The fragment of claim 45, which is selected from the group consisting of §2. <5 _and 5. 48% by weight, <kg right claim 44, which is selected from the group consisting of X 1, 1-1-2, X 1-3 &lt; 14 &gt; 49. A method for identifying agents capable of modulating 1HL3 binding to HEM, comprising the step of contacting - 96 ICAM-3 o IM in the presence of the indicated agent and measurement of modulations of 1J3 / I * M binding. •, -g 50 · ^y ETHOD of claim 49, wherein said IL saglpsno · 1 designating it HOSH-3 oa purified is removed view "of the naturally occurring dontaminanti. 51. The method of claim 49, wherein said MI is expressed on the cell surface; h is said HCl3 purified from naturally occurring contaminants. 58 · A method according to claim 49, wherein said I6AM is expressed on the cell surface in said IM is purified from non-amorphous metamorphoses.