JPS62500025A - Polypeptide agents for immunotherapy - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Polypeptide agents for immunotherapy Background of the invention Antibody production is a highly protective response in vertebrates. Molecular factors that stimulate antibody production (e.g. virus particles) are called antigens. When an antigen is introduced into a higher vertebrate organism, Specific method B: Stimulation of IJ9 bulbs and antibodies that specifically bind to the antigen to prevent its further proliferation or otherwise immobilize it. antibodies and The study of its interaction with antibodies is a branch of immunology.

Antibodies that circulate in the blood or other body fluids are called humoral antibodies and are Distinguished from the salivary "membrane antibodies" that are bound to the spheres. The term immunoglobulin Used to generically refer to all antibodies. All immunoglobulins in humans are divided into five classes termed IgG, IgA, 1:gM, IgD and IgE2. Can be divided. Each immunoglobulin molecule is composed of two pairs of identical polypeptide chains. There is.

They are called "heavy chains" and are also known as gamma (γ), alpha (α), and mu (μ), respectively. , delta (δ) and nib70n (ε), the larger pair is labeled for each immune group. It is unique to each class of robulins and is characterized by the disulfide p (s-S) bond between each chain. connected. Each heavy chain has approximately 400 to 500 chains linked by polypeptide bonds. It is composed of amino acid residues. In contrast, each light chain has approximately 200 amino acids. It consists of an acid and is linked to the heavy chain, usually by one disulfide bond.

In 1969, GGrald Kdelman identified the amino acids of the entire human EGG molecule. The sequence was first determined. Both heavy and light chains are homologous units approximately 100 amino acids long. In other words, they discovered that they are organized into "domains." 4 other immunoglobulins Subsequent sequence analysis of the classes revealed that they were also structures with different amino acid sequences. It has been demonstrated that the organization is mainly organized around similar targets. both light and heavy chains The first, but not all, amine-terminal domain is a distinct domain within which considerable changes in amino acids occur. It has an area where it can be used. These domains are therefore referred to as variable MY domains, The heavy chain is represented by vH, and the light chain is represented by ■L.

The molecular associations of the L and VH domains within the intact immunoglobulin result in a highly An antigen-binding site is formed that can bind to a specific antigen with compatibility. of all light chains The main structure is the same regardless of the heavy chain class associated. Each light chain has two domains. one is the vL domain, and one is invariant and light, i.e. It is a domain with a relatively unchanged amino acid sequence called CL.

The heavy chains, on the other hand, have three chains called CH], CH2, CH3, and CH4. (), EnggA, In) or 4 (1gM, IgE) constant, i.e. C domain and one variable domain called vH. Or again C domains are labeled according to their stalwart class; i.e. C,4ii:I gE (nib/ron) le, button C) (indicates 4 domains.

Visualization of antibodies by electron microscopy or X-ray diffraction reveals that they have an rYJ shape. It is clear that this is the case. Furthermore, IgA and IgM antibodies each They combine in groups of two and five to form dimers and basic Y-shaped antibody monomers. and form a pentamer.

When antibodies are exposed to proteolytic enzymes, e.g. A few major fragments are generated.

The fragment that retains antigen-binding ability consists of the two “arms” of the Y-configuration of the antibody; Fab representing two Fab arms connected by disulfide bonds (flag ment-antigen binding) or Fab'2. The other main flag to generate The ment constitutes the “tail” or central axis of the Y, and it crystallizes from solution. It is called Fc (fragment-crystalline) because of its tendency to be easily crystalline. 1:gG , A, M and D Fc fragments are located between the two carboxy-terminal P-methods of each antibody. In (i.e., CH2 and CH3 in Engineering gG, Engineering gA and Engineering ED, IgM consists of a dimer of CH3 and CI(4). this On the other hand, the engineering gB Fc fragment has its three carboxy-terminal head domains (C 62, Cε3 and C54).

Fc fragments also allow antibodies to "communicate" with other immune system molecules or cells. production of antibodies, which can activate or modulate immune system defenses. Contains a physical "active site". Such “contact J” is the active site within the antibody domain. occurs when the Fc receptor binds to a molecule called an Fc receptor.

Fc receptors target molecules within the immunoglobulin Fc region with high affinity and specificity. A molecule that binds to a child active site.

Fc receptors exist either as integral protein mimics in the outer plasma membrane of cells or as , may exist as free "soluble" molecules circulating freely in plasma or other body fluids .

Each of the five antibody classes binds specifically to a particular class of Fc region and has distinct There are several types of Fc receptors that perform distinct functions. That is, engineering gE FC receptors have high affinity for IgE Fc region only or isolated It binds to the isolated IgE Fc fragment. Try to recognize various positions within the Fc region. It is known that there are various types of class-specific Fc receptors that bind to these receptors. ing. For example, some IgG Fc receptors are activated by the second constant domain of IgG (C receptors that mediate other immune functions are the third invariant of IgG. Binds only to domain (CH3). Other IgG Fc receptors are CH2 and It binds to the active site located in both the CH3 domain and the isolated Cannot be combined with main.

Antibody Fcg4 Area Active SiteActive SiteOnce activated, Fc receptors activate various important mediate immune-killing and regulatory functions. For example, certain IgG Fc receptors mediates direct ligation of antibody-bound cells via its Fab arms [antibody dependent cytotoxicity (ADCC)). Other IgG Fc receptors When it becomes more occupied, it stimulates the white blood cells in certain cells to become finer cells through a process known as phagocytosis. It takes in and breaks down bacteria, viruses, cancer cells, or other things. B IJ ball The Fc receptors of certain types of white blood cells known as Regulates growth and development into follicles. Basic staining cells and mast cells (mast cells Fc receptors for engineered gE, located on certain white blood cells known as When occupied by cross-linked IgE, it causes allergic reactions characteristic of hay fever and asthma. cause.

Certain soluble Fc receptors that are part of the blood complement system are Initiates an inflammatory response that can kill cancer cells. Other Fc receptors are Collectively known as lymphokines that stimulate the white blood cells of the body and promote immune defense. secrete potent regulatory or cytotoxic molecules. These are activated by antibody Fc receptors. These are only a few representative examples of immune activation mediated by the immune system.

The active site within the Fc region can bind to Fc receptors and activate them because the antibody It binds to antigen but only after undergoing agglutination in some other way. Therefore, Fc receptors are the critical link between antibodies and the rest of the immune system.

Therefore, binding of Fc receptors to antibody Fc region active sites is mediated by antibody function. It can be characterized as the ``final common path.'' Antigen-binding antibodies are Fc receptors If the antibody does not bind to the immune system, it cannot activate other parts of the immune system and Therefore, it is functionally immobilized.

All peptides that have the ability to bind to immunoglobulin Fc receptors Because of its ability to modulate capacity binding, it is therapeutically useful as an immunomodulator. Fc like this Receptor "blockers" occupy the immunoglobulin binding site of Fc receptors and ``short-circuit'' the activation ability of immunoglobulins.

Summary of the invention Most of the amino acids that make up antibodies form the antibody structure, which is a highly regular three-dimensional shape. It functions as a determining molecule “scaffolding”. some a Proper exposure and spatial positioning of antibody active sites consisting of amino acid clusters It is this skeleton that performs the critical function of feeding. Specific according to its function The active site of the cell may already be exposed and therefore available for binding to cellular receptors. There is a potential. Alternatively, the specific active site may be hidden and the antibody binds to the antigen. Only then can the backbone change direction and subsequently expose the active site of the antibody. There is. The exposed active site is then placed on the cell surface or on a molecular molecule (e.g. binds to its specific Fc receptor located as part of the complement Causes immune activation.

The function of an antibody's "skeleton" is that its active site binds to cells or soluble molecules. The active site of the antibody is isolated and positioned to hold and position the peptide. Synthesized as 71/? − In some cases, the entire antibody molecule performs an immunomodulatory function. Wear.

The active site is conjugated to a specific type of Fc receptor. , can stimulate or inhibit immune function. Fc receptors act by binding to the Fc region. or the Fc active site. Stimulation has the potential to occur if the peptide stimulates its receptor. resulting thorns The most severe types include (but are not limited to) antibody Fc regions - Fc receptors. Functions that are mediated directly or indirectly by body binding are included. This kind of functionality Examples include (but are not limited to) certain classes of white blood cells ( Stimulation of phagocytosis by morphonuclear neutrophils, monocytes and macrophages:)); macrophages Diactivation; Antibody-dependent cytotoxicity (ADCC); Natural killer (NK) ) Cellular activity; proliferation and development of B and T lymphocytes and lymphocyte-mediated Caines (molecules with killing and immunomodulatory activities) are included.

The ability to stimulate immune system functions, including those listed above, may be due to bacterial, viral or fungal origin. infections caused by the disease, conditions in which the immune system is deficient due to congenital or acquired conditions, cancer or and many other human or animal diseases. It is known that Such immune stimulation is also administered as a vaccine the body's defensive cell and antibody responses to certain substances that are injected or orally administered It is also useful for promoting This description is intended to be all-encompassing. of a disease or condition for which immune stimulation has achieved therapeutic utility, rather than simply A representative example is shown.

The active site waves are not activated by mere binding to the Fc region. Inhibition of immune system function can occur when binding to certain Fc receptors. child Different Fc receptors are usually used for several functions within antigen-antibody aggregates or immune complexes. The Fc region binds to several Pc receptors simultaneously and cross-links them. ) becomes ``activated'' only when it is brought into a ``activated'' state. Not like this Cross-linking of Fc receptors by several Fc regions may affect the activity of certain types of Fc receptors. It appears to be a critical signal required for sexualization. Binds to such Fc receptors and by blocking it, the active site waveforms are activated by immune complexes or anti-antibiotics. Prevents the Fc region within the original antibody assembly from binding to the receptor, thereby It comes to prevent receptor activation.

This ability to block immune system function can be caused by allergies, autoimmune diseases such as rheumatoid arthritis, etc. and systemic lupus erythematosus, certain kidney diseases, inflammatory bowel diseases e.g. enterocolitis and focal ileitis (Crohn's disease), certain inflammatory lung diseases e.g. idiopathic lung Fibrosis and hypersensitivity pneumonitis, certain demyelinating neurological diseases such as multiple sclerosis autoimmune hemolytic anemia, idiopathic (autoimmune) thrombocytopenic purpura, certain endocrine disorders such as Grages' disease or Hashimoto's goiter and certain heart conditions It is known to be therapeutically useful in the treatment of diseases such as horse fever. Ru. Immunosuppression may also occur due to organ transplantation or certain types of leukemia. The harmful immune “rejection” response that occurs during bone marrow cell transplants used to treat benign anemia It is therapeutically useful in preventing symptoms. What is listed here is not exhaustive , a representative example of a disease or condition for which immunosuppression is known to be of dual use as a treatment. show.

The known active site of VeptiP detailed description In each section below, A! The amino acid components of peptides are shown in abbreviations for convenience. child These abbreviations include both D- and L-integrated, but L-integrated is preferred. Delicious.

L-methionine Met L-cystine Cys L-phenylalanine Phe L-tyrosine Tyr L-tryptophan Trp L-histidine Hiθ Amino acid abbreviation L-asnoξlagic acid Asp L-Asuno? Ragin Asn L-glutamic acid Glu Carbobenzoxyamino acid 2-amino acid N-acetylamic acid Ac- Amino acids■, complement-inhibiting peptides The classical pathway of complement activation is activated and begins with the first complement component CI, C5, Ends with the "attack complex" of cells consisting of C6, C7, C8 and C9 It consists of a group of plasma proteins that form a biochemical series. of its activation/ The ♀ turn is highly specific, with C1 being either engineered, gGj, or IgM antibody-antibody. The active site of the Fcg4 region within the primitive spine begins. of C1, called CIq. The small molecular unit is χ・J and contains six identical Fc receptors. Ru. CIQ is not tethered to cell surface membranes and exhibits its biological activities (cytolysis and inflammation). This is an example of an I′iT-soluble-IP″C receptor that activates complement activation, which leads to disease. . Amino acid residues that contribute to the Fc active site for C1q in human egG, It is localized in co2 F main. Mr. Johnson and Mr. Thames, [Journal of Immunology 10G (y, Immunol, ) 117.1491 (1975)] and Pokle ( Boackle), Johnson (John day on) and Coma 7 (Ca. ughman) et al. [Nature, 282°742] (1979) ] is ]274-28 aa (amino acid sequence) (Lye-Phe -Asn-Trp-Tyr-Val-Asp-Gty) in h) IgG1 Bobuti12, which has a sequence derived from cH2, has been shown to be adsorbed to red blood cells. They found that it has substantial complement activating ability when used as a protein. In particular, (Lye -Aza -ASp -Trp -Tyr -Vat-A[]p-Gt7) Peptides with an aa of 1gG It was almost as effective as the immune complexes formed by

The aforementioned researchers attributed this activity to the active binding site of the peptide to the C1qFC receptor. This is based on the ability to work as a senior official.

In this IgG region, or in the CH4 aa 487-491 region (Gz Other syntheses with sequences derived from u-Trp-Met-Gtn-Arg) Petide, e.g. Lys-Phe-Asp-Trp-Ala-Va-Asp-()lyLys- Phe-Glu-Trp-Tyr-Val-Glu-Gly-Val-Glu- val-Hls-Glu-Ala-Lys-A]-a LysPro-Gly -ArgTrp-Tyr-Val-Asp-GlyLys-Tyr-Asp-T rp-Tyr-Val-ASp-GlyTyr-Asp-Tyr-Tyr-Va l-Aep-GcoyLyS-Phe-ASp-Ala-Tyr-Val-AI3 p-GlyZ-Vaney Glu-Trp-Gly Tyr-Van-(34u-Trp-Guy-G, 1u-Arg-GlyGLu -Trp-Tyr-Glu-Arg-GiyZ-Asn-Trp-Tyr-Va ] Tyr-Glu-Arg-Gcoy Z-Glu-Trp-Tyr-Glu-Arg-011 os less active = while Trp-Leu and Tyr-Gtu-Ata-G zy was inactive.

After that, Mr. Prystoweky et al. [Biochemis] Lee (Biochemistry), 20.6349 (1981),: 1 and Mr. Lukas et al. [Journal of Immu/Cl. , Engineering mmunol, ), 127.2555 (1981)) is aa28 ] to 292 directly adjacent CH2 regions are inhibitors of C1-mediated hemolysis. It was demonstrated that In detail, Ip;G, CH2 residues 281-290 (Gly-Val-Gln-Val-His-Asn-Ala-Lys-Thr -Lys) and aa 282-292 (Val-Gln-Va knee His -Asn-Ala-Lys-Thr-L7E+-Pro-Arg-OH) The peptide had approximately the same activity as the complete monomeric IgG as an inhibitor. other Peptide, i.e. aa 272-290 (Phe-Asn-Trp-Tyr -Val-Asp-Gly-Val-Gln-Val-Hls-Asn-Ala -Lye-Thr-L7S), aa 275-279 (Ac-Phe-A 8n-Trp-Tyr-Vat), aa 289-292 (Thr-Lys -Pro-Arg) was less active.

Other researchers include Burton and Ujidera.

288, 338 (1980)) used other criteria to determine whether IgG, C1q binding We conclude that the site is located within -(2 residues aa 316-340). However, they did not report on the complement inhibitory activity of 3-peptides from this region. Not yet.

■, immunostimulating active site wave from engineering gG buti r tuftsin is Thr=Lyθ-Pr It is a tetrapeptide with the sequence Q-4rg, and all human 6G subclasses present in the second constant domain of the mouse and aa 289-292 in guinea pig IgG. There is. Tuftsin is phagocytized by granulocytes, monocytes and macrophages. by Mr. Nayar (Naj, tar) who discovered that it stimulates in vitro It was first isolated from a tan-Q digestate of G.G. ．． It is described in the specification of No. 426. Subsequent research revealed that tuftsin was found to be nanomole at concentrations in many organisms, including humans, cows, dogs, rabbits, guinea pigs, and mice. It has been shown to be active in species. In addition to its ability to stimulate phagocytosis, tufts The main factors are ADCC, natural killer (NK) cell activity, and macrophage-dependent - T-cell sensitization and T-cell-dependent and antigen production against antigens It has been shown to be stimulatory in vitro and in vivo. Tuftsin is a condylar By binding to stereospecific receptors on granulocytes, macrophages and phospho-9 cells It is thought that this effect is more effective. Analysis of these receptors reveals their number and It was shown that both cancer r dissociation constants are similar to that of the gG Fc receptor. has been done. Ratcliffe and Stanworth tanworth) et al. [Immunologica/L, -L/Meta-Immunol , Lett, ), 4゜21! '+ (1982) 'II and by us Recent research has shown that tuftsin is a human IgG receptor for human monocyte IgG Fc receptors. demonstrated that it binds to rgG Fc receptors by competitively inhibiting the binding, ing. Therefore, the immunostimulatory ability of tuftsin is due to its immunoglobulin Fc receptor is attributed to the binding ability of

B. Riggin CH2 and Co having the sequence G/, y-Gtn-Pro-Arg 3 domain aa: Located in the human egg G dipeptide region spanning 341-34fi A tetrapeptide analogue of tuftsin [Vere Tenikova] TennikOva et al., Int.

J’, Peptide Protej, n Res, 17.430 ( 1981)). It has phagocytosis-stimulating ability similar to tuftsin and is 4. :353.82: Described in the specification of No. 3.

C, Rainbow 1-residue immunostimulatory peptide In 1982, Morgan, Huguli and Mr. Weigle et al. (Proc, Natl, Acad.

Sci, USA, Disc, 5388 (1982)) 24 residues equal to IgG aa 3:35-358 with the ability to catalytically activate The sequence of the base peptide was reported. This peptide is used for z　l) clonal B cell expansion, Translating antigen-specific antibody responses and natural killer (NK) cell-mediated misconceptions i'yr: dshik. KotV-<Buchi IF (Thr-11e Ser-Lye-41aLy　-G　1y-G　In-Pr　o-Arg- G　u　u-P　ro　-G4　n-Va　1-Tyr-Thr-L　e　u　 -PrO-8er-Arg-Glu-Glu-Met) and carboxy terminus N-residue peptider lacking methionine binds to lymphocyte Fc receptors for IgG. It is presumed that this works by

In 1975, Clccimara et al. [I Proc.

Natl, Acad, Scj, USA, 72.2081 (197F i))) is a human monocyte IgG that can inhibit IgG binding to Fc receptors. reported the sequence of the decapeptide from human IgG. This sterile r is IgG aa 4Q7-41fi (Tyr-8er-Lys-Leu-Thr-Val-As p-Lye-8er-Arg). On the other hand, Stanworth (Sta (n-worth) said that it is true that this peptide can inhibit monosynthetic gG binding. I couldn't prove it. However, he found that this Takubuti r was a macrophage agent in mice. gG was shown to inhibit human egG binding to Fc receptors [Stanwo In 1982, Ratcliffe and Stanworth Stanworth et al. [Immunological Letter (Immunol. , Lett, ), 4.215 (1982)] is an IgG aa29 5-301 (ozn-Tyr-Asp-8or-Thr-Tyr-Arg) Equivalent peptides slightly inhibit IgG binding to human monocyte IgGFc receptors I have proven that I can do it. For this Jl, IgG, Cn2, aa 289-301 The related Vepti 12, which is equivalent to the residues in Igc), had no single-acting Igc) inhibitory activity.

In 1975, Mr. Han/ζ- (Humburger) IgEC, 3 Derived from aa320-324 (Asp-3er-Asp-Pro-Arg) Ribbon ivy takubuchi 1, which has a suru arrangement, causes a local skin allergic reaction. -kyu77. Tunnel (Prausnj, tz-Kust-ner)] is about 9 0f) Reported that it can be inhibited [)・Nberger, Science, 189.3 1'19 (1975) and U.S. Patent Nos. 4,171,299 and 4,16 1,322 Specification]. This peptide was then used in humans after injection via the subcutaneous route. It has been shown to inhibit systemic allergic diseases.

Recent studies have shown that this peptide has a significant effect on the IgE FC receptor of human basophils. Human gB-binding gold 7 has a strong affinity for basophilic gE Fc receptors. Mr. Plummer has demonstrated that it can be inhibited by up to 0%. etc., Fed.

Proc, 42.713 (1983)). conopeptitonimilarerhi The ability of Takuputide to inhibit systemic allergic diseases is due to its cellular IgE Fc receptor. This is due to its ability to bind to the body. [Mr. Hamburger, Advance P. Arago Rosie Ann r imix / o no (A(), V, Allergology engineeringmmuno1. )=　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 on Proc8: New York).

(1980), pp. 591-593).

B, hexapeptyl from human gE In 1979, Mr. Hamburger developed Cs2 aa 476-41' (1 (Pro- Asp-Ata-Arg-His-8er) In the Lin-R blastoid cell line (wtt-2Wt), [Hanno Z-Ger, Immunologist] Immu-nOIOl, 38.781 (1979)').

This Takubuti r has already been shown to inhibit the binding of engineered gE to human basophil IgE Fc receptors. (U.S. Pat. No. 4,161). , No. 522 specification).

v2 Hi) Other bioactive waves from IEK In 1982, Stanwo Mr. Stanworth (Mol.

Im+r+uno1. , 19.1245 (1,982)') is human I ( gK (7) aa505-515 (Val-Phe-8er-Arg-Le Sequence equivalent to the part of u-Glu-Val-Thr-Arg-Ala-Glu 125 IgG against mouse macrophages reported that it significantly increases the binding of However, this VeptiR and Fc receptor No interaction with the body was demonstrated.

In 1979, Stanworth et al. 495-506 (Pro-Arg-Lys-Thr-Lys-Gly-8e r-Gly-Ph e-Ph e-Va mini-Ph) Certain rod peptides and their smaller derivatives are found in humans and rodents. granule reduction in mast cells, thus making it suitable for allele desensitization therapy. demonstrated the potential to be useful (Biocbem, J., 180.665 (1979); Biochθm*J-+i81゜623 (1979') : and European Patent Publication EP 0000252 :).

However, these peptides may be affected by binding to immunoglobulin Fc receptors. There is evidence that it acts by inhibiting IgG Fc receptors on neutrophils. Previous attempts to isolate or synthesize peptides capable of Ru. Obtained by enzymatically or chemically degrading IgG7 Studies testing fragments for Fc receptor inhibitory activity revealed that the complete Fc fragments as small as υ have no measurable Fc receptor interaction. It has been demonstrated that there is no indication at all. [Barnett-Foster Foster et al., J.

Immunol, 120.407 (1978) Starr et al., Mol, Immunol, 19.407 (1982) ].

Total isolation or Previous attempts at synthesis have been uniformly unsuccessful. Decompose gE enzymatically or by chemically decomposing the fragments by other methods to obtain Fc receptor inhibitory activity. Studies that test for sex have shown that complete Fc fragments as well as small fragments are It has been demonstrated that the fragment shows no measurable IgF:Fc receptor interaction. It was proven. (Mr. Takateu et al., J, Immunol, , 114.18: U8 (1975); Immunological Review (Eng. Mmunol, Rev. ), 41, 3 (1978); Pere z-MOn, tfOrt) et al., Mol Engineering mmun, ol, 19, 11.13 (1982)].

Detailed description of the invention The present invention provides a method for producing gc! -For FC receptors ) Binding of IgG immune complexes, monocytes and macrophages: ) (MM) and its EgG and EgE on other leukocytes Eg, G and EgE to Pc receptors A novel and useful sequence of Takubuti P that can inhibit the binding of immune complexes is described.

Another objective is to develop such novel and useful peptides and their analogs and How immune complexes and derivatives contribute to the pathogenesis of certain human diseases. The purpose of this article is to describe whether or not it can be used for the treatment of. For such diseases (this (but not limited to), rheumatoid arthritis, systemic lupus erythematosus glomerulonephritis, serum sickness, polyarteritis nodosa and other forms of vasculitis, and Other diseases listed under the comprehensive category of "autoimmune diseases", idiopathic pulmonary fibrosis , pneumoniasis hypersensitivity, asthma and other diseases and conditions.

Another purpose is how such a takuputide can be used to treat certain autoimmune diseases. autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura, respectively. The purpose is to describe how such decomposition of red blood cells and platelets can be prevented.

Yet another objective is how some of these peptides can be Other classes of leukemia that enable Unatakudetide to perform additional therapeutically useful functions. Describe whether it can bind to Fe receptors on spheres (phospho-9 cells and basophils) There is a particular thing.

Other objects and advantages of the invention will become apparent to those skilled in the art from the foregoing and following description of the invention. It will become clear.

PMNs and MMs (71 cells are immature macrophages) are responsible for most acute immune responses. It is generally recognized that large numbers accumulate at sites of epidemiologically induced tissue damage. . These cells are not just passive "bystanders" in the inflammatory process, but rather , has recently been recognized to directly contribute to tissue inflammation and destruction. PMN For example, proteolytic enzymes and inflammatory mediators are all hidden in an attached, inactive form. The state contains cellular microtubules known as lysosomes. A keyaki condition Down below, PMNs and MMs are stimulated to transfer the contents of their lysonome to external cells. released into the environment, 7 leading to significant tissue inflammation and cell death. Such inflammation and Blast death is mediated by various biologically active substances. PMN and MM litho, no Muscle granules contain many different proteins that cause direct destruction of cartilage, connective tissue, and cells. ξ-degrading enzymes and glycolytic enzymes (i.e., sulcolagenases, which degrade collagen; Elastase, which breaks down ethistin, breaks down chiru seed type carbohydrate polymers Contains phosphoryme, etc. Some of these enzymes are found in the blood Can activate the coagulation system or inflammatory mediators such as bradykinin or complement . Other important inflammatory mediators released by PMNs and MMs include a variety of potent Prostaglandins (PGs) and leukotrons that have inflammatory and immunomodulatory effects Lien (LT) is included. Some of these actions are listed below along with their effective substances. Raise it.

1) Prostaglandin g2 (pGE2)...PGK2 causes vasodilation, erythema, Increased vascular permeability, edema (swelling), and the inflammatory effects of histamine and pradikinin enhances pain-producing and pain-producing effects, and inhibits leukocyte activation induced by bacterial endotoxins. stimulate collagenase production [Ku, et al., Science , ■, 978 (1980)).

PGE2 also has a strong immunosuppressive effect and mediates NK and ADCC. cancer cell killing effect, T cell colony proliferation, delegated granulocyte-macrophage stem Clonal expansion of cells and antigen- and mitogen-induced 8972 Maturation of spheres into antibody-secreting plasma cells can be suppressed. pox2 is also short-lived T-zapretzerin l1 bulbs (they suppress other defensive immune functions with it) ) can be activated directly. The immune system mediated by such PGK2 Suppression appears to be important in producing the immunosuppression that often accompanies various forms of cancer. [ Mr. Gutdwin ()ood-win, C11n, ImmunOl, Eng. munopath, , 15.106 (1980); (0rollor ) et al., Ce1l, Immunol, 39.165 (1978) i Leung et al., J. Immunol. , 129.1742 ( 1982); Fischer et al., J. mmuno1. ．． 126.1452 (]981); Klein et al., Immu nol, 48.337 (1983) Goodwin ) et al., Cancer engineer mmu-nol, ■mmunother, 1 3. 3 (1980)].

2) Leukotriene C4 (LTC4), D4 (LTD4) and E4 ( LTB4)...These leukotrienes are responsible for many inflammatory diseases in various combinations. and allergic diseases, especially anaphylaxis, which is considered to be important in the pathogenesis of asthma. Constitutes a slow reactant (5R8-A). These leukotrienes are responsible for inflammation and On a molar basis, it is several hundred times more active than histamine in its effect on producing air and air preconstriction. ~ Thousands of times more powerful [Samuelsson, f. Yes, μ4.

568 (198:3)].

:3) Leukotriene B4 (LTB4)... Conoleukotriene is found in certain persimmons. It is one of the most powerful chemoattractants known for human leukocytes. It's human Produced from preparations of peripheral leukocytes, neutrophils, skin cells and other cells. L Both TB and 4 attract all the neutrophils and eosinophils that are present in large numbers at the site of inflammation. .

LTB4 still contains lysozyme-containing lysozyme from neutrophils, which directly mediates tissue destruction. Stimulates somal enzyme release. LTB4 has a high concentration in the joints where T and TB4 are involved. Rheumatoid arthritis and rheumatoid arthritis are involved in the pathogenesis of many inflammatory conditions. Estimated [Samuelsson, Science, 2 20.568 (1983); Science, 215.1382 (1982)) .

Immune complexes also directly damage PMNs and MMs to the tissues they contact. Releases highly reactive free radicals such as Sue Q-oxide anion (02-) [Weiss et al., Immunol, 129. 309 (1982); Fantone, J. Pat hol, 107.397 (1982)].

Of particular importance to the present invention is that engineered gG or engineered gE can be linked to Fab-mediated binding or IgG and IgP2-containing immune complexes that bind by passive surface adsorption (“complexes”). Phagocytosis (complexes, particulates and potent stimulation of cellular uptake and digestion) and subsequent release of enzymes and inflammatory mediators The fact is that it is a drug. Such stimuli are located on the surface of PMN or MM cells. The binding of the IgG or IgFi Fc region within the immune complex to the Fc receptor located It is known that it depends on the

The exact molecular form that the Fc region presents to PMN Fc receptors (e.g., or engineered gE antigen complex, thermally agglomerated engineered gG or engineered gE, which is absorbed on the surface of cells or microparticles. Dynamically adsorbed enzymes or enzymes (e.g., e.g., e.g., e.g., e.g., e.g., e.g., It is known that it is not important in causing release.

The critical factors common to these forms of IgO or gE stimulation are fixed and relatively The presence of multiple Fc regions in immobilized form allows for multiple PMN or MM Fc recipients. It is a point that simultaneously connects to the body. In this way, the Pc receptor is multiply bound. Ritz-Muenzyme 1 then triggers the release of inflammatory mediators.

Rinone mediated by immune complexes The release of mucosal enzymes or inflammatory mediators is associated with inflammation. and diseases contributing to tissue destruction. It is thought that RA lesions primarily occur within the joint space. not yet identified There are no agents or conditions that affect IgG and IgGM antibodies against the 'B'C region of IgG. Causes local intra-articular synthesis of the body. Such “rheumatoid factor (RF) (a type of immune complex) accumulates in the joint, and PMN gold-containing Kanakura blood cells and complement system Fc receptors. Such binding is linked to leukocytes in the bloodstream, especially PMNs. triggers an initial inflammatory response that attracts Large numbers of PMNs move into the joint space and There, R is responsible for rinsosomal enzyme secretion and subsequent cartilage and tissue destruction. Encounter the F immune complex.

Other white blood cells, including monocytes and macrophages, are also involved in inflammation through similar processes. However, PMNs often constitute the majority of cells present; It is also possible to exceed 25,000 PMN/. Works with PMNs and other cells and molecules to produce the tissue destruction characteristic of this disease Activating the complement system [Perez et al., text] Book of Ryumatorono (Textbook of iuxeumatoJogy) , Vol. 1. , Zone f-, X: Philadelphia (W, B, 5aun dera: Phi core adelphia.

1.981), pp 179-194.3 o Shida Taku Petit detailed in this invention Part of the process involves the production of IgG immune complexes against PMNs, monocytes and macrophages. can inhibit the binding and thereby reduce the inflammation and inflammation of rheumatoid arthritis. idiopathic by reducing or preventing tissue destruction and other immune complex-mediated inflammation Pulmonary fibrosis (IFF) is a condition in which the alveoli, which are the breathing units of the lungs, are normally thin and gas permeable. The wall becomes markedly thickened and replaced by a large amount of relatively gas-impermeable, fibrous connective tissue It is in a state of being given. As a result, the respiratory capacity of the lungs decreases significantly, and May lead to chronic lung failure and death. IFF is often idiopathic interstitial pneumonia , and rheumatoid arthritis, systemic lupus erythematosus, kyosei syndrome, and polymyositis. Dermatomyositis accompanied by interstitial pneumonia [Dryschiff (Drθ1-sin) et al., N, F Organization in jngl, J, Mod, 298.353 (1978) lo"" The final common routes to destruction include systemic or localized within the lung parenchyma. It is thought that an IgG-immune complex is involved [Law -rence) et al., N, En, gl, J, Med, 302.1187 (1980) l). Once immune complexes are localized within the lungs, PMNs and monocytes are It enters from the blood and accumulates in large numbers within the interstitium and alveolar structures. Next, monocytes mature into macrophages. develops into lophages and joins the normally present pulmonary macrophages. immune complex The gGFC region in the body then binds to PMN and MM Pc receptors and release of enzymes and inflammatory mediators, resulting in inflammation and alveolar destruction. Mr. Hunninghame et al., Chin, Immunol, Rev. , If31.337 (19R1-1982)]. As a result of the Kono process, “Keikon” "formation" and generalized pulmonary fibrosis. Some of the waveptides detailed in this invention are PM N, IgG-immune complex for IgG Fc receptors on monocytes and macrophages. It can inhibit the binding of coalescence and thereby cause idiopathic pulmonary fibrosis and other immune complex-mediated diseases can be reduced or prevented.

m, immune complex-induced glomerulonephritis The glomerulus of the kidney is a filtration device that separates plasma ultra-P fluid, which ultimately becomes urine, from the blood. It is a place. The glomerulus is formed by blood, immune complexes that accumulate as a result of the filtration process. susceptible to injury due to the inflammatory process initiated. Immune complex-induced glomerular injury early stage In , monocytes and macrophages accumulate in the glomerular vascular membrane where immune complexes occur. Meet the body.

The IgG Fc region in these complexes is responsible for the activation of these monocytes and macrophages. It binds to the GFC receptor and is stimulated to produce the aforementioned linome enzymes and Releases inflammatory mediators. These substances can lead to kidney failure and subsequent death. glomerulonephritis (glomerulonephritis) [Holnswort h) Mr. J, Eng mmuno1. ．． 130.7: (5 (1983) i-strike Mr. Kerr, J. Exp, Med.

-Length 19.127 (1979) i Hunsicke, r ), J.

EXp, Mad, 150.413 (1979)). Immune complex-mediated thread Globonephritis and resultant renal failure can occur, for example, in patients with systemic lupus erythematosus. [Mr. Robbins (S, L., Robbins) and Co., Ltd.] Tora 7 (R, S, cotran) payment, Saunders Co. (W, B, 5 under day) City of Philadelphia, 1979 Published by Kumar in Bang Kumar in Patholo gic Ba5is of Disease), p, 304). many others conditions such as rheumatoid arthritis, other autoimmune diseases, infections such as streptococcus or Hepatitis virus infections are associated with glomerulonephritis caused by immune complexes. Main departure Some of the peptides described in detail are the receptors of monocytes and macrophages. can inhibit the binding of IgG immune complexes to IgG and therefore immune complex-mediated glomerular It can reduce or prevent inflammation and tissue destruction caused by body nephritis.

■ Immune complex-mediated pulmonary inflammation of hypersensitive Pneumoniatis ( HP) is associated with exposure to a wide range of inhaled organic dusts and particles. It includes a range of conditions characterized by tumor interstitial and alveolar filling. The affected person is Synthesizes a relatively large amount of IgG against unpleasant inhaled dust, and still maintains IgG immunity within the lung parenchyma. produces a complex.

These complexes act as IgG Fc receptors on PMNs, monocytes, and lung macrophages. When bound to lysonomal enzymes, they are stimulated as described above to produce acute pneumonia. release substances and inflammatory mediators. If this process continues for a certain period of time, lung damage results in chronic granulation. It may become permanent in the form of interstitial pneumonia (Mr. Stankue) , Acolgologie, Sat, s(+qs+)). Book As detailed in the invention, some of the ξptide can inhibit the binding of engineered gG-immune complexes to GFc receptors, and This reduces inflammation and inflammation in Pneumonitis hypersensitivity and other immune-complex mediated diseases. and tissue destruction can be reduced and prevented to a certain extent.

■GE-immune complex-mediated inflammation in asthma Breath sensitizes lung mast cells and circulating basophils by IgF binding to FC receptors. Inflammatory, which causes them to release inflammatory mediators when exposed to allergens (antigens) It is a disease. IqE that has not yet bound to cellular Fc receptors is also a sensitizing allergen. 7) It is also possible to combine with Are known. Circulating IgE immune complexes are isolated from monocytes or macrophages. gE binds to FC receptors and releases various inflammatory mediators described in 1ifJ. You can make it come out. Furthermore, IgG against the sensitizing antigen is present. It may also produce a pseudo-G-Al/Aldane immune complex. child These complexes then release Ig ( ) can bind to Fc receptors and thereby inhibit rhinosomal enzymes and inflammation. Contributes to the release of disease vectors. Some of the putidos detailed in this invention include monocytes and macrophages. Inhibits IgK-immune complex binding to IgE Fc receptors on lophages and thereby reduce the inflammation characteristic of the pathogenesis of asthma and other diseases. can be reduced or prevented [Mel, ewickz et al., C. 11n, Bxp, engineering mmuno1. ．． 49.364 (1982) ;’/ Spiegelberg et al., Dan, 124 (1983) ); Scott et al., Fed, Proc, 42°129 (1983'): ].

Certain immune system cells recognize antigens on red blood cells as foreign and attack red blood cells. This autoimmune disease occurs when antibodies (usually IgG) are synthesized. This “anti-red” Hemocytogen gJ then opens its Fc region with its Fc region exposed to the outside of the red blood cell. ab binds to red blood cells via the antigen-binding arm (in ~ macrophages, and to a lesser extent To a lesser extent, monocytes also subsequently engage in such activation via cell surface IgG Fc receptors. Binds to IgG-sensitized red blood cells. The majority of such binding occurs in the spleen; As a result, phagocytosis and red blood cell destruction occur, resulting in anemia.

Some of the peptides detailed in this invention have been shown to be effective for IgG receptors on monocytes and macrophages. IgGFc-mediated destruction of red blood cells and subsequent Poverty can be reduced or prevented [Engelfree 1-(En-ku θ1f riet) Ujigu's A Seminar on Immunomedicine Aids 12 Cell. Destruction (A　Sem1nar　onImmunemediated, cell deirraction) pp, 93-13Q (19111J l), American Blood Bank Association Publishing, Wangton DC].

iTP is caused by circulating antiplatelet antibodies that lead to platelet destruction by phagocytic leukocytes. This syndrome is characterized by chronic thrombocytopenia (low platelet count). most cases In humans, the antibodies are of the IgG class and also contain normally present platelet-related antigens. It is for. Especially in the spleen, IgG-coated platelets are found in macrophages. Upon encountering platelets and monocytes, the exposed engineered gGFc region on platelets becomes a macrophage. Binds to the FC receptors of di- and monocytes, and stimulates platelets and monocytes. Stimulating destruction [McMillan, N., Bngl, J. , supra xea, 304.1135 (1981)). macrophages and Drugs that block IgGFc receptors on monocytes and monocytes have been shown to be effective in treating this condition. Are known. For example, Mr. Fehr et al. (N, F, ngl, J, Med,, Asia 6.1254 (1982)) Oyohiinhanoha (King) (Lancot, June 6, 1981, p. 122) 8) showed that intravenous administration of monomeric IgG to iTP patients significantly reduced platelet destruction. It has been demonstrated that it can be lowered. They attributed this observed effect to macrophages and their This is due to inhibition of IgG FC receptors of other phagocytic leukocytes.

Will it be explained in detail in the present invention? Part of Bubuti 2, macrophage and monocyte engineering Can inhibit Fc receptors and is therefore significantly more effective than intravenous Ig, G means improvement.

This is because Bobuchi-P is relatively inexpensive to produce and is less susceptible to infectious diseases associated with human blood products (e.g. This is because there is no risk of introducing hepatitis (hepatitis).

Vepti 12 disclosed in the present invention is effective against immune complex-mediated inflammation and tissue destruction. Therapeutically effective in the treatment of human disease as well as reducing or preventing damage. may have other important effects on the immune system that may prove to be .

As described earlier in this disclosure, the protein-gG complex binds to the protein-gG Fc receptor on monocytes. Together, monocytes contain prostaglandin E, which inhibits many important immune defense functions. 2 (PG 2). These inhibited functions include natural killer (N K) Cancer cell death effect of cells and ADCC, proliferation of 17773 cells and development, and granulocyte-macrophage stem cells and antigen and mitogenic factors. This includes the maturation of 131J cells induced by plasma cells into protective antibody-secreting plasma cells. .

Furthermore, PGE1 directly activates short-lived suppressor-lymphocytes and also acts on this receptor. The immune system can also suppress other protective immune functions. Therefore, monocytes: IgG Fc The anti-gG receptors described in the present invention inhibit the IgG immune complexes? Is that so? Their immune complex-mediated PGK2 secretion 1511 has a detrimental effect on 1511: You can expect to work.

Some of the anazotides according to the present invention also contain IgG and and/or the ability to impair the binding ability of Tgg immune complexes. like this The ability can be expected to be therapeutically useful in several ways.

■ Immune stimulation All antibodies are synthesized by plasma cells that develop from B-8 cells. Therefore , 73 The development of lymphocytes into plasma cells is critical for the production of protective antibodies. child Substances that inhibit the development of antibodies can lead to insufficient antibody concentrations and make humans more susceptible to infection. There is a possibility that the Of particular importance to the invention are antigens called immune complexes. The complex or aggregate of 33 and antibodies is said to be a strong inhibitor of lymphocyte development. That is true. Such inhibition is thought to occur by several mechanisms. However, in all of them, the Fc region of the antibody in the immune complex is linked to the phosphorus/Q cell Fc receptor. Requires combining.

One of the well-characterized methods of suppressing immune complex-induced B IJ growth is The IgG Fc region in the BIJ complex binds to the IgG Fc receptor on the BIJ protein/e bulb. Occurs when Such immune complexes contain two or more IgG Fc regions. Because two or more Fc receptors bind simultaneously, the antigen-antibody combination There is a possibility of being "crosslinked" (Figure 3). This Fc receptor cross-linking causes B IJ lymphocytes. Inhibition It is thought that total inhibition occurs [Ohherbar/Scheidt (0berbarn Immunol, 35.151 (1978) Mr. Kolsch et al., part of the B1772 ball It can bind to Fc receptors and thus prevent immune complex binding. Takubuchi I-'' do not cause Fc receptor cross-linking, so they are not mediated by immune complexes. 731J can prevent inhibition of e-bulb development. Kononami Una Wave Petido The clinical effect of this drug would be to cause stimulation of protective antibody synthesis.

Other mechanisms by which IgG-J or IgEFc receptor blocking peptides can stimulate antibody synthesis Immunoglobulin-binding factor (IBF) is involved in this. F was activated by 'll' from 1772 bulbs, PMNs and optionally monocytes and macrophages It is a soluble F'C receptor that is released. From IgG, F is B 1,17 no ξ sphere is a strong inhibitor of the development of antibodies into antibody-secreting plasma cells.

In order to cause such suppression, IgGIBF must first inhibit the Fc of the IgG molecule. % range, and it is necessary to bind to the molecular structure on the surface of the B IJ-2 sphere. available. When the binding of F to the IgGFc region is prevented, F1 becomes more IgG than F1. It is known that S-mediated inhibition ceases [Fridman et al. , Immunologica/l/・L/Bi, -L-(Immunol, Rev, ), 56.51 (1981); Mr. Bich-Thuy 1. T. Immunol.

Omi, 150 (1982)]. Therefore, it binds to more Fc receptors and Therefore, aptide, which inhibits this, also inhibits IBF-mediated BIJ inhibition. It is expected that. These scleroptides should cause stimulation of protective antibody production .

A third mechanism by which the morphids of the present invention can stimulate immune responsiveness includes T cell replacement factor (T It involves the regulation of a substance known as RF. TRF is an antigen or Under activating conditions, such as exposure to artificial mitogens, certain types of TJ2 bulbs (" secreted by ``Hell s-T cells''). TRF is then on B Lin 2 balls. It binds to receptors, which causes it to develop into plasma cells. TRF receptor is IgG There is considerable evidence that it also binds to the Fc region and is an acid Fc receptor. exists. TRF binds to the TRF/Pc receptor and thereby By preventing IgG immune complexes from binding to the same receptor, 3972 cells It is thought to stimulate development. This IN groove allows TRF to directly Stimulates the development of the bulb and prevents the inhibition of immune complexes on its development [Corsi Kolsch et al., Immu L/Oshikail, Immu Nol, Rev.), 49.35 (1980): l.

Some of the peptides described in this disclosure, similar to TRF, act on the B phosphoryl 2 bulb FC receptor. and therefore expected to share some of the immunostimulatory activity of TRF. be done.

■Immune regulation Interactions between the blood cells within each cell arm of the immune system contribute to normal immune function. It is necessary. Most immune responses are induced by T-phosphorus and antigen-presenting cells. caused by the interaction between In this process, 'l' IJ's appearance of two balls A 4-tab set has grown, Il, Per, Suppressor, Ind. or differentiate into functionally distinct cells that exhibit Giller talk. these cells can then participate directly in the immune defense, or other leukocytes, e.g. can activate the defense functions of macrophages or monocytes/macrophages.

A significant portion of these in vitro events are due to the autologous mixed phosphorus/ξ-globe reaction (AML). R). In AMLR, normal T lymphocytes/e cells are replaced by monocytes/macrophages. and stimulated when co-cultured with spheres in autologous non-TJ cells containing 3972 spheres. and multiply. This reaction approximates many of the cellular processes that occur during a normal immune response. Smolen et al., J. Imm. unol, , 129.1050 (1982) i-day care (Goeke n) et al., Hu, m., Immunol, , 79 (198:3) 1. Of particular importance to the present invention is that the engineered GG immune complex is a potent inhibitor of AMLR. It means that it is a drug. Immune complexes normally participate in the AMLR reaction. 772 directly by binding to their T177 gG Fc receptors. It is thought to have an inhibitory effect on two pitches [Kabelitz tz) et al., Kur, J, ■mmuno1. ．． 12. 687 (198 2):].

Total injection rhythematosus [Mr. Sakane (5akanθ) et al., etc.5. A, CHn, Investl, fi6. , 928 (1980)'], primary biliary liver cirrhosis Tames et al., J, Cl1n, Investl.

Town, 13+15 (1980)), Hodgkin Lin? Tumor [Engleman (E) ngleman) et al., Ding C Satin, Inver+t,, hJ 149 (1980): 1 and chronic phosphorus-Q cell leukemia [Sm1th et al. , J', Natl, Cancer Engineering,, , 58.579 (1, 977) :] K Contains h jZ autoimmune disease (bow, new disease patients AMLR is markedly suppressed, and this suppression is due in part to normal T-phosphorylation. sphere function It is thought that this is due to the inhibitory effect of the TgG immune complex induced by cancer. During the invention Disclosed: Some of the Szotides inhibit the binding of T-phosphorylated IgG immune complexes to B-cells. It is therefore thought to be important in the etiology of the conditions mentioned above. Immune complex-induced: (t1 damage can be prevented.

Namibuti 1, which inhibits the binding of immune complexes to Fc receptors, is a powerful drug against cancer. Cellular cells known to be important in protection against certain infectious diseases such as tuberculosis Alternatively, it can be expected to stimulate delayed type hypersensitivity (DTH). immune complex Experiments using mice have shown that coalescence significantly damages DTH [:l'-7e] (Douvas), Ann, Eng., InGt.

Pa5teur, 132 C,: 307 (198])) o Like this Inhibition is dependent on the presence of FCC sites within immune complexes that bind to cellular Fc receptors It is known.

11'l, immunity 1>l: i harm Antibody-dependent cytotoxicity (Ai'+cc) is 'l' 17773 cells, monocytes/ A process in which macrophages and polymorphonuclear neutrophils destroy foreign bodies or infected cells. Ru. IgG antibodies are targets that sensitize cells for recognition by ADCC cells. It must bind to the antigen on the cell. Upon encountering an IgG-sensitized target, the ADC The DingG Fc receptor on the C cell binds to the M-exit Fc region on the optical surface of the labeled cell. child Fc receptor binding activates ADCC cells and directly lyses their target cells. and kill it.

Chronic active hepatitis [Kochran+3] et al., Lancet.

1.53 (1973)] and other conditions that cause inflammation and organ destruction. It is thought that some of this is mediated by inappropriate cell death via ADCC. . Some of the hard butides disclosed in the present invention inhibit Lin Q Pope gGFc receptors. and therefore useful in inhibiting ADCC-mediated killing. This kind of closure The drug is expected to prevent much of the inflammation and tissue destruction characteristic of the aforementioned diseases. It will be done.

Peptides exerting a direct anti-allergic effect of the peptides described in the present invention Some have anti-allergic activity in addition to the aforementioned effects. gF2-mediated Allergies [i.e., allergic rhinitis (hay fever), asthma type, insect stings] Allergic reactions to wounds] are caused by the activation of gE through its Fc region in mast cells and It is produced by a mechanism of binding to IgE Fc receptors located on basophils and basophils. It is known that Causative allergy 7 (the one that first induced IgE production) antigen) is presented to such sensitized mast cells and basophils and cell-bound I When bound to gE, it is an inflammatory mediator that immediately produces the allergic reaction characteristic of allergy. debris is released. However, sensitized gE-, mast cells or basophilic Ig E If binding to Fc receptors is prevented, mediator release will not occur. Mast cells and basophil gE Fc receptors are described in the aforementioned U.S. and foreign patents. chemically isolated IgE Fc fragments or certain It is known that scales are inhibited by the administration of Such compounds are IgE It has an affinity for Fc receptors and therefore binds to it and inhibits the binding of gE. hinder. In this way, the allele is isolated from the specific antigen that induced gE production. It is possible to stop the response [Hamburger, service]. Jens, I89. : U89 (1975); Mr. Noh Burger, Adv. AllergOyuogytech H+muno1. pp 591-593 (= Yu ”-Riichi, Q-Gamon Publishing 1980), Bluff-y-(Plummer ) et al., Fed, Proc.

42,713 (tqsa) :).

The present invention describes that a portion of ButyR binds to the gE Fc receptor on human basophils. and the subsequent EEE combination is 1! II can be harmful. Therefore These monobutides are anti-allergic agents that are useful in the treatment of allergies in animals and humans. - have characteristics.

Active site peptides of the invention As mentioned above, the present invention provides a method for inhibiting Ij1 of immune complex-mediated inflammation, and a method for treating immune complex-mediated inflammation in various fields. A novel therapeutic composition containing these wavebutys 1 having therapeutic value; and how to use them.

The present invention provides active site peptides having the following sequences: (2) R-butyl r as described in clause (a) of claim 1.

■, the wave pattern 12° IIN described in clause fb) of claim 1, claim 1 The wave spots 10■ described in clause (C) of Claim 1, - as described in clauses (d and j of Claim 1) 2-f'chi r0V, wave spot r0■ described in clause (e) of claim 1, claim A peptide according to clause (f) of range 1.

The scope of the present invention covers unsubstituted butyl P, as well as It also includes those in which the terminal is substituted with one or more functional groups that do not affect the It should be noted that From this description, it can be seen that these functional groups are free amino acyl groups. (particularly with formyl or acetyl groups) and amides of free carboxylic acid groups Conventional substitutions such as It will be understood that it includes The R buty r of the present invention is extremely unusual. Why? They are similar to the much larger G-G or I-G, which they are partially similar to. Can it bind to and inhibit cellular Fc receptors in the same way as gE molecules? It is et al. Some of these 2 peptides are (1) PMN IgG receptors; (11) IgG and IgE receptors on phospho2ocytes; and (iii) IgG and IgE receptors on monocytes. Words that can combine with and inhibit them are especially unusual and serious. Ru. This is because scientific researchers who are proficient in the technical fields described here are ~． At least IgG and Fc receptor binding as described in 3. Recent literature has concluded that a complete Fc region of an IgE molecule is required. It is et al. [Barnett-FO8ter] et al., Mol, Irnmunol, 19.407 (1982): Bar Nesotho-Foster et al., J. Immunol, 120.407 (] 978); Pu I/7 Tumo 77 Auto (Perez-Montfort) Mr. et al., Mol.

ler) et al., Immunobiol, 158.254 (1981) ).

Therefore, the requirement for a molecule's activity is determined by the stereochemistry of each molecule, i.e., the specific "folding" of the molecule. It is thought that it is controlled by "Tami". In this regard, Horipepti P Since the joint is not rigid but flexible, the points It should be understood that it can exist as a As a result, molecules are flexible. Then, in a certain way, it will be ``folded''. In the present invention, Ail Similar to the long-chain family polypeptides, they are “folded” and therefore have the same biomolecules. It was found that 17 exhibiting physical properties. For this reason, the peptide has a biologically do not substantially affect the activity of the molecule or interfere with the natural “folding” of the molecule. It can be substituted with various functional groups unless otherwise specified.

The ability of these amphibians to retain their biological activity and natural folding. is that they have similar Fc receptor binding activity to their parent antibody molecules. exemplified by fruit. The peptides of the present invention have Fc receptor activity as described herein. Although it is thought that it works by "inhibiting" sexual intercourse, the present invention does not It is not limited to a fixed mechanism of action.

The Fe receptor inhibitory activity of the peptides that are the subject of the present invention can be determined by well-established methods and methods. and procedures. In particular, monomers obtained from human myeloma serum Rosette measurements using chemically or thermally assembled human 1gG or IgE The law was used. [Gon-ZILleZ-MO Yuina ) Mr. J, C Yuin, xnvest, Mutual! , 616 (1977) Spiegelberg et al.'s immunoassay: 1980 Nical Laboratory Technique for the 198Q (C11nical Laboratory Techniques for the19so’e ) Alan 7, R-Lees (Alan R, Li5s) = Knee 3-ri, 19 1980, pp. 287-300). Trip that ``gG'' or ``gE'' next. It is adsorbed to bovine hemocytes that have been pretreated with aldehyde or asexual aldehyde. Next, Fresh human cells PMN, monocytes and halophils from basic chronic myeloid leukemia patients, and human cell lines (RPM Knee 8866 for lymphocyte Fc receptors, and Daudi and monocytes/macrophers:) for FC receptors. 0937) for 15 minutes before adding indicator bovine erythrocytes to an equal concentration of inhibitor (0937). in the presence or absence of monomeric IgG or IgGK, or Takubuti r). Cubated. In the absence of inhibitors, cells expressing surface Fc receptors 3 or more indicator red cells bound to cells by exposed Fc regions on the red blood cell surface A rosette, a tuft-like structure of blood cells, was formed. Inhibitor myelomatan? Rimata If +ifl is added, the diluent phosphate buffer etc. Divide the rate of rosettes formed when saline was used alone as a control. Then, the degree of rosette formation calculated by multiplying the calculated quotient by 100 is It decreased with good reproducibility.

Table 1 shows the inhibition observed for intact monomeric myeloma tan. Showing the inhibition observed by representative peptide inhibitors, calculated as . In other words, 50% inhibition means that the peptide inhibits the complete myeloma to which it is compared. The degree of inhibition of Roma protein! l) indicates that it was equal to 0%.

Table 2 shows the Peptide 1 of the present invention! One of the Lys-Ala-Lys-Gly-GJn-Pro-Arg Normal human mononuclear side 7 capsules (lymphocytes and mononuclear cells) separated by lonidazole gradient. Figure 1 shows representative immunostimulatory and immunomodulatory activities when incubated with There is.

The cells were exposed to PeptiP (final wave ButiR concentration = 100 micrograms/at). After that, various plant-derived lectins with well-characterized immunomodulatory activities (mitogen) was added. Lectins with mitogenic effects act as anti-leukocyte It is thought that it mimics some of the events that occur in cells due to primary stimulation. Among them, it is a useful indicator of habitual immune reactivity. After lectin addition, the cells are cultured for several days, and at specific intervals, the newly synthesized DN of the dividing cells is Radioactive iodine-7-uridine, which will be incorporated into A, was .

After the cells are harvested and washed, the remaining cell-associated radioactivity is used to proliferate the cells. The degree of stimulation can be evaluated. Table 2 shows the proportion of the 6 types of loincloths in which the above-mentioned Pepti R is added. This indicates that the mitogenic effect of the mitogenic factor was strongly inhibited; peptides can substantially modulate the proliferation ability of immunologically important mononuclear 7 cells. Therefore, it has been shown that it can be used as an immunomodulatory agent. Soaked buti r alone However, the mitosis (proliferation) of mononuclear cells is 50 times on the third day, 331 times on the fifth day, and 7 times. Stimulated by 283% on day 1.

This suggests that the peptide dramatically reduces immunity by increasing the proliferation of mononuclear cells. This shows that it can act as a

Other tests that can be used to measure the activity of these butides are: Hess et al., J1 Immunol, 130. 717-721 ( 1983; Human phosphorus 9-ball response); Mr. Ishizaka et al. 1. T. Immunol, 102.884-892 (1969; Histamine release Alkan, Eur, J. Immunol, 8. 112-118 (1978; Mouse Nilin... (legal antigen-induced proliferation assay); Mr. Starkebaum et al. 1. r, Lab, C! l in.

Med, 98.280-291 (1981; Intratubular chemical fluorescence analysis) There is.

In carrying out the method of the present invention, an effective amount of dIJ vepti r as described above is used. or its derivatives, or pharmaceutical A and compositions containing it, in the art. alone or in addition to the present invention, by any conventional and acceptable method known to those skilled in the art. - or other drugs such as antihistamines, corticosteroids, etc. Administered in combination with steroids, etc. i.e. these compounds or compositions The product can be administered orally, sublingually, topically (e.g. on the skin or in one root), parenterally. (e.g. intramuscularly, intravenously (subcutaneously or subcutaneously) or by inhalation) and solid, liquid or gaseous dosage forms such as tablets, suspensions, etc., as detailed below. It can be administered in the form of a suspension or an aerosol. Its administration may be single for continuous therapy. be administered in a single unit dosage form or, in the case of ad hoc therapy, in a single dose. Can be done.

In one preferred embodiment, the method of the invention provides a It will be carried out in case of emergency or emergency. In another preferred embodiment, the book The method of the invention is effectively carried out continuously or as a prophylactic treatment.

In view of the above, and also the severity of the condition to be treated, the age of the patient, etc. All factors can be determined by basic experiments by those skilled in the art) , the effective dosage according to the present invention can vary over a wide range. patients are individual Part 1! 'c receptor content, the effective overall dosage according to the present invention is , preferably 2×10 to 2×10’ times the Fc receptor content on a molar scale. It can be written as For the average patient, this will depend on the strength of the compound. It depends, but it will be about 0.5-500~/kg/day.

Of course, local treatments (for example of the respiratory system) require relatively small amounts of substances. Become.

Pharmaceutical carriers useful in preparing the compositions of the invention are solid, liquid, or gaseous. Can be done. That is, the compositions may be prepared as tablets, tablets, capsules, powders, enteric-coated or other protected formulations (e.g. ion exchange resins or other carriers). attached to the body or incorporated into cubesicles with lipid-tans/added Adding a terminal amino acid or replacing a terminal amino acid with a D-type amino acid (depending on It can take the form of an arosol, etc. The carrier can be a variety of oils, such as petroleum, Contains synthetic, cultivated or synthetic oils such as peanut oil, soybean oil, mineral oil, and sesame oil. selected from. Water, saline, aqueous dextrose, and glycols are It is a preferred liquid carrier, especially for (if isotonic) injection solutions. Preferred pharmaceutical excipients These include starch, cellulose, talc, glucose, lactose, and sucrose. gelatin, malt, rice, flour, chalk, silica gel, stearic acid mug Na/um, sodium stearate, glycerol monostearate, sodium chloride Lime, dried skim milk, glycerol, phlopyrene gellicol, water, ethanol, etc. This includes: The compositions may be applied by conventional pharmaceutical means such as sterilization. , as well as customary pharmaceutical additives such as preservatives, stabilizers, wetting or emulsifying agents, osmotic pressure agents, etc. It may contain adjusting salt, buffering agent, etc. Suitable pharmaceutical carriers and their treatment Mr. Martin (E, W, Martin) “Remington’s Pharmacy” Remington's Pharmaceu tical (5 science days). Such compositions are In order to prepare the proper dosage form for proper administration to the host, , will contain an effective amount of the active ingredient along with an appropriate amount of carrier.

Effective prevention or treatment of allergic reactions requires that the therapeutic agent be actually used. It is important that the drug be relatively non-toxic, non-antigenic and non-irritating at the levels used. Ru.

The abutide of the present invention is well tolerated. They have low toxicity and especially cytotoxic effects. It is characterized by a lack of improvement in neutrophil function, and also in patients with decreased neutrophil function, such as neoplastic For the treatment of infants, elderly or immunosuppressed patients; suppression of immune rejection of transplanted organs. For example, allergic diseases, autoimmune diseases such as rheumatoid arthritis or phthisis. (9 days 0r1-atric) Arthritis, erythematous sores, ulcerative colitis, localized Ileitis (Crohn's disease), sero-neg-active 5pondyloarthropathyθe), ankylosing spondylitis (spo-n dylitis ankylosa), Reichl syndrome, hypersensitivity vasculitis, hemolysis Sexual anemia, Grages' disease, demyelinating neurological diseases such as multiple sclerosis, postviral myelitis , contact dermatitis, pso-riasis, diabetes mellitus (diabetes type), Horse fever, some forms of leukemia and cancer, Hodgkin IJ7zQ tumors, bacterial infections (e.g. tuberculosis), viral or fungal infections, and the aforementioned diseases. I can be there.

Of the compounds defined in claim 1, those in clauses (a) to (f) of that claim Particularly preferred are compounds having the amino acid sequence according to

(,) A is Thr, B is Van, C is Leu, and D is Hj- s, E is +Mn, F is Asn, G is Trp, and ■( is L eu, ■ is Asp, and 1. ■ is Gdy, K is Lyr+,] ) is G6u, M is Tyr, and N is Val. thing.

(b) Y is Ser, 2 is ASn, A is Asn, B is G, 17 , C is (Mn, D is pro, E is Glu, F is ASn , G is Akin, H is Tyr, Engineering is Lys, and J is Th. r and K is Thr (a compound of t, l).

(c) Y is His, 2 is Akin, A is Glu, and B is Va l, C is GJn, D is Leu, E is Pro, F is A8 p, G is Ala, ■( is Arg, engineering is His, J is S er, K is Thr, L is Thr, M is Gln, and N is P ro, 0 is Arg, P is LyE3, Q is Thr, and Compounds of clause fc) in which R is Lys.

(d) A is Pro, B is Val, C is aly, and D is Thr , E is Arg, F is AEIp, G is Aha, and H is Engineering. θ, engineering is Glu, and J is Gl! y, K is Glu, and Compounds of clause (d) wherein L is Thr.

(e) W is Tyr, X is Ser and l, Y is Lys, and Z is Xj78 , A is Thr, B is Engineering 1e, C is Ser, and D is Lys. , E is Ala, F is Lys, G is Gly, and H is Gin. , ■ is Pro, J is Arg, K is Glu, and L is Pro. , M is Gln, N is Val, and O is Tyr (e ) compounds.

(A is Arg, B is Ser, C is Th, r, D is Thr , E is Lys, F is Thr, G is Ser, and H is (ll y and engineering is Pr.

, J is Arg, K is Ada, L is Ala, and M is Pro. , the node (f ) compounds.

Synthesis of peptides The peptides of the invention can be prepared by any method known to those skilled in the art, e.g. , Hou-ben-Weyl, Methoden Dell ・Methoden der Organisch en Chemie), Volume 15/■, Pages 1-806 (1974), Georg-Th1.eme Publishers, Stuttgart -Verlag) or U.S. Patent No. 4,161,522 It may be synthesized by those described in the references cited in .

Furthermore, it is also possible to produce VeptiP of the present invention with the help of genetic engineering. . In addition, very long chain peptides (which are produced by genetic engineering) They can also be produced by decomposition, in particular by specific enzymatic decomposition.

The Vepti-R of the present invention can be obtained using the solid-phase Vepti-P synthesis method, namely Merrifield (Merryfield). It is preferable to synthesize by the fie'ld method. This established and versatile Methods, including experimental procedures, are described in the following multiauthor literature: Merrifield ( Merrj, field), Journal of American, Chemical Society Sci., 85.2149-2154 (1963).

Mr. Meienhofer, [Hormonal Prote Hormonal Protθ1-n5andP eptide8) Edited by J.C.H. Riichi (c, a, Li), Volume 2 (Aka) Demik Publishing (1973), pp, 45-267° Barany ) and Merrifield et al.'s ``The+A type'' The Peptide Day) J Gross (v.

Gross) and Meienhofer (F, Meienhofer) Daino 1■2 volumes (Academic Publishing Co., Ltd. 1980), 1) I), 3-285゜ko In a preferred method of growing Any desired chain can be created by stepwise addition of amino acids to the takuzotide chain. Peptides of any desired length and sequence are produced.

In a preferred commercial application of this method, the C-terminus of the growing Vepty r chain is attached to a reagent particle. and an amino acid having a protected amine group is covalently bonded to Add it step by step like this. One of the preferred amine protecting groups is the t-BOC group. , which is stable to butylation conditions, yet does not destroy the butide bond. The chiral center in the butide chain can be easily removed without racemization. Be able to do it. Once the procedure is finished, under acidic conditions (e.g. with hydrobromic acid and trifluoride) The final Decompose Takubuchi P from the resin and remove all remaining protecting groups; Decomposition from the resin is carried out under basic conditions using, for example, triethylamine, and then Protecting groups may be removed under acidic conditions.

Degraded peptides can be processed by means well known in the art, e.g., by freezing. After drying, remove using a polysaccharide del medium such as Sephadex G-5. isolated and purified by partition chromatography or countercurrent partitioning. It will be done. The final peptide composition is determined after degrading the peptide by standard means. This can be confirmed by amino acid analysis.

Salts of the carboxyl groups of peptides can be prepared by converting one or more of the peptides into salts using conventional methods. an equivalent of the desired base such as a metal hydroxide base such as sodium hydroxide; carbonate or bicarbonate bases such as sodium carbonate or sodium bicarbonate; also is contacted with an amine base such as triethylamine, triethanolamine, etc. It can be manufactured by

, 1! Addition salts of repeptides contain one or more equivalents of the peptide. It can be prepared by contacting with the desired inorganic or organic acid such as hydrochloric acid. Wear.

The ester of the carboxyl group of ribebutide is an ester of the carboxylic acid or precursor. may be manufactured by any conventional method known in the art to convert the I can do it. Polywave butide of the present invention when using the above-mentioned Norifil 2 synthesis method One preferred method for making esters is basic or basic, depending on the resin. is acid! The completed polypebutyl r in the presence of the desired alcohol under 2tE conditions. This is a method of decomposing the oil from the fat-resistant part. That is, when released from the resin, the C- The terminus is directly esterified without isolation of the free acid.

The amide of Holiwabutide of the present invention also converts the carboxylic acid group or precursor into amide P. manufactured by methods well known in this technical field to Can be done. Preferred method for forming an amide at the C-terminal carboxyl group One method is to separate the polypeptide from the solid support using a suitable amine. Alternatively, the desired amine can be decomposed in the presence of an alcohol to form an ester, and then the desired amine can be used. This is a method in which aminolysis is carried out using

The N-acyl derivative of the amino group of the polypeptide of the invention is the N-acyl derivative for the final condensation. -Using acyl-protected amino acids or acylating protected or unprotected peptides It can be manufactured by 0-acyl derivatives can be used, for example, for free hydro can be produced by acylation of oxypeptides or peptide resins. Each a Sylation can be carried out using standard acylating agents such as acylno\lides, anhydrides, acylimidas. This can be done using sol or the like. N- and O-acylation is optional. You can also do it together.

Coupling, deprotection/degradation reactions, and production of derivatives of the polypeptide of the present invention , about -10-+50°C1, very preferably at a temperature of about 20-5°C. Delicious. The temperature range for any individual reaction depends, of course, on substrates, reagents, and solvents. depending on the agent, etc., all of which are well within the skill of those skilled in the art. . Specific reaction conditions for these methods can be gleaned from the examples. .

The following examples are presented to enable those skilled in the art to more fully understand and practice the invention. those should not be considered a limitation on the scope of the invention, but rather an illustrative and representative example thereof. should be considered as such. Unless otherwise specified, Rf values are for n-buttons. Cellulose using nol:pyridine:acetic acid dihydrate (15:To:3:12) By thin layer chromatography (TL(!)), Rf” was determined to be n-butanol. : Determined by TLC on silica using ethyl acetate:acetic acid:water (1:1:1:1) Established. The purity of the produced di-tide was determined by high performance liquid chromatography, except by TLC. This was demonstrated by totography, amino acid analysis and P paper electrophoresis.

Implementation example 1 11-Peptide (or undecapeptide), Thr-Val-Leu-Hl Production of s-Gin-Asn-Trp-Leu-Asp-Gly-Lys 5.3 fnoc1-t-Boo-t -C6-Z-lysine resin (0,372 mol amino acids/2 resin) was subjected to a deprotection-neutralization cycle using the following strategy: a) Three washes with methylene chloride.

b) Treatment with 30% TF'A (refluoroacetic acid) in methylene chloride for m minutes Deprotection by

C) Three washes with methylene chloride.

d) Two washes with ethanol.

θ) Washing with methylene chloride three times.

f) Treatment with 10% triethylamine in methylene chloride for 10 minutes Neutralization.

g) Three washes with methylene chloride.

A 3-fold excess of t-BOC, which is the next amino acid in the sequence! - equivalent amount of glycine Amino7 of lysine using chlorhexylcarbodiimide (in methylene chloride) group was acylated. After a 2 hour coupling time, a sample was taken and The completeness of the reaction was confirmed by qualitative tests.

If incomplete, the compling was repeated as described above. kampling anti Once the reaction was complete, the peptide resin was washed three times with ethanol. the peptide resin is subjected to a deprotection-neutralization cycle and t-BOC derivatization of the next amino acid in the sequence (suitably side chain protected form) according to the policy described for the first amino acid. Let's couple together.

The coupling of t-BOC-asparagine and t-BOC-glutamine is performed using equivalent in the presence of 1-hydroxybenztriazole. Combine the last remaining ships Complete the synthesis and dry the 3rd part, Mibutide Jugetsuji (7,3y). Step 1: Add a few drops of DMS (dimethyl sulfide), 9 ml of anisole and The mixture was treated with an HF (hydrogen fluoride) device using 7Q ml of liquid HF. that much After allowing the decomposition reaction to proceed for ω minutes at 0° C., the HF was removed under reduced pressure. Remove residual substances and extracted with 5Q ml of 50% acetic acid and 240 ml of water. . 2.2 f! by freeze-drying! The crude deprotected undecapeptide was obtained.

First purification step: Butanol: Acetic acid: Water: Ethanol (4: 1: 5: This was carried out by COD (countercurrent distribution) using a solvent system with a ratio of 0.02). 200 times After transfer, tubes 39-59 were pooled to yield 1.27 materials.

It uses a solvent system of acetic acid: ethyl acetate: water: n: butanol (1:1:1:1). The TI,C (thin layer chromatography) used showed some tailing. . This product was further purified by partition chromatography on a 5G50 column; and eluted using the upper phase of a solvent system of n-butanol:acetic acid:water (4:1:5). . 156 mq of pure peptide (RfO, 68) was obtained.

Each of the peptides of the present invention is a growing peptide that covalently binds solid # to fat. Produced by a similar procedure by stepwise addition of the desired amino acid to the thi-r chain can do.

Implementation example 2 Pro-Asp-Ala-Arg-Hln-3er 1□9-59 α-t-D OC-sOr (onzi) resin (0,46 mmol amino acids/7 dendrites) Deprotection, neutralization and coupling cycles followed the strategy described in Example 1. I put it on.

For subsequent coupling steps, a 4-fold molar excess of synchhexylcarbodiimide was added. and protected amino acids, histidine, arginine, alanine, Asunoguragi acid and zoroline were used.

The completeness of the coupling reaction was determined by a semi-quantitative ninhydrin test on a small sample. I confirmed. After completion of the last coupling reaction, dry R-butyl resin (6,8f ) was placed in the reaction vessel of the HF decomposition device, and 60 ml of liquid HF and 5 ml of anisole at 0° C. for printing. After extraction and lyophilization, 1. 52 crude wavebutides were isolated.

The entire batch was prepared using a solvent system of n-butanol:acetic acid:water (4:1:5 ratio). C[J) (countercurrent distribution) purification. After 200 transfers, the chew 1.35L from Bu 6-24? of materials were collected. Rf O, 27゜ Implementation example 3 Tetosideca is butide Sar-Val-Met-H1s-G11x-Ala-Le u-Hle-Asn-Hls-Tyr-Thr-Gln-Lye3.655' (It　-BOC-e-Cl-Z-lysine resin i (0,414 mmol/1 Resin) was subjected to the deprotection and neutralization cycle described in Example 1. 4 equivalents of t- BOC! -glutamine, DCC (cyclohekyl/lupodiimide) and 1- Hydrogen/benztriazole was used in the next coupling cycle. basic arrangement Appropriately protected amino acid residues corresponding to the sequences are coupled in subsequent steps. and 7.42 protected tetrazocabebuty P resins were obtained. HF decomposition is 5. r ) ml of anisole, a few drops of dimethyl sulfide and 4Q me liquid HF' was added and the mixture was stirred for ω minutes at 0°C. That HF and wash the residual material with diethyl ether and add 60 ml of 50' Extracted with 1 aqueous acetic acid and then 240 ml of water. Lyophilize the solution and 1.82 of the crude material was obtained, which was mixed with n-butanol:acetic acid:water (4:1:5 Purification by countercurrent partitioning (270 transfers) using a solvent system with a ratio of

The main fractions (tubes 26-37) were diluted with ammonium acetate at pH 4.5. Carboxymethylcellulose ion exchange using a gradient (0.01-0.3M) Further purification was achieved by chromatography. The substance corresponding to the main peak was It was purified by partition chromatography on a G25 gel column. RfO, 55 ゜ Implementation example 4 Purification of Ac-Gln-Pro-Glu-Asn After HF decomposition, the crude material (400μ ) was purified by COD using n-butanol:acetic acid:water (4:1:5 ratio). I put it on. After 250 transfers, fractions 33 to 37 were pooled to yield 53 A pure product was obtained. Rt: 0.37° Example 5 Purification of Thr-Arg-A/a-Glu HF-decomposed crude Thr-Arg-A/ a-G4u (300m9) to n-BuOH:HOAC:H2O (4:1 : When the upper layer of 5) was purified using an a-25 distribution ram using the eluent, Partially purified Thr-Arg-A/+a-Glu (163m7) was obtained. Ta. This sterilized butide was used as an elution solvent in reverse phase using HOAc as an elution solvent. Further purification by liquid chromatography (C-18, 10 microns) yields pure Thr-Arg-Ala-G6u (54In) was obtained. Rf O, 31 ゜Example 6 Purification of 01u-Lye-Gln-Arg mv-<butyl n-BuOH: HO When purified by countercurrent distribution using AC: H2O (4:1:5) system, G lu-Lys-Gln-Arg was obtained. This wave is 0.14HOAc Purified by reverse phase liquid chromatography (C!-18,40 micron) using Then, pure G6u-Lye-()A'n-Arg was obtained. Rf　O,06゜ Implementation example 7 Arg-8er-Thr-Thr-Lys-Thr-8er-Gly-Pro - Arg purified dry wave butylene resin (4,1?) is placed in the reaction vessel of the HF decomposer. and 40 ml of liquid HF and 5. □ml of anisole at 0°C. The reaction was allowed to take place for ω minutes. After extraction and lyophilization, 750 mg of crude peptide was isolated. did.

The entire batch was prepared using a phase medium system of n-butanol:acetic acid:water (4:]:5 ratio). Purified by COD (counter space current distribution). 200 times After transfer, both aliquots 81-85 were pooled to obtain 200 mg of pure product. It was. Rf　0.19゜ Implementation example 8 Purified dry peptide resin (7,3f) of Asp-Lys-8ar-Arg was HF into the reaction vessel of the decomposer, and add 60πt of liquid HF and 3 ml of anisotropic The mixture was treated for ω minutes at 0°C using a vacuum cleaner. After extraction and lyophilization approximately 11 crude peptides P was isolated.

The entire signature was washed using a solvent system of n-butanol:acetic acid:water (4:1:5 ratio). Purified by ID (countercurrent distribution). After 220 transfers, fraction 6 Approximately 12 products were obtained by pooling 5-110. The product is cation exchanged It was purified by liquid chromatography using a column and a partition column. Rf O, 11° Implementation example 9 The following Veptyl r was produced in the same manner as in Example 1 (the N-acyl derivative has a terminal t -BOC! - the amino acid to a suitable N-acylamino acid, e.g. produced by substitution with luteamine (AC-Gln): Leu-As p-Gly-Lys, Rf O, 41Leu-His-Gln-A, sn, Rf　O,34Thr-Val-Leu=H1s-CFIn-Asn-Trp- Leu-Asp-Gly-Lys-Glu.

Rf　O,58 Th　r-Va　1-Le　u-Hl　a　-G　In-A　8n-T　rp- Leu-As p-G 1y-Lys-G 1u-Tyr, Rf O, 66 (For silica) Thr-Va 1-Leu-Hi S-G In-As n -T rp-Leu -A s p-()ly-Lys-G 1u-Tyr -L7El, Rf O, 63Thr-Va 1-Leu-Hl e-G 1 n-As n--Al a-Leu, -A sp-G 1y-Lys, Rf0.55 Lys-Thr-11e-8er-Lys-Ala-Lys-Gay-Gln- Pro-Arg, RfO019 Thr-11e-8er-Lys-Ala-Lys-Gly-Gln-Pro- Arg 1 Rf O, 28Ser-Arg-Glu-Glu, Rf O, 2 9Asp-Lys-8er-Arg-Trp-Gln-Gln-1,y-Asn , Rf O,07 (for silica) Tyr-8er-Lys-Leu-Thr-Val-Asp-Lye-8er- Arg, Rf O, 11Ac-Gln-G4n-Gly-Aen, Rf O ,52Ser-Asn-Asp-()1y-Glu-Pro-Glu-Asn- Tyr　%Rf　O,33Ser-Asn-Gly-Gln-Pro-Glu- Asn-Tyr, Rf O, 29Aen-Gly-Gin-Pro, R, f　O+22fly-Gln-Pro-Glu-Asn　, Rf　O,19Gl n-Pro-Glu-Asn-Asn%Rf　O,28Ac-Gln-Pro- Glu-Asn-Asn-Tyr　, Rf　O,53Ac-Gln-Pro-G l, u-Asn-Aen-Tyr-Lys, Rf O+45G17-Gln-P ro-Glu-hen-A, 8n, Rt O, 24 (for silica) Ac -Glu-Pro-G'1u-Asn-Aθn%Rf　O,35Ac-Glu- Pro-Glu-Asp-Asn　, Rf　O,44Ac-Gln-Pro-G lu-Asp-Asn　%Rf　O,40H1s-Asn-His　-Tyr　 , Rf O, 24Glu-Ala-Leu-Hls-Asn-Hls-Tyr , Rf 0.21Thr-Lye-Thr-8er-Gly-Pro-Ar g, Rf O, 23Thr-8er-Gly-Pro-Arg, Rf O , 26Gly-Thr-Arg-Asp, Rf O, 17Thr-Gln-Pr o-Arg, Rf O, 17Thr-Thr-Gln-Pro-Arg, Rf O,30Ala-Arg-His-8er, RfO,26ASI)-Al a-Arg-His, Rf O, 14pro-Asp-Aha-Arg, R f　O,20Ac-Gln-Leu-Pro-ASp-Ala-Arg, Rf　 O,53Glu-Val-Gln-Leu-Pro-Asp-A,1a-Arg , Rf　O', 48Hi　e　-A　e　n-G　1u-Va　1-G　In- Leu-P ro-As p-A 1 a-Arg-Hl 8, RfO 932 Pro-Asp-Ala-Arg-Hls-8er-Thr, Rf O, 31 Pro ASp-Ala Arg Hls-8er-Thr-Thr-Gln Pro Arg II Rfo, 28 Thr-Arg-Ala-Glu-Trp-Gln-Glu-Lye-Asp, Rf　alOGlu-Gln-Lys-Asp　, Rf　O,12Thr-A rg-Ala-Glu-Ala-Glu-Gln-Lys-A, sp 1 Rf O,14Arg-A 1a-Va 1-Hl 5-Glu-Al a-A 1 a -8or-Pr o -Se r-Gl n-Thr -Val, R f　O,13 Aflp-Lys-Bor-Lys, Rf O, 08° Example 10 A, 1 equivalent of an aqueous solution of the tetrapeptide Asp-Lye-8er-Arg, 1 treatment with NNaOH and the monosodium salt of the peptide by lyophilization. isolate 2 equivalents of 0. The corresponding dinatrium by using IN NaOH Mutual salt is obtained.

Similarly, this peptide can be modified with other metal salts by substituting the appropriate base. For example, K, Li, Ba, Mg, ammonium, Fe(II), Zn, M It can also be converted into n(II) and Al salts.

B. Adding 1 equivalent of Tri to a methanol solution of Thr-8er-Gly-Pro-Arg. After addition of ethylamine, mono-triethyl An ammonium salt is obtained. Similarly, replace this peptide with the appropriate amine. Other amine salts such as trimethylamine, tri(n-propylene) pyru)-amine, dicyclohexylamine, β-(:)methylamine) ethanol β-(diethyl-amino)ethanol, triethanolamine, tris(hydrogen) (Droxymethyl) aminomethane, arginine, lysine, histidine, N-ethyl Hyherizine, hydranomine, choline, betaine, ethylenediamine, glucosa Methylglucamine, theopromine, purine, piperidine, piperidine, carbonate It can be converted into feine and procaine salts, etc.

In the same manner as C0, the other butides of Examples 1 to 9 were treated with their corresponding metals and and amine salts.

Implementation example 11 Thr-8er-01y-Pro-Arg aqueous solution or methanol solution f: Neutralization with 1 or 2 equivalents of hydrochloric acid gives the mono- and dihydrochloride salts, respectively.

1,000 rL et al. freeze-dry the water F8 solution or convert it from a methanol solution with ether. Isolated by precipitation.

Similarly, this peptide can be modified by substituting the appropriate acid for hydrogen chloride. Other acid addition salts such as No1 P lobromy P1 sulfate, phosphate, Nitrate, acetate, oxalate, tartrate, succinate, male ate, fumarate, gluconate, citrate, malate, ascorbate, and benzoate, etc.

Similarly, other takubutides of Examples 1 to 9 were converted to their corresponding acid addition salts. can be exchanged.

Example 12 Suspend the appropriate Takubutide resin (1, Of) from Example 1 in anhydrous methanol. 40m1/? resin), triethylamine (50 mmol) and the The mixture is stirred at 22'C for an hour. The resin is separated and the combined F solution is concentrated in a vacuum. Shrink. The residue was dissolved in ethyl acetate saturated with hydrogen chloride (5 ml) and The solution is stirred at 22°C for a few minutes. The product was precipitated by addition of ether to T hr-Val-Leu-His-Gln-Asn-Trp-Ding+Elu-Asp -Gly-Ly-OMe is obtained.

Using other alcohols in place of methanol and increasing the reaction temperature to 45-80°C , by setting the reaction time to 45 to 90 hours, 1 equivalent of ethyl, propyl, butyl esters, hexyl, octyl, decyl, and dodecyl esters are obtained.

Using a similar procedure, the corresponding esters of Polypesib-P of Examples 1 to 9 were prepared. can be manufactured.

Implementation example 13 Asp L7S-8er Arg OMe in ammonia saturated G solution in methanol for 2 days at room temperature. Asp-Lys-8e was removed by removing the solvent under vacuum. r-Arg-NH2 is obtained.

Similar procedures were used to prepare the corresponding amides of other Hasozendo of Examples 1-9. can do.

Example 14 500 ~ Gln-Pro-(llu-Aen), 0.7 ml acetyl Lorai Y, 0.5 ml pyridine and 10. Mixture of nl TetrahyP Lofuran Keep things at mark ° for 12 hours. After evaporating the mixture, the residue was purified by TLC. Ac-Gin-Pro-G4u-Asn is obtained. Rf　O, 37゜ Implementation example 15 In the same manner as in Example 14, from Asp TJ78 S er Ar g to N, N, 0-triacetyl g4 body is obtained. Using a similar procedure, the sterilizers of Examples 1-9 were It is possible to prepare the corresponding acyl derivatives of tirr, especially the N-terminal acetyl derivatives. Wear.

Next, the compound of the present invention exemplified by Thr-8er-Gly-Pro-Arg 1 illustrates a typical pharmaceutical composition.

Example A: Aerosol composition (per dose) Thr-3er-G4y-Pr o-Arglo mf sodium chloride 6.9■ Sodium-basic phosphate 1 permanent product: 5.8 lbs. Adjust to 1.0 d with water.

Example B: Injectable composition (per dose) Thr-8er-Gly-Pro- Arg 10 ~ Sodium chloride 11>, 9■ Sodium-basic phosphate monohydrate 5.8■ Methylparaben 0.25 ■ Propyl Nograben 0.14■ With water 1. Let it be Oml.

Example C: Dry powder composition for inhalation Thr-Ser-Gly-Pro-Arg 1.07'+S+Lactose 30 ■ As used herein and in the claims, active site peptide r refers to immunoglobulin activity. It is a peptide having an amino acid sequence derived from a sexual site. immunoglobulin active part The protein physically binds to the immunoglobulin Fc receptor and thereby modulates Fc receptor function. It is the part of the immunoglobulin molecule that is activated. The active site peptide is Due to its similarity to some of the body's immunoglobulin molecules, immunoglobulin Fc receptors It can bind to cells and thereby exert an effect similar to that of intact immunoglobulin. Wear. This type of binding stimulates specific immune functions normally mediated by its receptors. or can be inhibited.

lymphocytes Lymphocytes are some white blood cells that make up part of the "cellular arm" of the immune system. So These include peripheral blood vessels, phosphorous fluid, and the body, including the pancreas, thymus, lymph nodes, and bone marrow. It is recognized that it circulates in the lymph nodes in the body and in other organs.

Phosphorocytes play a central role in the development and defense of the immune system.

They act as regulators of white blood cell proliferation and development in the treatment of infectious or foreign substances. It acts as a “killer” cell that directly attacks the cells of the human body, and as an immunoglobulin emperor It works.

Lin Q balls can be roughly divided into three groups. In other words, thymus-derived T I7 lymph nodes cells (T, ME cells), B lymphocytes (B cells) and lack characteristics of T and B cells It is a "null cell" which is a lymphocyte. B cells produce all body antibodies. It is the main body of the developing immunoglobulin-producing plasma cells.

T cells are two cells involved in immune system regulation and direct killing of infectious or acquired cells. It has a function defined by the dog. , J! 4 Healthy T cells (T health・♀- 1T Sazoresser, T Amblifier/Inducer, etc.) are T and Regulates the proliferation and development of B phospho-Q cells and possibly other white blood cells.

Such regulation induces lymphokines, which are potent activating and growth-regulating molecules, to become T-responsive. This is thought to be caused by the secretion of the Q-balls.

One class of T cells also has the ability to kill cells directly. This kind of killing effect can be promoted by IgG-bound antigens on defeated cells [antibody-dependent #1 ( 11. Cell-mediated cytotoxicity (ADCC)] or MY extended-type hypersensitivity This can occur in an antibody-independent manner.

Null cells recognize and kill many cancer cells without prior exposure to them. Contains 9 balls of phosphorus that can be played. mediate this spontaneous killing effect Null cells are called natural killer cells (NK cells) and are important for protection against cancer. It is thought that.

Lymphocytes are also important activators of white blood cell defense functions and are There is also. For example, certain substances secreted by antigen-stimulated lymphocytes are Significantly enhances the bactericidal and tumor-killing activity of lophages; other 9772 sphere-derived substances Attracts a variety of leukocytes to the site of the immune response, thereby triggering a local defense response. improve the answer.

The proliferation, development and activity of phosphoryl cells are related to the proliferation, development and activity of phosphoryl cells and non-phosphoryl cells. It is also regulated by regulatory molecules secreted by the cells. These molecules are responsible for the thymus Includes lumons, interleukins, immunoglobulins and their pond molecules. Book Of central importance to the invention is that the various immunoglobulins are Ability to regulate proliferation and activity of lymphocytes through interaction with c-receptors It means having power.

Various other modifications will be apparent to those skilled in the art without departing from the scope of the invention (and) It is to be understood that this can be easily done by one skilled in the art. Therefore, attached to this The scope of the pertinent claims is not limited to the foregoing description, but rather The scope of the invention shall include all features of patentable novelty present in the invention. All features that would be treated as equivalent by a person skilled in the relevant technical field. It should be thought of as encompassing all aspects (including signs).

international search report In1m1IIsI16IlalA#ellemll#AN--PCT/EII 84100242ANNEX To T&: INTERkJATXONAL 5EARCHREPORT　0NINT’mJAT WORK 0NAL　APPLICA TXON No, PCT/EP 8400242 (SA 7778) FR- A-13677758E-A--634436US-A-3972773031 08/76 None

Claims (1)

[Claims] 1. for an immunoglobulin Fc receptor selected from the group consisting of: Active site compounds that inhibit immune complex binding to lymphocyte Fc receptors and/or inhibit immunoglobulin binding to lymphocyte Fc receptors: 1. ] A peptide having an amino acid sequence selected from the group consisting of the following: (a) [Sequence exists], [Sequence exists], [Sequence exists], [Sequence exists], [Sequence exists] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ has an array], [has an array], and [has an array] (where A is Thr, Ser, or Ala; B is Val, Leu. I1 e, or Ala; C is Leu, Val , He, or Ala; D is His; E is Gln, Asn, Glu, or Asp; F is Asn, Gln, As p, or Glu; G is Trp, Tyr, Phe, Ala , Val, Le u, or He; H is Leu, Val, Ala, or He; I is Asp, or Glu; J is Gly, or Ala; K is Lys, Arg, or Orm ; L is Glu or Asp; M is Tyr; and N is Val, Leu, He, Ala, or Lys); (b) [There is an array], [There is an array], [The array [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array ], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], and [I have an array], ( where Y is ser; Z is Asn or Ser; A is Asn, Asp, Gln or Glu; B is Gly, Ala, β-A la, Sar or ser; C is Gln, Asn, Glu or Asp; D is Pro, Val, Leu, He, or Ala; E is Glu or Asp; F is Asn, Gln, or Asp; G is Asn or Gln H is Tyr or Phe; I is Lys, Arg, or Orn; J is Thr, Ser, or Ala; and K is Thr, Ser, or Ala); (c) [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ There is an array], [There is an array], [There is an array], [There is an array], [There is an array], and [There is an array], (where Y is His; Z is Asn ; A is Glu, or Asp; B is Val, Leu, Hele, Ala, or Ser; C is Gln, Glu, Asn, Asp, or Val; D is Leu, Val, He, Ala, or Met; E is Pro, Val, Leu, He, Ala, or His; F is Asp, or Glu; G is Ala, Gly, Ser, or Thr; H is Arg, Lys, Orn , or Leu; I is His, Phe, Tyr, or Ala; J is Ser, Thr, Ala, Glu, or Asn; K is Thr, Ser, Lys, Ala, Trp, or His; L is Thr, Ser, Leu, Glu, Gln or Tyr; M is Gln, Lys, Arg, Orm, Glu or Thr; N is Pro, Va1, Leu, He, Ala, Lys or Gln; is Arg, Lys, Orn, or Asp; P is Lys, Arg, or is Orn; Q is Thr, Ser, or Ala; and R is Lys, Ar g, or Orn, except for [array], [array], and [array]); (d) [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [has an array], [has an array], [has an array], [has an array], and [has an array], (where A is Pro, Leu, Ile, or Val; B is Val, Leu, He, or Ala; C is Gly, or Ala; D is Thr, Ser, or Ala; E is Arg, Lys, or Orn; F is Asp, or Glu Yes; G is A1a, Gly, or Glu; H is He, Leu, Val, or I is Glu, or Asp; J is Gly, Ala, or Ser; K is Glu, or Asp; and L is Thr, Ser, or Ala); [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [Array [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array ], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [Array [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array ], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [Array [there is], [there is an array], [there is an array], [there is an array], and [there is an array], (where W is Tyr; X is ser; Y is Lys; Z is Lys or Leu; A is Thr, Ser, or Ala; B is He, Val, Leu, or is Ala; C is Ser, Thr, or Ala, or Asp; D is Lys, Arg, or Orm; E is Aln, Gly, Ser, Thr, or Pro. F is Lys, Arg, or Orn; G is Gly, Ala, Thr, Ser, or Trp; H is Gln, Asn, Lys, Leu, Ala, or Pro; I is Pro , Val, Leu, He, Ala, or Gln; J is Arg, Lys, Orn, or Gly; K is Gu, Asp, or Asn; L is Pro, Val, Leu, He, or Ala M is Gln・Asn, Arg, or Lys; N is VaL, Leu, He, or Ala; and O is Tyr or Phe, but (f) [has an array], [has an array], [has an array], [has an array], [has an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], (Here A is Arg, Lys, Orn, Gln, or His; B is ser, Thr, Ala, or Gly; C is Thr, Ser, Ala, Gly, or Val; D is Thr, Ser, Ala, Gly, or His; E is Lys, Arg, Orn, His, or Glu; F is Thr, Ser, Ala, or Gly; G is ser, Thr, Al a, or Gly; H is Gly, Ala, Thr, Ser, Lys, Ar g, or Orn; I is Pro, Val, Leu, He, or Ala; J is Arg, Lys, Orn, His, or Ser; K is Ala, Thr, Ser, Gly, or Gly; L is Ala, Thr, Ser, or Gly; M is Pro, Val, Leu, He, or Ala; N is Glu, or Asp; O is Val, Leu , He, or Ala; P is Tyr, or Phe); 1.2 their esters; 1.3 their amides; 1.4 their N-acyl derivatives; 1.5 their O-acyl derivatives; and 1.6 pharmaceutically acceptable salts thereof. 2. A compound according to claim 1 having the amino acid sequence according to (a). A compound according to claim 1 having an amino acid sequence according to 3(b). 4. 5. Compound o according to claim 1 having the amino acid sequence according to (c). A compound according to claim 1 having the amino acid sequence according to (d). 6. A compound according to claim 1 having the amino acid sequence according to (e). 7. A compound according to claim 1 having the amino acid sequence according to (f). 8. [There is an array] 9. [There is an array] 10. [There is an array] 11. [There is an array] 12. [There is an array] 13. [There is an array] 14. [There is an array] 15. [There is an array] 16. [There is an array] 17. [There is an array] 18. [There is an array] 19. [There is an array] 20. [There is an array] 21. [There is an array] 22. Peptides selected from the group consisting of: [sequence is], [sequence is], [sequence is], [sequence is], [sequence is], [sequence is], [ [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array], [I have an array] [There is], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array] , [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [ [There is an array], [There is an array], [There is an array], [There is an array], [There is an array], [There is an array]. 23. The peptide according to claim 1 is liberated from its corresponding functional derivative, which may be covalently bonded to a solid resin, by treatment under acidic or basic conditions and, if desired, The peptide obtained by Stellification, 7midation and/or acylation to give the corresponding ester, 7mido, N- and/or O-acyl derivatives, or treatment with bases or acids. The claimed invention is characterized in that it is converted into a pharmacologically acceptable salt thereof by A method for producing the compound according to item 1. 24. a compound according to claim 1 and at least one pharmaceutically acceptable A pharmaceutical preparation consisting of a carrier. 25.25.1 Peptides selected from the group consisting of: 25.2 Their esters, 25.3 Their amides, 25.4 Their N-acyl derivatives, 25.5 Their O- A pharmaceutical preparation comprising a compound selected from the group consisting of acyl derivatives, 25.6 pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier. 26. an immunoglobulin Fc receptor comprising administering an effective amount of at least one compound according to claim 1 to modulate immune complex-mediated immunosuppression. A method of inhibiting immune complex binding to. 27. 24. The method of claim 23, comprising administering an effective amount of at least one compound to reduce immune complex-mediated inflammation or tissue destruction. 28. an effective amount of at least one of the above compounds to reduce allergic reactions in humans; 24. The method of claim 23, comprising administering an agent. 29. 24. The method of claim 23, comprising stimulating immunoglobulin production in response to an antigen by administering an effective amount of at least one of said compounds. 30. 24. The method of claim 23, comprising inhibiting immunoglobulin production in response to an antigen by administering an effective amount of at least one of said compounds. 31. Claim 22 in an amount effective to modulate immune complex-mediated immunosuppression. A method of inhibiting immune complex binding to an immunoglobulin Fc receptor, the method comprising administering at least one of the compounds described above. 32. 24. The method according to claim 23, wherein the compound has the following sequence. 33. The method according to claim 23, wherein the compound has a sequence. 34. 24. The method according to claim 23, wherein the compound has a sequence. 35. The method according to claim 23, wherein the compound has a sequence. 36. A is Thr, B is Val, C is Leu, D is His, E is Gln, F is Asn, G is Trp, H is Leu, I is The compound according to claim 2, wherein J is Gly, K is Lys, L is Glu, M is Tyr, and N is Val. thing. 37. Y is Ser, Z is Asn, A is Asn, B is Gly, C is Gln, D is Pro, E is Glu, F is Asn, and G is 4. The compound according to claim 3, wherein H is Tyr, I is Lys, J is Thr, and K is Thr. 38. Y is His, Z is Asn, . A is Glu, B is Val, C is Gln, D is Leu, E is Pro, F is Asp, G is Ala, H is Arg, I is His, J is Ser, K is Thr, L is Thr, M is Gln, N is Pro, O is Arg, P is Lys, Q is Thr and R is Lys. 39. A is Pro, B is Val, C is Gly, D is Thr, E is Arg, F is Asp, G is Ala, H is He, and I is 6. A compound according to claim 5, wherein the compound is Glu, J is Gly, K is Glu, and L is Thr. 40. W is Tyr, X is Ser, Y is Lys, Z is Lys, A is Thr, B is Ile, C is Ser, D is Lys, and R is Ala, F is Lys, G is Gly, H is Gln, I is Pro, J is Arg, K is Glu, L is Pro, M is Gln. , N is Val, and O is Tyr. A compound according to item 6. 41. A is Arg, B is Ser, C is Thr, D is Thr, E is Lys, F is Thr, G is Ser, H is Gly, and I is Pro, J is Arg, K is Ala, L is Ala, M is Pro, N is Glu, O is Val, and P is Tyr. Compound according to item 7.