CN116789762A - Antagonist binding polypeptide molecule of human CD200 receptor and application thereof - Google Patents

Abstract

The invention belongs to the field of biomedicine. In particular to an antagonist binding polypeptide molecule of a human CD200 receptor (CD 200R) and application thereof. The amino acid sequences of the polypeptides are shown as SEQ ID NO.1 to SEQ ID NO.2, wherein the 1 st amino acid and the 80 th amino acid of the SEQ ID NO.1 and the SEQ ID NO.2 form a ring through peptide bonds. The cyclic peptides shown in SEQ ID No.1 and SEQ ID No.2 can further obtain a series of derivative small cyclic peptides and linear peptides by decompression technology. The antagonist binding polypeptide molecule of the human CD200 receptor (CD 200R) provided by the invention can block the interaction of human CD200 ligand and human CD200R, antagonize the immunosuppressive effect (de-inhibition) of the CD200 pathway, and can be used for preparing medicines for treating diseases related to the CD200/CD200R pathway.

Description

Antagonist binding polypeptide molecule of human CD200 receptor and application thereof

Technical Field

The invention belongs to the field of biomedicine. In particular to an antagonist binding polypeptide molecule of a human CD200 receptor (CD 200R) and application thereof.

Background

CD200 (also known as OX2, OX-90, MOX-2) is a cell surface glycoprotein with a molecular weight of 48kDa, a gene located on chromosome 3q13.2, a member of the immunoglobulin superfamily I. In the central nervous system, the protein is mainly expressed on neurons and vascular endothelial cells, and is also expressed on astrocytes, oligodendrocytes, neural stem cells and other cells, is a signal for down-regulating the functions of bone marrow cells, and can co-stimulate the proliferation of T cells. CD200 has structural similarity to immune checkpoint molecules such as CD47, PD-1, CTLA-4, etc., which comprise 2 extracellular immunoglobulin-like domains: 1 single transmembrane domain and 1 short cytoplasmic tail without signal motif.

CD200R (CD 200R 1-5 in mice; CD200R1, R2 in humans) is also a member of the immunoglobulin superfamily of type I, a cognate receptor for CD200, with 2 extracellular immunoglobulin-like domains and 1 cytoplasmic NPxY motif. CD200R is expressed primarily in myeloid cells, as well as detected on lymphoid lineage cells, such as natural killer cells (NK) and T cells, and contains a cytoplasmic tail that is capable of initiating downstream signaling cascades.

CD200 expression is relatively conserved across different species, suggesting that CD200/CD200R signaling pathways may have important physiological functions. The D200R family has five members of CD200R 1-5, only CD200R1 has longer intracellular fragments, and downstream molecules are recruited to play a physiological function; while other receptors of the CD200R family than CD200R1 are thought to function differently from CD200R1 by bridging unknown molecules through lysine residues in the transmembrane region and short sequences within their cell.

CD200 is an immune tolerance signaling molecule that plays an important role in maintaining the body's autoimmune tolerance. CD200-CD200R interactions inhibit the expression of pro-inflammatory molecules such as TNF- α, IFN- γ and inducible nitric oxide synthase, which in turn protects immune-privileged sites, stem cells and other important tissue cells from immune injury by modulating the activation threshold of inflammatory immune responses, and promotes peripheral immune tolerance. In addition, the immunosuppressive effects of CD200-CD200R play a critical role in tissue repair processes, graft rejection, autoimmune disease and cancer monitoring. Binding of CD200 to CD200R results in phosphorylation of tyrosine 302 in the NPxY sequence of CD200R, activating the Dok2-RasGAP complex, inhibiting Ras-ERK signaling, and thus inhibiting myeloid cell activation. The interaction of CD200 and CD200R can also effectively inhibit T cell immune response and NK cell killing activity, promote macrophage to secrete indoleamine-2, 3-dioxygenase (IDO) which is an immunosuppressive tryptophan catabolic enzyme, and induce regulatory T cell expansion, so that Th1 cytokines are converted into Th2 cytokines, thereby inhibiting immune response. CD200/CD200R plays an important role in tumor and non-tumor diseases primarily through modulation of immunity and angiogenesis. It follows that CD200/CD200R plays an important role mainly by modulating immunity and angiogenesis. In addition, CD200 promotes central nervous system neurogenesis and is not involved in immunomodulation.

The CD200 inhibitor Samalizumab (ALXN 6000, sand Ma Zushan) is a novel recombinant humanized monoclonal antibody against CD200, and can specifically bind to CD200, block the interaction with CD200R, and perform preliminary research

The results support that Samalizumab can play a role as an immune checkpoint inhibitor in the treatment of chronic lymphocytic leukemia (chronic lymphocytic leukemia, CLL), but currently relevant clinical trials are still in the primary phase and require further clinical trial studies. Chinese patent CN114728048A discloses an antagonist polypeptide molecule involved in binding to the human CD200 receptor (CD 200R), compositions comprising such antagonist polypeptide molecule and methods of treating cancer using such antagonist polypeptide molecule.

The use of peptide inhibitors as immunotherapies is a further advantage over therapeutic monoclonal antibodies. Peptides have lower toxicity, higher stability and higher efficiency. Due to its smaller size, it has unique properties and has high targeting accuracy, which means that the risk of potential side effects is smaller. In addition, peptides can be easily synthesized, altered, and produced at lower cost than antibodies, making them a more advantageous therapeutic approach, and thus, there remains a need for human CD200R binding antagonist polypeptide molecules.

Disclosure of Invention

In order to solve the defects in the prior art, the invention provides an antagonist binding polypeptide molecule of a human CD200 receptor (CD 200R) and application thereof.

In one aspect, the invention provides an antagonist-binding polypeptide molecule of human CD200 receptor (CD 200R), the amino acid sequence of which is shown in SEQ ID NO.1 to SEQ ID NO.2, the specific amino acid sequence of which is shown in Table 1, wherein the 1 st amino acid and the 80 st amino acid of SEQ ID NO.1 and SEQ ID NO.2 form a loop through peptide bonds.

TABLE 1 amino acid sequences of the invention

The polypeptide with the amino acid sequences shown as SEQ ID NO.1 and SEQ ID NO.2 is 80 cyclic peptide obtained by detecting the change of calcium ion concentration in cells from a polypeptide library through a high-throughput screening technology, wherein the discovery of the cyclic peptide comprises the dissolution and dilution of the polypeptide library, and the screening from the polypeptide library is carried out according to the inhibition rate result of the polypeptide by using ELISA and TR-FRET screening methods.

In one aspect, the invention provides an antagonist-binding polypeptide molecule of the human CD200 receptor (CD 200R), which polypeptide molecule is obtained by decompressing SEQ ID NO.1 and SEQ ID NO. 2.

Preferably, the invention provides an antagonist of human CD200 receptor (CD 200R) binding polypeptide molecule with the amino acid sequence shown in SEQ ID NO. 3-11. SEQ ID NO.3 to SEQ ID NO.11 are cyclic peptides, and specific sequences are shown in Table 1.

In one aspect, the invention also provides a polynucleotide molecule comprising a polynucleotide capable of encoding one or both of the antagonist polypeptide molecules of human CD200R described in any of the foregoing.

Preferably, the polynucleotide molecule comprises a polynucleotide capable of encoding one or both of the polypeptide molecules capable of encoding SEQ ID No.1 to SEQ ID No. 11.

In another aspect, the invention provides a pharmaceutical composition comprising (a) a safe and effective amount of a polypeptide of the invention or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier or excipient. The amount of polypeptide of the invention is generally 10. Mu.g to 100 mg per dose, preferably 100 to 1000. Mu.g per dose.

In general, the therapeutic compositions may be formulated as an injectable, such as a liquid solution or suspension; it can also be made into a solid form suitable for incorporation into a solution or suspension, and a liquid carrier prior to injection.

Once formulated into the compositions of the present invention, they may be administered by conventional routes including, but not limited to: intratumoral, intramuscular, intravenous, hepatic, oral, subcutaneous, intradermal, or topical administration.

When the pharmaceutical composition of the present invention is used for actual treatment, various different dosage forms of the pharmaceutical composition can be employed according to the use condition. Preferably intravenous or hepatic arterial drug formulations or intratumoral drug injections.

These pharmaceutical compositions may be formulated by mixing, diluting or dissolving according to conventional methods, and occasionally adding suitable pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents (isotonides), preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers and cosolvents, and the formulation process may be carried out in a conventional manner according to dosage forms.

The pharmaceutical compositions of the present invention may also be administered in the form of a slow release formulation.

In another aspect, the invention also provides the use of the polypeptide, polynucleotide or pharmaceutical composition described above for the manufacture of a medicament for the treatment of a disease associated with the CD200/CD200R pathway.

Further, the diseases associated with the CD200/CD200R pathway include solid tumor cancers, hematological malignancies, neuroendocrine tumor cancers.

Preferably, the solid tumor cancer may be selected from neuroblastoma, breast cancer, bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, testicular cancer, or thyroid cancer.

Preferably, the hematological malignancy may be selected from B-cell lymphoma, T-cell lymphoma, leukemia, hodgkin's lymphoma, myeloma, myelodysplastic syndrome, or plasmacytoma.

Preferably, the neuroendocrine tumor cancer may be selected from large cell neuroendocrine cancer or pancreatic neuroendocrine cancer

The above-described preparation of a medicament for treating a disease associated with the CD200/CD200R pathway may be administered in combination with one or more immunological agents simultaneously, separately or sequentially.

Terminology

The polypeptide library is obtained by adopting PICT (Peptide Information Compression Technology) patent technology by the SangZhi full peptide Biochemical Co., hunan, and the technology compresses polypeptide information by using biological means, so that the information of a plurality of polypeptides can be integrated into one polypeptide, and the aim of containing larger polypeptide information with relatively smaller storage capacity is fulfilled; a cyclic peptide library containing approximately 73000 80 amino acids was constructed by the PICT technique. Specific construction methods can be seen in patent CN201580081102.3 and patent CN201780089941.9.

The meaning of "peptide" or "polypeptide" as used herein is well known to those skilled in the art. Typically, a peptide or polypeptide is one in which two or more amino acids are linked by an amide bond, which is formed by the amino group of one amino acid and the carboxyl group of an adjacent amino acid. The polypeptides described herein may comprise naturally occurring amino acids or non-naturally occurring amino acids. May be modified to include at least two amino acids such as analogs, derivatives, functional mimics, pseudopeptides, and the like. A polypeptide of a particular amino acid sequence may include modified amino acids and/or additional amino acids unless the N-and/or C-terminus comprises a modification that prevents further addition of an amino acid. Such modifications include, for example, acetylation of the N-terminus and/or amidation of the C-terminus.

The polypeptides of the invention may be modified (typically without altering the primary structure) in a form that includes: chemically derivatized forms of polypeptides in vivo or in vitro include, but are not limited to, acetylation, carboxylation, alkylation, acylation, carbamylation. Modifications also include glycosylation, such as those resulting from glycosylation modifications during synthesis and processing of the polypeptide or during further processing steps. Such modification may be accomplished by exposing the polypeptide to an enzyme that performs glycosylation (e.g., mammalian glycosylase or deglycosylase). Modified forms also include sequences having phosphorylated amino acid residues (e.g., phosphotyrosine, phosphoserine, phosphothreonine). Also included are polypeptides modified to improve their proteolytic resistance or to optimize solubility.

The polypeptide of the invention may be a recombinant polypeptide or a synthetic polypeptide. The polypeptides of the invention may be chemically synthesized, or recombinant. Accordingly, the polypeptides of the invention may be synthesized synthetically by conventional methods or produced recombinantly. One preferred method is to use liquid phase synthesis techniques or solid phase synthesis techniques. Another approach is to use recombinant techniques to produce the polypeptides of the invention. The polynucleotides of the invention may be used to express or produce recombinant polypeptides of the invention by conventional recombinant DNA techniques. Because the polypeptide of the present invention is relatively short, it is contemplated that a plurality of polypeptides may be linked together in series, and the expression product may be obtained after recombinant expression, and then the desired small peptide may be formed by methods such as cleavage.

The polypeptides disclosed herein, including their salts, may also exist in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, and may be used for crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); thus, the compounds of the present invention include solvated and unsolvated forms.

As used herein, a "human CD200R antagonist" refers to blocking the interaction of a human CD200 ligand with human CD200R, antagonizing the immunosuppressive effects of the CD200 pathway (disinhibition). Synonyms for CD200R are CD200R1, OX2R, MOX2R and HCRTR2.

The term "binding" as used herein refers to a molecular interaction between two molecules, e.g. CD200 and CD200R, a polypeptide molecule of the invention and CD 200R.

As used herein, "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent. The term refers to such agent carriers: they do not themselves induce the production of antibodies harmful to the individual receiving the composition and do not have excessive toxicity after administration. Such vectors are well known to those of ordinary skill in the art. A sufficient discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (MackPub.Co., N.J.1991). Such vectors include (but are not limited to): saline, buffers, dextrose, water, glycerol, ethanol, adjuvants, and combinations thereof.

Compared with the prior art, the invention has the following advantages:

(1) The polypeptide library used in the invention has a polypeptide compound amino acid sequence with much larger information than that of the traditional chemically synthesized polypeptide library, and each compound in the library is independently produced and is identified and accurately weighed by mass spectrum, so that the screening accuracy and stability are ensured, and the problem of distortion (the actual library capacity is far lower than the theoretical value) of the traditional mixed compound library such as a phage library is avoided.

(2) The present invention provides a series of human CD200R antagonist binding polypeptide molecules that block the interaction of human CD200 ligand with human CD200R, antagonize the immunosuppressive effects of the CD200 pathway (de-repression), and are useful in the manufacture of a medicament for the treatment of diseases associated with the CD200/CD200R pathway, including but not limited to solid tumor cancers, hematological malignancies, neuroendocrine tumor cancers.

Drawings

FIG. 1 shows the inhibition results of the ELISA method of example 1 by different concentrations of SEQ ID NO.1 and SEQ ID NO. 2;

FIG. 2 shows the results of the inhibition of different concentrations of SEQ ID NO.1 and SEQ ID NO.2 by the TR-FRET method of example 1;

FIG. 3 shows the inhibition results of the ELISA method of example 2 with different concentrations of SEQ ID NO.3 to SEQ ID NO. 8;

FIG. 4 shows the inhibition results of the ELISA method of example 2 with different concentrations of SEQ ID NO.9 to SEQ ID NO. 11;

FIG. 5 shows the inhibition results of the TR-FRET method of example 2 at different concentrations from SEQ ID NO.3 to SEQ ID NO. 8;

FIG. 6 shows the inhibition results of the TR-FRET method of example 2 at different concentrations from SEQ ID NO.9 to SEQ ID NO. 11.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The invention will be better understood from the following examples. However, it will be readily appreciated by those skilled in the art that the description of the embodiments is provided for illustration only and should not limit the invention as described in detail in the claims.

The general screening method comprises the following steps:

(1)ELISA

namely enzyme-linked immunosorbent assay, is a common immunoenzyme technology. The method mainly comprises the steps of adsorbing known antigen or antibody on the surface of a solid phase carrier, incubating the antibody or antigen marked (coupled) by enzyme, adding a color developing agent for developing color, measuring the difference between the color of the object to be measured and the color of a standard object by an enzyme-labeling instrument, and drawing an enzyme activity curve to obtain the concentration of the object to be measured.

(2) Time-resolved fluorescence resonance energy transfer (Time-resolvedfluorescence resonance energy transfer, TR-FRET)

Is a non-radiative energy transfer phenomenon between two fluorophores with specific spectral properties. To facilitate an understanding of FRET occurrence, the emission spectrum of one fluorophore (i.e., the "donor") must overlap with the excitation spectrum of a second fluorophore (i.e., the "donor"), and when the donor is excited by incident light, energy can be transferred to the acceptor by long Cheng Ouji-dipole interactions, resulting in fluorescence emission from the acceptor. FRET can only occur when the donor and acceptor are sufficiently close (less than 10 nm). When using fluorescent donors with long excitation half-lives (to 1500 mus) such as the rare earth metals Eu or Tb, a Time delay (50-150 mus) between the donor excitation and acceptor emission recordings is allowed to avoid other fluorescent signal interference, a technique called Time Resolved (TR) FRET, TR-FRET, also called homogeneous Time Resolved fluorescence technique (Homogeneous Time Resolved Fluorescence, HTRF) the principle of which can be referred to as Assay Guidance Manual.

As a CD200R antagonist polypeptide screening method, the assay is based on time-resolved fluorescence energy transfer on a microscopic plate reader, labeling CD200R antagonist polypeptide and its target CD200R with two fluorophores, with strepavidin-Eu as fluorescence donor, and goatvti-Human IgG Fc-Alexa Fluor647 as fluorescence acceptor. The interaction between the two molecules brings the two fluorophores into close proximity to each other and causes energy transfer between them, causing them to fluoresce specifically at a specific wavelength. By measuring this specific wavelength on a microscopic plate reader, potential CD200R antagonist polypeptides can be screened in a short period of time.

The detection method combining the TR-FRET and the antibody technology has the advantages that: (1) The antibody has the advantages of selectivity, strong specificity and high signal to noise ratio; (2) The interference of autofluorescence of the compound to the experiment is well avoided; (3) The fluorescent signal has longer stability time and does not need to be detected immediately; (4) homogeneous reaction, easy high-pass.

Example 1 screening of CD200R antagonist 80 Cyclic peptide

Dissolution of polypeptide pool: the polypeptide library 96-well deep well plate is placed in a centrifuge at 4000rpm for centrifugation for 2-3 minutes. 200. Mu.L/well of ultrapure water was added to the 96-well deep-well plate using an automatic liquid separator. Sealed with a silica gel cap and placed in a 95℃water bath for 5 minutes. And (3) injection: the polypeptide concentration at this time was about: 50. Mu.M. The dissolved 96 deep-hole plate polypeptide is placed in a centrifugal machine at 4000rpm for centrifugation for 2-3 minutes.

Dilution of polypeptide pool: the dissolved polypeptides were transferred to 384-well plates using a workstation and diluted to 10. Mu.M with loadingbuffer (Tris-HCl buffer, pH 7.4).

Wherein the polypeptide library is self-made by Cheng full peptide Biochemical Co., ltd.

ELISA screening

(1) Coating: CD200 was diluted to 0.125. Mu.g/mL with coating solution, 25uL to 384 well plates were added to each well, covered with a plate seal, and coated overnight at 4 ℃.

(2) Washing the plate: 100uL of washing liquid was added to each well, shaken for 5 minutes, the washing liquid was sucked off, tapped on paper and the liquid was completely drained. Repeated 5 times.

(3) Closing: 100uL of blocking solution was added to each well, and the mixture was blocked at 37℃for 2 hours.

(4) Washing the plate: 100uL of washing liquid was added to each well, shaken for 5 minutes, the washing liquid was sucked off, tapped on paper and the liquid was completely drained. Repeated 3 times.

(5) Sample adding: CD 200R-biotin-conjugated was diluted to 0.5. Mu.g/mL with SA-HRP (1:5000 dilution) 1:1 premix for 1-2 hours, add 12.5uL premix to 384 well plates, add 12.5uL dilution/polypeptide solution, incubate at 37 ℃ for 1 hour.

(6) Washing the plate: 100uL of washing liquid was added to each well, shaken for 5 minutes, the washing liquid was sucked off, tapped on paper and the liquid was completely drained. Repeated 3 times.

(7) Adding a substrate: 25uL of substrate chromogenic solution (TMB Kt: mixing A with B1: 1) was added to each well, shaken for 5 minutes, incubated at 37C for 30 minutes in the absence of light until the color developed to the desired shade.

(8) Terminating the reaction: 25uL of 1MHCl was added to each well.

(9) And (3) detection: the OD450 was used to detect absorbance immediately after termination of the addition of hydrochloric acid.

TR-FRET screening

And verifying the large-scale entity polypeptide library by using a TR-FRET screening method. Different concentrations of polypeptide, 4nM CD200R and 8nM CD200, and fluorescence donor Strepitavidin-Eu and fluorescence acceptor Goatti-Human IgG Fc-AlexaFluor647 were sequentially added to 384 well plates and after incubation for 2 hours at room temperature, TR-FRET signals were detected. Positive control: no polypeptide, only 4nM CD200R and 8nM CD200, and fluorescence donor strepitavidin-Eu and fluorescence acceptor Goatti-Human IgG Fc-Alexa Fluor647; the negative control was: no polypeptide, only one of 4nM CD200R and 8nM CD200 or 2, and fluorescence donor strepitavidin-Eu and fluorescence acceptor GoatAnti-Human IgG Fc-Alexa Fluor647. And calculating the inhibition rate.

Repeated experiments are carried out on the polypeptides screened in the beginning, so that the inhibition rate of the SEQ ID NO.1 and the SEQ ID NO.2 screened from the self-made 80-cyclopeptide library is finally determined to be higher, and then concentration dependency verification is carried out. Inhibition was calculated and plotted using graphpad. The experimental results are shown in table 2, and the concentration response curves are shown in fig. 1 and 2.

TABLE 2 screening results for CD200R antagonist 80 cyclic peptide

Example 2 screening of CD200R antagonist Polypeptides

The sequences of the 80 cyclic peptides SEQ ID NO.1 and SEQ ID NO.2 screened in example 1 were analyzed and disassembled by using an internal cyclic peptide decompression technique, and 10-80 linear peptides or cyclic peptides with different amino acid sequences were designed. The designed linear or cyclic peptides of 10-80 different amino acid sequences were screened according to the screening procedure of example 1 and IC was performed on the designed linear or cyclic peptides of 10-80 different amino acid sequences that were active ₅₀ And (5) verification.

For designed IC with 10-80 different amino acid sequences ₅₀ After the verification, the concentration dependence verification is further carried out on the active polypeptide, the experimental results are shown in table 3, and the concentration response curves are shown in fig. 3 to 6.

TABLE 3 screening results for CD200R antagonist polypeptides

The present invention provides a method and a method for inhibiting human CD200R antagonist polypeptide and application thereof, and the method and means for realizing the technical scheme are numerous, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principles of the present invention, and the improvements and modifications should also be regarded as the protection scope of the present invention. The components not explicitly described in this embodiment can be implemented by using the prior art.

Claims (10)

1. A human CD200R antagonist-binding polypeptide molecule, characterized in that the amino acid sequence is shown in SEQ ID No.1 to SEQ ID No.2, wherein amino acids 1 and 80 of SEQ ID No.1 and SEQ ID No.2 are looped by peptide bonds.

2. A human CD200R antagonist-binding polypeptide molecule, wherein said polypeptide molecule is obtained by decompression of SEQ ID No.1 and SEQ ID No. 2.

3. The antagonist-binding polypeptide molecule of human CD200R according to claim 2, wherein the amino acid sequence is as shown in SEQ ID No. 3-11, SEQ ID No. 3-11 being cyclic peptides.

4. A polynucleotide molecule comprising a polynucleotide capable of encoding one or both of the antagonist polypeptide molecules of human CD200R of any one of claims 1-3.

5. The polynucleotide molecule of claim 4, wherein said polynucleotide molecule is capable of encoding one or both of the polypeptide molecules of SEQ ID No.1 to SEQ ID No. 11.

6. A pharmaceutical composition comprising (a) a safe and effective amount of a polypeptide of the invention or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier or excipient.

7. Use of a polypeptide molecule according to any one of claims 1 to 3, a polynucleotide molecule according to any one of claims 4 to 5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment of a disease associated with the CD200/CD200R pathway.

8. The use according to claim 7, wherein the diseases associated with the CD200/CD200R pathway comprise solid tumor cancers, hematological malignancies, neuroendocrine tumors.

9. The use according to claim 8, wherein the solid tumour cancer is selected from neuroblastoma, breast cancer, bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, hepatocellular cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, renal cancer, testicular cancer or thyroid cancer; the hematological malignancy may be selected from B-cell lymphoma, T-cell lymphoma, leukemia, hodgkin's lymphoma, myeloma, myelodysplastic syndrome, or plasmacytoma; the neuroendocrine tumor cancer may be selected from large cell neuroendocrine cancer or pancreatic neuroendocrine cancer.

10. The use according to claim 7, wherein the medicament prepared for the treatment of a disease associated with the CD200/CD200R pathway is administered simultaneously, separately or sequentially in combination with one or more immunological medicaments.