WO2012121429A1 - Méthode d'identification de biomarqueur de cellules cancéreuses et biomarqueur de cellule cancéreuse sans rapport avec le nmd identifié au moyen de la méthode - Google Patents

Méthode d'identification de biomarqueur de cellules cancéreuses et biomarqueur de cellule cancéreuse sans rapport avec le nmd identifié au moyen de la méthode Download PDF

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Publication number
WO2012121429A1
WO2012121429A1 PCT/KR2011/001558 KR2011001558W WO2012121429A1 WO 2012121429 A1 WO2012121429 A1 WO 2012121429A1 KR 2011001558 W KR2011001558 W KR 2011001558W WO 2012121429 A1 WO2012121429 A1 WO 2012121429A1
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cancer
genes
cancer cell
cancer cells
present
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PCT/KR2011/001558
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English (en)
Korean (ko)
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김호근
유권태
김원규
이한나
신나라
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연세대학교 산학협력단
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Priority to PCT/KR2011/001558 priority Critical patent/WO2012121429A1/fr
Publication of WO2012121429A1 publication Critical patent/WO2012121429A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to a method for identifying a cancer cell biomarker and an NMD-independent cancer cell biomarker identified by the method.
  • Microserrit is a sequence of DNA that repeats a specific base, and every individual has a different length, but everyone has a microserrit. It is common and normal to repeat a particular sequence several times. However, if a problem occurs in the DNA repair system, the length of the microserite may be abnormally shortened or lengthened, which may cause various problems. For example, such an unstable state of microserite is known as an important factor in cancers such as colorectal cancer, uterine cancer, ovarian cancer and stomach cancer.
  • MSI-H microsatellite instability
  • MMR DNA nucleotide mismatch repair
  • the mechanism of tumorigenesis in MSI-H tumors is thought to be involved in the frameshift mutation of the microseret repeat sequence within the coding region of the affected genes, and inactivation of these genes is directly involved in tumor development and progression. It is thought to be involved [5, 6].
  • the frameshift mutation can produce abnormal mRNAs and proteins, and thus tumor specific antigens can be produced.
  • the inventors have described a novel biotechnologically simple and accurate method for cancer cells. Efforts have been made to develop a method for identifying markers, and as a result, the present invention has been completed by identifying a large amount of genes present in a frame shift mutation state in cancer cells at one time.
  • Another object of the present invention is to provide a biomarker for cancer cells identified by the above method.
  • Another object of the present invention to provide a kit for diagnosing cancer comprising the biomarker.
  • Another object of the present invention is to provide a method for screening a cancer therapeutic agent.
  • Still another object of the present invention is to provide a method for preventing or treating cancer, comprising administering the pharmaceutical composition to a subject in need.
  • the present invention provides a biomarker identification method for cancer cells, comprising the following steps:
  • the first screening step of the present invention in order to identify biomarkers by selecting genes having a certain number of mononucleotide repeats in a human gene, selecting a gene having 9 or more mononucleotide repeats is selected. desirable. Frame shift mutations can easily occur when there are nine or more mononucleotide repeats.
  • a database providing a list of genes of humans may be used for the above range setting.
  • An example of such a database is
  • SelTarbase (w. Seltarbase.org).
  • SelTarbase provides information on all human genes, which allows for simple and accurate selection of genes with more than nine mononucleotide repeats.
  • the repetition of the mononucleotide in the primary screened gene is in the coding region, and the immature stop codon is in the last exon or within 55 bp upstream from the last axon binding region. Screening.
  • Nonsense mRNAs resulting from frameshift mutations are well degraded by nonsense-mediated mRNA decay (NMD), which avoids the adverse effects associated with the production of truncated proteins.
  • NMD nonsense-mediated mRNA decay
  • the immature stop codon is at the last exon or is within 55 bp upstream from the last exon binding site, it is not recognized by VIII, so some NMD-functional mRNAs may escape from NMD. If the nonsense mRNA is not destroyed by NMD and the protein is expressed, it causes a disease such as cancer in the human body.
  • Range of genes that can be biomarkers for cancer cells by repeating mononucleotides in the coding region and by selecting genes where the immature stop codon is at the last axon or within 55 bp upstream from the last exon junction Can be set narrower.
  • the method of determining the location of immature stop codons can be by conventional methods known in molecular biology and related art. For example, an open reading frame, an axon junction site, a start codon and a stop codon may be selected using a VectorNTI software or NCBI database to select only genes that satisfy the criteria.
  • the biomarker identification method for the cancer cells is that the gene selected in the second screening step after the second screening step is actually present in the frame shift mutation state in the microserial unstable cancer cells It further comprises the step of checking.
  • Cancer cells capable of confirming whether the gene selected in the second screening step is present in a frame shift mutation state can be used without limitation as long as the cancer cells are known to have microserit instability, and preferably colon cancer cells and uterine cancer cells.
  • it may be more preferably one selected from the group consisting of colon cancer cells uterine cancer cells, ovarian cancer cells and gastric cancer cells.
  • the method for confirming whether the candidate gene selected in the second screening step exists in a frame shift mutation state may be used without limitation as long as it is a method commonly used in molecular biology and related arts, and preferably, isotope PCR It is available.
  • the biomarker identification method for cancer cells further comprises the step of identifying mRNA or polypeptide produced from the second screened gene. If a gene is found, Identification of mRNA markers and peptide markers can be readily performed by methods commonly used in the field of molecular biology and the related art.
  • the present invention provides a novel nucleotide sequence corresponding to SEQ ID NO: 1 to 49, identified using the biomarker identification method for the cancer cells.
  • the nucleotide sequence is the nucleotide sequence of the gene in which the frame shift mutation occurred, and when the sequence is expressed, cancer cell specific mRNA and protein are generated.
  • the amino acid sequence of the protein encoded by the nucleotide sequence is an amino acid sequence described in SEQ ID NO: 50 to 95.
  • the cancer cell specific protein protein comprising an amino acid sequence selected from the group consisting of the novel nucleotides corresponding to SEQ ID NO: 1 to 49 or the amino acid sequence described in SEQ ID NO: 50 to 95 is a colon cancer cell specific Can be used as an enemy marker.
  • the present invention provides a kit for diagnosing cancer comprising an antibody or peptide 3 ⁇ 4 tammer that specifically binds to the cancer cell-specific protein and a primer or probe that specifically binds to the novel nucleotide sequence. It provides a kit for diagnosing cancer.
  • the antibody included in the cancer diagnostic kit may be prepared as a polyclonal antibody or a monoclonal antibody, preferably a monoclonal antibody.
  • Antibodies that specifically bind to the cancer cell specific protein are methods commonly practiced in the art, such as fusion methods (Kohler and Mil stein, European Journal of Immunology, 6: 511-519 (1976)), Recombinant DNA methods (US Pat. No. 4, 816, 56) or phage antibody library methods (Clackson et al, Nature, 352: 624-628 (1991) and Marks et al, J. Mo I. Biol., 222: 58 1-597 (1991). General procedures for antibody preparation are described in Harlow, E.
  • the polyclonal antibody is injected into a suitable animal by injecting a cancer cell specific protein, ie, an antigen, comprising an amino acid sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NOs 50-82, and collecting antisera from the animals.
  • a cancer cell specific protein ie, an antigen
  • the antibody can then be obtained by separating the antibody from the antiserum using known affinity techniques.
  • the aptamer of the present invention included in the kit for diagnosing cancer specifically binds to a protein including an amino acid sequence selected from the group consisting of amino acid sequences set forth in SEQ ID NOs 50-95, and has a peptide structure.
  • peptide refers to a linear or cyclic, preferably linear, molecule formed by binding amino acid residues to each other by peptide bonds.
  • Peptides of the invention can be prepared according to chemical synthesis methods known in the art, in particular solid-phase synthesis techniques (Merri field, J. Amer. Che. Soc. 85: 2149-54 (1963). Stewart, et al., Solid Phase Peptide Synthesis, 2nd.ed., Pierce Chem. Co .: Rockford, 111 (1984)).
  • the probe or primer used in the cancer diagnostic kit of the present invention has a sequence complementary to a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to 49. Terminology herein
  • complementary is meant to have a degree of complementarity that can be selectively hybridized to the nucleotide sequence of the frame shift gene described in SEQ ID NOS: 1-49, under certain specific homogenization or annealing conditions.
  • the term “complementary” has a different meaning from the term perfectly complementary, and the primers or probes of the present invention may selectively hybridize to the nucleotide sequence of the genes described in SEQ ID NOS: 1 to 49. Come To the degree it may have one or more mismatch sequences.
  • the term “probe” refers to a linear oligomer of natural or modified monomers or linkages, includes deoxyribonucleotides and ribonucleotides, and can specifically hybridize to a target nucleotide sequence, It is either naturally present or artificially synthesized.
  • the probe of the present invention is preferably single chain.
  • the probe is an oligodioxyribonucleotide.
  • Probes of the invention can include naturally occurring dNMPs (ie, dAMP, dGMP, dCMP and dTMP), nucleotide analogues or derivatives.
  • the probe of the present invention may also include ribonucleotides.
  • the probes of the present invention may be selected from the group consisting of backbone modified nucleotides such as peptide nucleic acids (PNA) (M. Egholm et al., Nature, 365: 566-568 (1993)), phosphorothioate DNA, phosphorodithioate DNA Phosphoroamidate DNA, amide-linked DNA, I-linked DNA, 2'-0-methyl RNA, alpha -DNA and methylphosphonate DNA, sugar modified nucleotides such as 2'-0-methyl RNA, DNA 2'-fluoro RNA, 2'-amino RNA, 2'-0-alkyl DNA, 2'_0-allyl DNA, 2'-alkylyl DNA, nuclear source DNA, pyranosyl RNA and anhydronucleocytosis And nucleotides having base modifications such as C-5 substituted pyrimidines (substituents are fluoro-, bromo-, chloro-, iodo-
  • primer refers to a single that can serve as an initiation point for template-directed DNA synthesis under suitable conditions (ie, four different nucleoside triphosphates and polymerases) in a suitable complete solution at a suitable temperature. -Refers to stranded oligonucleotides. Suitable lengths of primers are typically 15-30 nucleotides, although varying with various factors, such as temperature and the use of the primer. Short primer molecules generally require lower temperatures to form a stable complex with the complex.
  • the sequence of the primer does not need to have a sequence that is completely complementary to some sequences of the template, and is sufficient if it has sufficient complementarity within a range that can be hybridized with the template to perform a primer-specific function. Therefore, the primer in the present invention does not need to have a sequence that is perfectly complementary to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 49 as a template, and can be hybridized to the gene sequence to act as a primer. If there is a complementary complement within the range it is divided.
  • the invention provides a method for screening a cancer therapeutic agent comprising the following steps:
  • the present invention is (a) a pharmaceutically effective amount of an antibody or peptide aptamer specifically binding to the cancer cell specific protein; And (b) provides a pharmaceutical composition for preventing or treating cancer comprising a pharmaceutically acceptable carrier.
  • the present invention provides a method for preventing or treating cancer, comprising administering the pharmaceutical composition to a subject in need.
  • treatment refers to alleviation of symptoms, reduction in the extent of disease, maintenance of disease that does not worsen, delay of disease progression, improvement or alleviation of disease state (pal hat ion), partial or complete remission. Include. Treatment can also mean increased survival compared to the expected survival if untreated. Treatment includes simultaneously prophylactic measures in addition to therapeutic means. Cases in need of treatment include those already with the disease and cases in which the disease should be prevented. Alleviation of a disease is when the clinical manifestations of the undesired disease are delayed or the progress of the disease is delayed or prolonged compared to the untreated situation.
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier refers to a cell or human exposed to the composition, which is not toxic.
  • the carrier may be used without limitation as long as it is known in the art as a buffer, preservative, analgesic, solubilizer, isotonic agent, stabilizer, base, excipient lubricant, preservative.
  • compositions of the present invention can be prepared according to techniques commonly used in the form of various formulations.
  • injectables can be prepared in the form of unit dose ampoules or multiple dose inclusions.
  • the formulations may be in the form of solutions, suspensions, syrups or emulsions of oil or aqueous medium, or may be in the form of axes, powders, granule powders, granules, tablets, or voxels, and may further comprise dispersants or stabilizers.
  • dispersants or stabilizers for a general principle of the pharmaceutical formulation of the pharmaceutical composition according to the present invention, reference can be made to several documents (W. Sheridan and G.
  • Suitable dosages of the pharmaceutical compositions of the present invention may vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and reaction in response to the patient. It may be prescribed. Preferred dosages of the pharmaceutical compositions of the invention may be administered at 0.001 mg / kg body weight to 500 rag / kg body weight on an adult basis.
  • the pharmaceutical composition of the present invention is colon cancer, uterine cancer, ovarian cancer, gastric cancer, brain tumor, It can be used as a prophylactic and therapeutic agent for cancer selected from the group consisting of laryngeal cancer, breast cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, gallbladder cancer, prostate cancer, bladder cancer, childhood cancer and skin cancer.
  • the present invention is a biomarker identification method for cancer cells, a biomarker for cancer cells identified by the method, a kit for cancer diagnosis comprising the biomarker, a screening method of cancer therapeutic agents and cancer specific proteins It provides a pharmaceutical composition for preventing or treating cancer, comprising a pharmaceutically effective amount of an antibody or peptide 3 ⁇ 4tammer binding to.
  • the biomarker identification method for cancer cells of the present invention is a method of screening genes that are well mutated through bioinformatics technology, rather than testing individual genes individually to test their potential as biomarkers. By using, it is possible to identify a plurality of biomarkers very easily and accurately.
  • the present invention also provides a novel NMD-independent cancer cell biomarker identified using the above method, thereby providing a kit for cancer diagnosis, a screening method for a cancer therapeutic agent and a medicament for preventing or treating cancer using the novel marker. Provides basic data on pharmaceutical compositions.
  • 1 is a 6% polyacrylamide gel electrophoresis result of the amplified DNA product obtained by PCR using a primer prepared based on sequence information of the AIM2 gene.
  • FIG. 26 shows Western blotting results for AIM2 protein.
  • SelTarbase (www. Seltarbase.org) is a database that provides a list of all human genes with mononucleotide repeats. In this Seltarbase all genes in humans with at least 9 mononucleotide repeats (eg 9 or more repeats regardless of A, C, G and T) were found. 447 genes were found. Among the 447 genes, they included a wide variety of genes, from relatively well-known to little-known genes.
  • Only immature stop codons were found in the last exon or within 55 bp in the direction of the start codon at the last exon binding (ie, within 55 bp upstream from the last axon binding).
  • all of the 447 genes were selected using the VectorNTI software (Invitrogen) and NCBI database to display only the open reading frame, the axon junction site, the start codon and the end codon. It was a dog. Of the 66 genes, 15 previously reported mononucleotide repeats, but not reported. There were 51 things that were not.
  • MSI-H high microsatellite instability
  • MSS microsatellite stability
  • the primer to be used for PCR is based on the information of the AIM2 gene obtained from SelTarbase, and the Primer 3 program (http: //frodo.wi .mit .edu / primer3 /) or
  • ⁇ 3 Made using the Blast program (NCBI). Specifically, the sequence of the prepared primer is as follows:
  • Reverse Primer TTGGCTTGMTTGGTCCTTT. 2 genome DNA obtained from each colorectal cancer cell line of Table 1 (50 l ⁇ ), 2 ⁇ 10x Gold Taq complete solution (Applied Biosystem), 1.2 25 mM MgCl 2 (Appl ied Biosystem), 2/10 mM dNTP (Ap lied Biosystem), 2 ⁇ 20 pM primer, 0.2 ⁇ Alpha P-32 (BMS), 0.2 ⁇ 1000 U Gold ⁇ (Applied Biosystem) and 10.6 ⁇ distilled water. PCR cycles were performed. At this time, the length of the PCR product was mostly adjusted to about 100 bp, and the isotope used was a -P 32 (BMS). PCR temperature conditions were set as follows: 30 cycles of 95 ° C. 10 minutes, 95 ° C. 30 seconds, 55 ° C. 30 seconds and 72 ° C. 30 seconds and then 72 ° C. 10 minutes.
  • This isotope-PCR can also distinguish 1 bp of difference.
  • 6% polyacrylamide gel electrophoresis was performed on the amplified DNA product. Each line (1-12) of the gel was loaded with the PCR amplified DNA product of the colorectal cancer cell line of Table 1, and electrophoresis was performed, and the results are shown in FIG. 1.
  • primers prepared based on sequence information of each of TCF7L2, TRIM59, GBP3, GAFA1, KCTD16, IN080E, FBXL3, and KIAA2018 genes were used.
  • FIGS. 2-25 Experimental results of Examples 2-25 after the electrophoresis method are shown in FIGS. 2-25.
  • Figure 2-25 it can be seen that the frame shift mutation of each gene in the experimental group MSI-H colorectal cancer cells.
  • the nucleotide sequence of each specific frame shift mutant gene is listed in SEQ ID NO: 4 to 49.
  • the result of Example 1-25 was put together, and it was summarized in Table 3 below.
  • Example 2 ASTE1 + 1 / W -1 / W + 1 / + 1 / W + 1 / W 2 ⁇ 2 -2 / -3 W — 2 / -3 W w
  • Example 9 RGS22 WWW -1 / WW -1 / WWWWWWww
  • Example 10 FLT3LG WWWW + 1 / WW + 1 / W + 1 / WW + 1 / WW w
  • Example 11 ASH1L WWWWW -1 / -1 -1 /- 1 -1 / WWW w
  • Example 12 MED8 WWW -1 / W -2 / WW -1 / W -1 / WWW w
  • Example 13 ⁇ W -1 / WW -1 / WW -2 — 2 / W -2 / W + 1 / -2 W w
  • Example 14 SLAMF1 W -1 / WW One 1 / WWWWW -1 / W -1 / WW w
  • Example 15 L0C100127950 WWW -1 / W -1 / WW + 1 / W -1 / W -1 / WW w
  • Example 16 SFRS12IP1 WWWW -1 / -2 W + 1
  • Example 22 CTD16 W -1 / WWW -1 / WW -1 / W -1 / W -1 / WW w
  • Example 23 ⁇ 080 ⁇ -1 / WW -1 / W -1 / -1 One 1 / -1 -II --1 / W — 1 / W -1 / -1 / WW w
  • Example 24 FBXL3 W W W w w w w w w w w w
  • Examples 26-31 Confirmation of the potential of six genes, including CIRl, as a colorectal cancer marker
  • Example 2 The same procedure as in Example 1 was performed except that primers prepared based on sequence information of each of CIR1, HOXAll, L0C643677, RXFP2, ERCC5, and L0C100128175 genes were used.
  • MSI colorectal cancer cell lines used for isotope PCR when Western blot was performed using the purchased antibodies (anti-AIM2, anti-TTK).
  • anti-AIM2, anti-TTK purchased antibodies
  • each MSS cell line which was selected as a control line and used as a control, one of four colon cancer cell lines was used.
  • SNUC4 wild type was selected as the normal type, DLDl (-1 / w) as the hetero mutation, LoVo (-1 / l) as the homo mutation, and WiDr (wild type) as the control cell line.
  • the reason for the treatment with MG132 (proteasome inhibitor) is to prevent the breakdown of the mutant protein by the proteasome.
  • the normal type is DLD1 (wild type)
  • the heterologous mutation is HCT116 (-lAv)
  • homo SNIC4 (+ l / -2) was selected as a mutation
  • WiDr wild type

Abstract

La présente invention concerne : une méthode d'identification de biomarqueur de cellules cancéreuses ; un biomarqueur de cellules cancéreuses identifié au moyen de la méthode ; un kit de diagnostic de cancer contenant le biomarqueur ; une méthode de criblage d'agents anticancéreux ; et une composition pharmaceutique pour prévenir ou traiter un cancer, contenant une dose pharmaceutiquement efficace d'un anticorps ou d'un peptide aptamère qui se lie spécifiquement à une protéine spécifique d'un cancer. La méthode d'identification de biomarqueur de cellules cancéreuses de la présente invention n'implique pas l'examen des gènes individuels un par un afin de déterminer leur potentiel en tant que biomarqueurs, et fait plutôt appel à une méthode impliquant un double criblage de gènes dans lesquelles une mutation se produit fréquemment, au moyen d'une technique de bioinformatique. La méthode de la présente invention permet donc l'identification d'une pluralité de biomarqueurs d'une manière simple mais néanmoins précise.
PCT/KR2011/001558 2011-03-07 2011-03-07 Méthode d'identification de biomarqueur de cellules cancéreuses et biomarqueur de cellule cancéreuse sans rapport avec le nmd identifié au moyen de la méthode WO2012121429A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016065038A1 (fr) * 2014-10-23 2016-04-28 Five Prime Therapeutics, Inc. Antagonistes de slamf1 et leurs utilisations

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
FERREIRA, A. M. ET AL.: "Mononucleotide precedes dinucleotide repeat instability during colorectal tumour development in Lynch syndrome patients", J. PATHOL., vol. 219, no. 1, September 2009 (2009-09-01), pages 96 - 102 *
MA, J. ET AL.: "Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer", J. CLIN. INVEST., vol. 119, no. 3, March 2009 (2009-03-01), pages 478 - 491 *
SUN, X. ET AL.: "Detection of mononucleotide repeat sequence alterations in a large background of normal DNA for screening high-frequency microsatellite instability cancers", CLIN. CANCER RES., vol. 12, no. 2, 15 January 2006 (2006-01-15), pages 454 - 459 *
WONG, Y. F. ET AL.: "Detection of microsatellite instability in endometrial cancer: advantages of a panel of five mononucleotide repeats over the National Cancer Institute panel of markers", CARCINOGENESIS, vol. 27, no. 5, May 2006 (2006-05-01), pages 951 - 955 *
XICOLA, R. M. ET AL.: "Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors", J. NATL. CANCER INST., vol. 99, no. 3, 7 February 2007 (2007-02-07), pages 244 - 252 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016065038A1 (fr) * 2014-10-23 2016-04-28 Five Prime Therapeutics, Inc. Antagonistes de slamf1 et leurs utilisations

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