WO1997000449A1 - Systeme pronostique et therapeutique du cancer - Google Patents

Systeme pronostique et therapeutique du cancer Download PDF

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Publication number
WO1997000449A1
WO1997000449A1 PCT/GB1996/001423 GB9601423W WO9700449A1 WO 1997000449 A1 WO1997000449 A1 WO 1997000449A1 GB 9601423 W GB9601423 W GB 9601423W WO 9700449 A1 WO9700449 A1 WO 9700449A1
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WO
WIPO (PCT)
Prior art keywords
mmp
antibody
protein
agent
reactive
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PCT/GB1996/001423
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English (en)
Inventor
William Thomas Melvin
Margaret Ellen Duncan
John Edward Fothergill
Graeme Ian Murray
Original Assignee
Aberdeen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9512085.3A external-priority patent/GB9512085D0/en
Priority claimed from GBGB9602982.2A external-priority patent/GB9602982D0/en
Application filed by Aberdeen University filed Critical Aberdeen University
Priority to AU60126/96A priority Critical patent/AU6012696A/en
Publication of WO1997000449A1 publication Critical patent/WO1997000449A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Definitions

  • the present invention relates to a prognostic and therapeutic system and further to the production of antipeptide monoclonal antibodies to an activated matrix metalloproteinase-1 and -9 proteins and to a therapeutic or diagnostic system incorporating such antibodies.
  • Colon, prostate, ovarian and oesophageal cancers are among the commonest malignant tumours with a relatively poor prognosis.
  • the outcome of such cancers depends on the extent of both local and particularly metastatic tumour spread.
  • Tumour invasion and metastases result from a multi-step process, one key step of which is degradation of the extracelluar matrix by proteolytic enzymes.
  • Initial tumour invasion depends upon the destruction of the basement membrane whereas further spread of tumour cells requires digestion of the interstitial connective tissue.
  • MMP matrix metalloproteinase
  • the extracelluar matrix consists of two components, basement membrane and interstitial connective tissue both of which can be digested by a matrix metalloproteinase.
  • Matrix metalloproteinases are a family of proteolytic enzymes which share specific properties. These enzymes act to cleave components of the extracelluar matrix, with substrate specificity varying between metalloproteinases. All of the members of the metalloproteinase family require a metal atom bound at the active site to function. They show optimal activity at neutral pH.
  • Metalloproteinases are synthesized as inactive pro-enzymes which are activated by cleavage of a pro-peptide.
  • Matrix metalloproteinases are products of related genes and show much homology of their genetic sequences between members of the enzyme family. Thus far many distinct members of the metalloproteinase family have been identified, of which the following are examples.
  • Collagenases interstitial MMP-1 collagenous neutrophil MMP-8 collagenous Gelatinases gelatinase A MMP-2 (72kDa) gelatinase B MMP-9 (92kDa)
  • tumour spread is assisted by some MMPs which destroy the connective tissue between cells and organs allowing tumour cells to break out of their original site and enter new areas.
  • MMPs matrix metalloproteinases
  • matrix metalloproteinases are involved in the spread of cancers and it has also been recognised that this might correlate with the status of the cancers (see for example Jos et al., Int J Cancer, vol 45 (1990) pl071-1078)
  • the present invention is based on the surprising discovery that the production of individual members of the matrix metalloproteinase family are highly significant for the survival of patients with certain cancers and that other members of the matrix metalloproteinase family are not significant in relation to survival with the same cancers.
  • collagenases matrix metalloproteinase expression of the collagenases is significant, particularly for cancers such as colorectal, prostate and oesophageal cancer and that gelatinases, particularly MMP-9, are important markers for ovarian cancer.
  • Marimastat A synthetic inhibitor of MMPs under the name Marimastat is now undergoing clinical trials. This binds to the zinc atom at the active site inhibiting extracelluar matrix degradation and possibly tumour metastases.
  • the invention is thus predicated on the discovery that in tumours such as colorectal and ovarian cancers, MMP-1 and MMP- 9 are found to be produced in the more aggressive forms of disease where the prognosis in terms of life expectancy is shortest. It is also predicated on the basis that this discovery gives rise to effective therapeutic targets.
  • a method for the in vitro prognosis evaluation of cancer status from a sample comprises contacting said sample with a monoclonal or polyclonal antibody specific for a selected matrix metalloproteinase such as a collagenase or a gelatinase, and screening for a positive response.
  • the positive response may be indicated by an agglutination reaction or by a visualisable change such as a colour change or fluorescence e.g. immunostaining, or by a quantitative method such as the use of radiochemical methods or enzyme-linked antibody (Eliza) methods.
  • the antibody is a monoclonal antibody which is specific for the collagenous MMP-1 or the gelatinase B; MMP-9.
  • the invention also provides an antipeptide monoclonal antibody which is reactive with amino acid residues 267 to 277 of the activated MMP-1 protein, or antipeptide antibodies reactive with amino acid residues 603 to 614 of the MMP-9 protein (Swiss prot database numbering, identification number C0G9) .
  • the peptides may be synthesized with a cysteine residue included at the N-terminus to enable coupling to a carrier protein with for example MBS, (m-maleimidobenzoyl-N- hydroxysuccinimide ester) and then coupled to ovalbumin and bovine serum albumin.
  • a carrier protein with for example MBS, (m-maleimidobenzoyl-N- hydroxysuccinimide ester) and then coupled to ovalbumin and bovine serum albumin.
  • Polyclonal or monoclonal antibodies can then be produced in the usual way.
  • the antibodies of the present invention may also be used to produce therapeutic agents comprising antibodies reactive with the matrix metalloproteinases of the present invention, such antibodies being complexed with toxic, radioactive or other molecules capable of exerting an antitumour effect either directly or indirectly, (for example by stimulating a biological response or by converting a non-toxic molecule to a toxic molecule in the vicinity of the tumour) .
  • MMPs in general and the collagenases and gelatinases in particular can be modified for example by preventing activation of MMPs, by blocking access of substrates or cofactors to catalytic sites on the enzyme, by altering enzyme conformation or by mimicking the peptide which is cleaved from the pro-enzyme, by reproducing the action of TIMPs, by blocking binding to the tumour cell surface or by inhibition of the MMP catalytic sites.
  • therapeutic antibodies to have direct inhibitory effects of the activity of MMPs or that they can be used in conjunction with enzyme inhibitors to either introduce these inhibitors to the vicinity of the tumour or to potentiate the action of these inhibitors.
  • a therapeutic agent comprising an antipeptide monoclonal antibody to a metalloproteinase, especially a collagenase or gelatinase B, bound to either an anti tumour agent or an MMP inhibitory agent.
  • the metalloproteinase is preferably an MMP-1 or MMP-9.
  • MMP-1 the antibody preferably corresponds to amino acid residues 267 to 277 of the activated MMP-1 protein.
  • MMP-9 the antibody preferably corresponds to residues 603 to 614 of the MMP-9 protein.
  • the antitumour agent may comprise the antibody complexed to a cytotoxic drug or agent or alternatively may indirectly trigger the release of an antitumour drug or agent in the vicinity of the cancer.
  • antipeptide monoclonal antibody is complexed to a liposomal or other encapsulated preparation of an antitumour drug including a range of antitumour moieties including toxic chemicals, toxins, genes or even MMP enzyme inhibitors.
  • the MMP-1 inhibitory agent may have the effect selected from preventing activation for example mimicking the peptide residues which are cleaved from a pro-enzyme, or by reproducing the action of a TIMP, or by blocking tumour cell surface binding or by inhibition of MMP catalytic sites.
  • the present invention illustrates the general principle that the presence of individual matrix metalloproteinases can be highly significant in the prognosis of certain cancers and it is apparent that there are likely to be other examples where matrix metalloproteinase production will relate to tumour prognosis. It will now be obvious to those skilled in the art that the present invention could therefore be applied in a number of ways following the identification of individual matrix metalloproteinases with high prognostic significance. In diagnostic applications, individual MMPs could be measured as an indicator of the prognosis of the cancer which might guide the clinician in choice of therapy for the individual patient.
  • MMPs could be used as markers to identify patients with good and bad prognosis prior to selection of patients for trials and MMPs could then be used as surrogate marker end-points as an alternative to patient survival to accelerate the trials.
  • specific MMP's could either be inhibited or targeted as a means for destroying or retarding tumour cells involved in the progression of the cancer.
  • antibodies of the present invention could be used to direct cytotoxic agents or other molecules capable of exerting an antitumour effect either directly or indirectly (for example by stimulating a biological response or by converting a non-toxic molecule to a toxic molecule in the vicinity of the tumour) or to direct other agents such as imaging agents to the tumour cells since the metalloproteinase has been shown to be present at the tumour cell surface.
  • Agents derived from the antibodies such as Fab 2 or Fab molecules produced by enzymatic digestion or molecules such as scFv or humanized antibody molecules produced by recombinant DNA methods may also be used for this purpose.
  • Figures 1 to 3 show in graphic form the production of MMP-1 and MMP-9 and survival of patients with colorectal, oesophageal and ovarian cancers respectively, and Figure 4 shows a plot of an assay to show antibodies specific for individual MMP's.
  • the region chosen for generation of a first anti-peptide monoclonal antibodies was SSFGFPRTVKH. This corresponds to amino acid residues 267-277 of the activated MMP-1 protein.
  • anti-peptide monoclonal antibodies for MMP-2 and MMP-9 were produced, respectively corresponding to amino acid residues 557 to 569 and 603 to 614.
  • Specificity of Anti MMP-1, MMP-2 and MMP-9 are shown in Figure 4.
  • the selected peptide were synthesised at the Krebs Institute, University of Sheffield, with a cysteine residue included at the N-terminus to enable coupling to carrier proteins by m- maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) .
  • MBS m- maleimidobenzoyl-N-hydroxysuccinimide ester
  • the peptides were coupled to hen ovalbumin and bovine serum albumin (BSA) (Fluka) by an adaption of the method described in Sambrook et al (1989) .
  • BSA bovine serum albumin
  • the conjugates were analyzed by mass spectroscopy to ensure successful coupling and their concentrations determined by amino acid analysis.
  • mice Female BALB/c mice were injected intraperitoneally with the peptide-ovalbumin conjugates in PBS. The first and second injections were 100 ⁇ g conjugate in Freund's complete and incomplete adjuvant, respectively, at an interval of 2 weeks. Three months later the mice were tested for antibody production by tail bleeds, and the best responding mouse received a third injection of 400 ⁇ g of conjugate with no adjuvant. Three days after the final injection, the mouse spleen was removed for the production of hybridomas by fusion of the spleen cells with mouse myeloma Ag8.653 cells by standard methods (Kohler and Milstein, 1975; Barnes et al 1987) . Antibody-producing hybridomas were identified by ELISA and immunoblotting and cloned twice by limiting dilution. Clones were isotyped using an Isostrip kit (Boehringer Mannheim) .
  • Wells of 96-well microtitre plates (Titertek, Flow Laboratories) were coated with peptide-BSA conjugate at 7.2 ⁇ g/ml in 50 mM carbonate-bicarbonate buffer, pH 9.6, by incubation overnight at 4°C.
  • the wells were washed once with PBS-Tween (PBS containing 0.05% Tween 20) and unoccupied non ⁇ specific protein-binding sites on the wells were then blocked by incubation with 1% BSA in 50 mM sodium carbonate/bicarbonate buffer, pH 9.6.
  • the wells were washed 3 times with PBS-Tween and then incubated with samples to be tested for antibodies (undiluted cell culture supernatant or 1/100 and further doubling dilutions of mouse serum) .
  • the wells were washed 3 times as before and incubated with alkaline-phosphatase-conjugated goat anti-mouse IgG (F c specific, Sigma cat. no. A2429) , diluted 1/2500 in PBS-Tween containing 0.5% BSA.
  • the alkaline phosphatase substrate p-nitrophenyl phosphate was added at 0.1% in 0.1 M glycine/NaOH buffer, pH 10.4, containing 1 mM ZnCl 2 and 1 mM MgCl 2 . All of the above incubations were at 37°C for one hour and volumes per well were 50 ⁇ l except for blocking and washing where 200 ⁇ l were used. The plates were read at 405 nm against a reference of 492 nm in a Titertek Multiscan plate reader to measure the formation of p- nitrophenol.
  • Sections of tumour were immunostained with a monoclonal antibodies to MMP-1, MMP-2 and MMP-9 using an alkaline> phosphatase anti-alkaline phosphatase method as previously described.
  • Formalin fixed wax embedded sections (4 m) of tissue were dewaxed in xylene, rehydrated in alcohol and then washed sequentially in cold water and 0.05M Tris-HCl (pH 7.6) containing 0.15M sodium chloride (TBS). Sections of tissue were incubated for one hour with the MMP antibodies. Sites of antibody binding were demonstrated using an alkaline phosphatase anti-alkaline phosphatase (APAAP) technique. Rabbit anti-mouse immunoglobulin (1/100 containing 1% normal human serum, Dako) and monoclonal APAAP (1/100, Dako) were sequentially applied to the tissue sections for 30 minutes each. Between antibody applications the sections were washed with TBS to remove unbound antibody.
  • APAAP alkaline phosphatase anti-alkaline phosphatase
  • Sites of bound alkaline phosphatase were identified using an enzyme substrate solution containing 3 mg bromo-chloro-indolyl phosphate (Sigma Chemical Co Ltd, Poole, Dorset) , 10 mg nitro blue tetrazolium (Sigma) , 6 mg sodium azide and 4 mg levamisole (Sigma) in 10 ml 0.05M Tris-HCl buffer (pH 9.0) containing 0.2% magnesium chloride. After incubating the sections for 30 minutes at room temperature, the reaction was stopped by washing the section sin cold tap water. The slides were then air-dried and mounted in glycerine jelly.
  • Sections were subjected to an antigen retrieval step by microwaving the sections for twenty minutes in 0.01M citrate buffer pH 6.0 prior to application of the primary antibody.
  • the slides were examined using light microscopy by two observers in order to determine qualitatively the presence or absence of immunostaining, and its distribution. Individual tumours were classified as positive if five percent or more of the tumour cells were positive. The follow-up data was obtained after determination of MMP immunoreactivity in the tumours.
  • Example 1 The immunohistochemistry method of Example 1 was also applied to 32 sections from ovarian cancer. The results are given in Figure 2. It will be apparent from Figure 2 that the cumulative survival rates in patients expressing MMP-9 was 60% at 40 months; wherein those patients with ovarian cancer but MMP-9 negative had an excellent prognosis in that all the samples were alive at 60 months.
  • the antibody from example 1 with specificity for MMP-1 was complexed with the radioactive label 131 I or 90 Y.
  • the antibody binds to MMP-1 associated with cells of the colon cancer and the accompanying radioactive emission irradiates and kills the cancer cells.
  • the antibody from example 1 with specificity for MMP-1 was complexed with a carboxypeptidase G2 enzyme.
  • the antibody binds to MMP-1 associated with cells of the colon cancer.
  • a pro-drug was injected into the patient which was converted by the action of the carboxypeptidase to a cytotoxic drug which kills the cancer cells.
  • MMPs are important in digesting different components of extracelluar connective tissue.
  • Individual MMPs may be active at different stages of tumour spread.
  • Initial tumour invasion depends on degradation of the basement membrane surrounding individual tumour cells while spread of established malignant tumours depends on degrading interstitial connective tissue. Therefore action of MMP-1 and MMP-9 which is the first step in digesting various components of interstitial connective tissue is possibly more important in facilitating the spread of established invasive tumours both locally and within distant organs.
  • expression of MMP-1 and MMP-9 in cancers are associated with a significantly poorer prognosis compared with those tumours which do not express MMP-1 or MMP-9.
  • MMP-1 and MMP-9 expression are important for tumours to spread.
  • MMP-1 degrades collagenase types I, II and III and increased collagenase activity towards type I and type III collagens is indicative of colorectal cancer.
  • MMP-1 degrades collagenase types I, II and III and increased collagenase activity towards type I and type III collagens is indicative of colorectal cancer.
  • MMP-1 and MMP-9 are prognostic factors which are altered by therapeutic intervention as they are targets for MMP inhibitors.
  • the monoclonal antibodies to MMP-1 and MMP-9 used in this study are reactive in formalin fixed wax embedded sections and thus can be used in routine diagnostic histopathology practice to evaluate MMP status in colorectal or ovarian cancers and identify those patients who may benefit from anti-MMP therapy.

Abstract

Cette invention concerne une méthode d'évaluation pronostique in vitro du stade d'un cancer colo-rectal, ÷sophagien ou ovarien, à partir d'un échantillon, à l'aide d'un anticorps monoclonal ou polyclonal spécifique d'une métalloprotéase de matricielle déterminée et la recherche d'une réponse positive. La métalloprotéase matricielle peut être une collagénase ou une gélatinase, en particulier une MPM-1 ou une MPM-9.
PCT/GB1996/001423 1995-06-14 1996-06-13 Systeme pronostique et therapeutique du cancer WO1997000449A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60126/96A AU6012696A (en) 1995-06-14 1996-06-13 Prognostic and therapeutic system for cancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9512085.3 1995-06-14
GBGB9512085.3A GB9512085D0 (en) 1995-06-14 1995-06-14 Diagnostic antibody system
GB9602982.2 1996-02-14
GBGB9602982.2A GB9602982D0 (en) 1996-02-14 1996-02-14 Diagnostic antibody system

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020860A1 (fr) * 1998-10-08 2000-04-13 Calbiochem Novabiochem Corporation Methode diagnostique de detection de metalloprotease matricielle-9 et utilisation de ladite methode
US7101975B1 (en) * 1999-07-13 2006-09-05 University Of Southern California Method and composition for inhibition of angiogenesis using antagonists based on MMP-9 and β1 integrins
WO2010060282A1 (fr) * 2008-11-27 2010-06-03 浙江大学 Application de mmp-9 en tant que marqueur diagnostique pour le carcinome ovarien
EP2581445A1 (fr) * 2007-08-15 2013-04-17 Yeda Research And Development Co. Ltd. Régulateurs de mmp -9 et leurs utilisations
US10260104B2 (en) 2010-07-27 2019-04-16 Genomic Health, Inc. Method for using gene expression to determine prognosis of prostate cancer
US10934338B2 (en) 2015-03-27 2021-03-02 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
CN114252609A (zh) * 2021-12-23 2022-03-29 武汉生之源生物科技股份有限公司 一种基质金属蛋白酶-9的检测试剂盒及其检测方法
US11365235B2 (en) 2015-03-27 2022-06-21 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors

Citations (1)

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WO1993020447A1 (fr) * 1992-03-31 1993-10-14 The Research Foundation Of State University Of New York Tests diagnostiques servant a mesurer les complexes gelatinases/inhibiteurs pour depister le cancer agressif et metastatique

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1993020447A1 (fr) * 1992-03-31 1993-10-14 The Research Foundation Of State University Of New York Tests diagnostiques servant a mesurer les complexes gelatinases/inhibiteurs pour depister le cancer agressif et metastatique

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Title
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S. ZUCKER ET AL.: "Immunoassay of type IV collagenase / gelatinase (MMP-2) in human plasma", JOURNAL OF IMMUNOLOGICAL METHODS, vol. 148, 1992, AMSTERDAM NL, pages 189 - 198, XP000609024 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020860A1 (fr) * 1998-10-08 2000-04-13 Calbiochem Novabiochem Corporation Methode diagnostique de detection de metalloprotease matricielle-9 et utilisation de ladite methode
US7101975B1 (en) * 1999-07-13 2006-09-05 University Of Southern California Method and composition for inhibition of angiogenesis using antagonists based on MMP-9 and β1 integrins
EP2581445A1 (fr) * 2007-08-15 2013-04-17 Yeda Research And Development Co. Ltd. Régulateurs de mmp -9 et leurs utilisations
US8999332B2 (en) 2007-08-15 2015-04-07 Yeda Research And Development Co. Ltd. Regulators of MMP-9 and uses thereof
WO2010060282A1 (fr) * 2008-11-27 2010-06-03 浙江大学 Application de mmp-9 en tant que marqueur diagnostique pour le carcinome ovarien
CN101738478A (zh) * 2008-11-27 2010-06-16 浙江大学 Mmp9作为卵巢癌的诊断标记物的用途
US10260104B2 (en) 2010-07-27 2019-04-16 Genomic Health, Inc. Method for using gene expression to determine prognosis of prostate cancer
US11407809B2 (en) 2015-03-27 2022-08-09 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11434273B2 (en) 2015-03-27 2022-09-06 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11365235B2 (en) 2015-03-27 2022-06-21 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11365234B2 (en) 2015-03-27 2022-06-21 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11407807B2 (en) 2015-03-27 2022-08-09 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US10934338B2 (en) 2015-03-27 2021-03-02 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11407810B2 (en) 2015-03-27 2022-08-09 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11407808B2 (en) 2015-03-27 2022-08-09 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11434274B2 (en) 2015-03-27 2022-09-06 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11965013B2 (en) 2015-03-27 2024-04-23 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11440947B2 (en) 2015-03-27 2022-09-13 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11459371B2 (en) 2015-03-27 2022-10-04 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11466072B2 (en) 2015-03-27 2022-10-11 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11702460B2 (en) 2015-03-27 2023-07-18 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11873329B2 (en) 2015-03-27 2024-01-16 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
US11897934B2 (en) 2015-03-27 2024-02-13 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various tumors
CN114252609A (zh) * 2021-12-23 2022-03-29 武汉生之源生物科技股份有限公司 一种基质金属蛋白酶-9的检测试剂盒及其检测方法

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