CN110526972A - A kind of purposes of anti-cd 47 antibody in the drug of preparation treatment lymthoma - Google Patents

A kind of purposes of anti-cd 47 antibody in the drug of preparation treatment lymthoma Download PDF

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CN110526972A
CN110526972A CN201910441395.1A CN201910441395A CN110526972A CN 110526972 A CN110526972 A CN 110526972A CN 201910441395 A CN201910441395 A CN 201910441395A CN 110526972 A CN110526972 A CN 110526972A
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ser
antibody
thr
val
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徐祖朋
廖成
杨昌永
张连山
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Abstract

The present invention relates to a kind of purposes of anti-cd 47 antibody in the drug of preparation treatment lymthoma.Further, the purposes in the drug of preparation treatment lymthoma is combined the invention further relates to a kind of anti-cd 47 antibody and anti-CD 20 antibodies.Anti-cd 47 antibody combines anti-CD 20 antibodies combination therapy lymthoma, compared to single therapy, can substantially reduce gross tumor volume.

Description

A kind of purposes of anti-cd 47 antibody in the drug of preparation treatment lymthoma
Technical field
The present invention relates to a kind of purposes of anti-cd 47 antibody in the drug of preparation treatment lymthoma.Further, this hair It is bright to further relate to a kind of anti-cd 47 antibody and anti-CD 20 antibodies combine the purposes in the drug of preparation treatment lymthoma.
Background technique
As the mankind go deep into what is recognized in immune system and elaboration of tumour mechanism, tumour immunotherapy has been had become The mankind are to antitumor powerful mean.
Cancer target monoclonal antibody is one of the important means of immunotherapy of tumors field.Macrophage plays phagocytosis effect Work simultaneously in requisition for two signals: one be target cell surface " eating me " signal activation, the other is same thin The inactivation of cellular surface " not eating me " signal.Any one signal lacks the generation for all being not enough to cause Phagocytosis.Increasingly More evidences shows that CD47 is a kind of " not eating me " signal, it presses down and the SIRP- α with Macrophage Surface be combined with each other The phagocytic function of macrophage processed.
CD47 is Mitochondrion IgG superfamily member, and wide expression is such as red thin in the cell surface of different tissues Born of the same parents, lymphocyte, blood platelet, liver cell.CD47 has higher expression on various tumour cells, and there have that researches show that kinds of tumors to be thin The CD47 expression quantity of cellular surface is higher than normal cell averagely more than about 3 times.In addition, cancer cell express the patient of a large amount of CD47 compared to CD47 expresses low-level patient with shorter life cycle.Research at present is it has been found that the anti-CD47 monoclonal antibody of blocking property There is very good effect in terms of oncotherapy, but the mechanism of action of this process is unclear.Existing correlation at present CD47 patent, such as PCT/CN2017113081, WO2016065329, WO2016109415, WO2014087248 and WO2014093678.It effectively blocks the combination between CD47 and SIRP- α and promotes internal macrophage gulping down for tumour cell It bites, there are good clinical landscapes.
Anti-CD 20 antibodies Rituximab is that the first monoclonal antibody for oncotherapy, FDA were criticized in 1997 in history It is mutatis mutandis in treatment non-Hodgkin lymphoma.Rituximab can cause the immune response of lymphoma cell dissolution in conjunction with CD20, can The mechanism of action of energy includes: the cytotoxicity (ADCC) of antibody-dependant cell；The cytotoxicity (CDC) of Complement Dependent；It lures Lead apoptosis；The release of inducing cytokine such as IL-2 and TNF；Act on antiidiotype network；Increase lymphoma cell to chemotherapy Sensibility (Coucxmum MS, Lopez AJ, the White CA.et al.Treatment of patients with of drug low Bcell lymphoma with the combination of chimeric anti CD20 monoclonal antibody andCHOP chemotherapy.Clin Oncol.1999；17:268-76).
In recent years, the treatment gone out shown by the malignant lymphoma and various autoimmune disease as CD20 targeted therapy Prospect and commercial value have more biotech companies to participate in the research and development and competition of the anti-CD 20 antibodies of a new generation.With CD20 is that the antibody drug of target spot can be divided into three generations: the first generation is source of mouse or chimeric antibody, such as rituximab, ibritumomab tiuxetan,Tositumomab；The second generation is humanized antibody, such as ofatumumab, ocrelizumab,veltuzumab；Obinutuzumab, ocaratuzumab, ublituximab of the third generation, therapy field It is also not limited to Fei Huoqi lymthoma, further includes multiple sclerosis, immune thrombocytopenia etc..
One of an important factor for drug combination is influence drug effect.When two or more Drug combination, both It can produce synergistic effect, also can produce antagonism.Anti-CD 20 antibodies are clinically controlled with a variety of drug combinations at present Treat tumour, but still it is not high there is Tumor response rate the problems such as, whether anti-CD 20 antibodies and anti-CD47 can be successfully applied to It is clinical to be still worth further investigation.
Summary of the invention
The present invention provides a kind of use of anti-cd 47 antibody or its antigen-binding fragment in the drug of preparation treatment lymthoma On the way, wherein the anti-cd 47 antibody includes any one or more CDR regions selected from the following:
The area HCDR of antibody heavy chain variable region: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 7, SEQ ID NO:8, SEQ ID NO:9 and with SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9 have the CDR of at least 85% sequence identity；With
The area LCDR of antibody's light chain variable region: SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO:12 and with SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 have the CDR of at least 85% sequence identity.
Wherein, mentioned-above each CDR sequence is as shown in the table:
In one embodiment of the invention, wherein the antibody heavy chain variable region includes SEQ ID NO:1, SEQ ID HCDR1, HCDR2 and HCDR3 shown in NO:2 and SEQ ID NO:3, or with SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 has the CDR of at least 85% sequence identity；And/or
The antibody's light chain variable region includes shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 LCDR1, LCDR2 and LCDR3, or have at least 85% sequence same with SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6 The CDR of one property.
In one embodiment of the invention, wherein the antibody heavy chain variable region includes SEQ ID NO:7, SEQ ID HCDR1, HCDR2 and HCDR3 shown in NO:8 and SEQ ID NO:9, or with SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9 has the CDR of at least 85% sequence identity；And/or
The antibody's light chain variable region includes shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12 LCDR1, LCDR2 and LCDR3, or there is at least 85% sequence with SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 The CDR of identity.
The present invention one apply in scheme, wherein the antibody includes: heavy chain variable region shown in SEQ ID NO:13 or Light chain variable region or its mutant nucleotide sequence shown in its mutant nucleotide sequence and SEQ ID NO:14；Or
The antibody includes: heavy chain variable region shown in SEQ ID NO:15 or its mutant nucleotide sequence and SEQ ID NO:16 Shown in light chain variable region or its mutant nucleotide sequence.
Wherein, mentioned-above each variable region sequences are as follows:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSSYLHWVRQAPGQRLEWMGWIYPESGNTKYNERFKGRVT ITRDTSASTAYMELSSLRSEDTAVYYCARRGDVFFAYWGQGTTVTVSS
SEQ ID NO:13
DIVMTQSPDSLAVSLGERATINCKSSQSLLTSGKQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK
SEQ ID NO:14
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQGLEWMGNIDPSDSETHYNQKFKDRVT MTRDTSISTAYMELSRLRSDDTAVYYCARWGYLGRSAMDYWGQGTTVTVSS
SEQ ID NO:15
DIQMTQSPSSLSASVGDRVTITCRTSKSISKFLAWYQQKPGKAPKLLIYSGSTLQSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIK
SEQ ID NO:16
In one embodiment of the invention, in which:
The mutant nucleotide sequence of light chain variable region shown in SEQ ID NO:14 includes mutation D66E；
The mutant nucleotide sequence of heavy chain variable region shown in SEQ ID NO:13 includes mutation selected from the following: R72A, M48I, E46D, V68A, I70L, R38K, R67K, A97S and combinations thereof；It is preferred that R72A, M48I, E46D, V68A, I70L and combinations thereof；
The mutant nucleotide sequence of light chain variable region shown in SEQ ID NO:16 includes mutation selected from the following: V58I, I2V, M4I, Q38E, A43T, P44H and combinations thereof；It is preferred that I2V, M4I and combinations thereof；
The mutant nucleotide sequence of heavy chain variable region shown in SEQ ID NO:15 includes mutation selected from the following: R72V, M48V, V68A, M70L, T74K, A40R, R38K, R67K and combinations thereof.
In one embodiment of the invention, wherein the antibody includes: heavy chain overall length sequence shown in SEQ ID NO:17 Column or its mutant nucleotide sequence and SEQ ID NO:18 shown in light chain full length sequence or its mutant nucleotide sequence；Or the antibody includes: Light chain full length sequence shown in heavy chain full length sequence shown in SEQ ID NO:19 or its mutant nucleotide sequence and SEQ ID NO:20 or Its mutant nucleotide sequence.
Wherein, mentioned-above each variable region sequences are as follows:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQGLEWMGNIDPSDSETHYNQKFKDRVT MTRDTSISTAYMELSRLRSDDTAVYYCARWGYLGRSAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:17
DVQITQSPSSLSASVGDRVTITCRTSKSISKFLAWYQQKPGKAPKLLIYSGSTLQSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:18
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSSYLHWVRQAPGQRLDWIGWIYPESGNTKYNERFKGRAT LTADTSASTAYMELSSLRSEDTAVYYCARRGDVFFAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:19
DIVMTQSPDSLAVSLGERATINCKSSQSLLTSGKQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:20
In one embodiment of the invention, wherein the anti-cd 47 antibody or its antigen-binding fragment and anti-CD 20 antibodies or its Antigen-binding fragment is used in combination.
In one embodiment of the invention, wherein the anti-CD 20 antibodies include rituximab, obinutuzumab, Tositumomab、ibritumomab tiuxetan、ofatumumab、ocrelizumab、veltuzumab、 Ocaratuzumab, ublituximab and SCT-400.
In one embodiment of the invention, wherein the lymthoma includes Hodgkin lymphoma and non-Hodgkin's lymph Tumor；Preferably, non-Hodgkin lymphoma includes follicular lymphoma, lymphoma mantle cell, Diffuse Large B-Cell Lymphoma, NK/T Cell lymphoma and t cell lymphoma.
In one embodiment of the invention, wherein to receive cyclophosphamide, adriamycin, Changchun new for the knot lymthoma One or more combined therapies in alkali, prednisone.
In one embodiment of the invention, wherein the anti-cd 47 antibody or its antigen-binding fragment dosage is selected from 0.1-50mg/kg, preferably be selected from 0.3mg/kg, 0.5mg/kg, 0.75mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 5mg/kg, 10mg/kg、20mg/kg、30mg/kg。
In one embodiment of the invention, wherein the anti-cd 47 antibody or its antigen-binding fragment dosage is selected from 6- 3000mg, preferably be selected from 18mg, 30mg, 60mg, 100mg, 150mg, 175mg, 200mg, 300mg, 400mg, 500mg, 600mg, 1000mg。
In one embodiment of the invention, wherein the anti-CD 20 antibodies or its antigen-binding fragment dosage are selected from 100-500mg/m2, it preferably is selected from 100mg/m2、150mg/m2、200mg/m2、250mg/m2、275mg/m2、300mg/m2、325mg/ m2、350mg/m2、375mg/m2、400mg/m2、450mg/m2、500mg/m2。
A effective amount of anti-cd 47 antibody above-mentioned is applied the present invention also provides a kind of methods for the treatment of, including to patient Or its antigen-binding fragment and anti-CD 20 antibodies or its antigen-binding fragment.
The present invention also provides a kind of medicine sleeve group or a kind of medicine package boxes, wherein containing above-mentioned a effective amount of Anti-cd 47 antibody or its antigen-binding fragment and anti-CD 20 antibodies or its antigen-binding fragment.
The present invention also provides a kind of pharmaceutical compositions, include a effective amount of anti-cd 47 antibody above-mentioned or its antigen binding Segment and anti-CD 20 antibodies or its antigen-binding fragment and one or more pharmaceutical excipients, diluent or carrier.
Detailed description of the invention
One, term
In order to be easier to understand the present invention, certain technical and scientific terms are defined in detail below.Except obviously at this It is separately explicitly defined at it in file, otherwise all other technical and scientific term used herein all has belonging to the present invention The normally understood meaning of the those skilled in the art in field.
Term " humanized antibody (humanized antibody) ", also referred to as CDR grafted antibody (CDR-grafted Antibody), refer to the antibody variable region frame that the CDR sequence of mouse is transplanted to people, i.e., different types of human germline antibody The antibody generated in frame sequence.Chimeric antibody can be overcome due to carrying a large amount of murine protein ingredients, so that induction is strong Antibody variable antibody response.Such frame sequence can be from public DNA database or public affairs including germline antibody gene sequences The bibliography opened obtains.As people's heavy chain and the germline DNA sequence dna of light-chain variable region gene can be in " VBase " human germ line sequences Database (can get) in internet www.mrccpe.com.ac.uk/vbase, and in Kabat, E.A. et al., and 1991 Sequences of Proteins of Immunological Interest is found in the 5th edition.
Term " antigen-binding fragment ", refers to the Fab segment with antigen-binding activity, Fab ' segment, 2 segment of F (ab '), And the Fv segment sFv segment in conjunction with people CD47；SEQ ID NO:1 to SEQ ID is selected from comprising antibody of the present invention One or more CDR regions in NO:12.Fv segment contains antibody heavy chain variable region and light chain variable region, but does not have constant region, and Minimum antibody fragment with whole antigen binding sites.Generally, Fv antibody also includes more between VH and VL structural domain Peptide linker, and structure needed for being capable of forming antigen binding.Two antibody variable regions can also be connected with different attachments At a polypeptide chain, referred to as single-chain antibody (single chain antibody) or scFv (sFv).
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.
1, experiment purpose: this experiment establishes tumor model in mouse hypodermic inoculation Raji cell, by the volume of tumour and Mouse weight evaluates drug combination to antitumor action and its safety.
2, experimental material and method:
2.1 experimental animals and material:
Mouse: it 60, is provided by Shanghai western Poole-Bi Kai experimental animal Co., Ltd, SPF grades.
Solvent: sodium chloride injection
Human IgG: Hengrui Pharmaceutical Co., Ltd., Shanghai, lot number: HRP00212-002
Anti-cd 47 antibody: SEQ ID NO:17 and SEQ ID NO:18 in its heavy, light chain sequence such as present invention, injection Appropriate normal saline dilution is added to required concentration, lot number P1715 in liquid.
Rituximab: it is provided by Roche Holding Ag.
Raji cell: 1640 culture mediums, 10% fetal calf serum, 37 DEG C, 5%CO2Culture.Cell symbol of the selection for implantation Close following four standard: 1) fast-growth；2) passage number is few；3) there is high viability.
2.2 experimental methods:
By Raji cell suspension withMatrix is mixed according to the ratio of 1:1, by 6 × 106A Raji cell note It injects in the left oxter of nude mouse.
To tumour growth to average external volume 100-200mm3Afterwards, it is administered after animal being grouped by knurl product is random.60 naked Mouse is divided into 6 groups: negative control group (100 μ of IgG4 g/ times), CD47 antibody low dose group (4 μ g/ times), CD47 antibody middle dosage Group (20 μ g/ times), CD47 antibody high dose group (100 μ g/ times), Rituximab group (10 μ g/ times), combination group (CD47 antibody 20 μ g/ times+10 μ of Rituximab g/ times), every group 10.The above each group animal subject is only given phase by administration capacity 0.2mL/ Tested material is answered, once every other day.
It weighs weekly and measures gross tumor volume 2 times, dosage period 25 days, weighed in the 25th day, measure gross tumor volume, Execution nude mouse takes tumor mass to weigh within 25th day, calculates relative tumour volume (RTV), Relative tumor appreciation rate (T/C), tumour growth Inhibit percentage (TGI) and tumor suppression percentage (IR), and carries out statistical analysis.
3, data representation and statistical procedures
Weight, gross tumor volume and the knurl weight of groups of animals, data mean+SD (Mean ± SEM) expression, T- Test carries out statistical analysis to data.Gross tumor volume calculation formula: volume=0.5236 × length × short × height
4, experimental result
Compared with negative control group, each group nude mouse weight has no significant change.
Compared with negative control group (100 μ of IgG4 g/ times) 1735 ± 230mm3 of gross tumor volume, CD47 antibody low dose group (4 μ g/ times), CD47 antibody middle dose group (20 μ g/ times), CD47 antibody high dose group (100 μ g/ times), Rituximab group (10 μ g/ times) and combination group (10 μ of g/ times+Rituximab of 20 μ of CD47 antibody g/ times) gross tumor volume be obviously reduced, volume is respectively 752 ± 98 (P < 0.001), 803 ± 136 (P < 0.001), 710 ± 167 (P < 0.01), 579 ± 66 (P < 0.001) and 377 ± 45mm3(P<0.001)。
Compared with negative control group (100 μ of IgG4 g/ times) RTV value 12.31 ± 3.00, CD47 antibody low dose group (4 μ g/ It is secondary), CD47 antibody middle dose group (20 μ g/ times), CD47 antibody high dose group (100 μ g/ times), Rituximab group (10 μ g/ It is secondary) and combination group (10 μ of g/ times+Rituximab of 20 μ of CD47 antibody g/ times) RTV value be substantially reduced, respectively 5.28 ± 1.24 (P < 0.05), 4.62 ± 0.42 (P < 0.05), 4.41 ± 1.11 (P < 0.05), 3.36 ± 0.45 (P < 0.01) and 2.28 ± 0.30 (P<0.01)。
CD47 antibody low dose group (4 μ g/ times), CD47 antibody middle dose group (20 μ g/ times), CD47 antibody high dose group (100 μ g/ times), Rituximab group (10 μ g/ times) and combination group (10 μ of g/ times+Rituximab of 20 μ of CD47 antibody g/ times) T/C value is respectively 42.88%, 37.56%, 35.80%, 27.27% and 18.54%, TGI value is respectively 57.12%, 62.44%, 64.20%, 72.73% and 81.46%.
Compared with negative control group (100 μ of IgG4 g/ times) 1.3086 ± 0.2540g of tumor mass weight, CD47 antibody low dosage Group (4 μ g/ times), CD47 antibody middle dose group (20 μ g/ times), CD47 antibody high dose group (100 μ g/ times), Rituximab group (10 μ g/ times) and combination group (10 μ of g/ times+Rituximab of 20 μ of CD47 antibody g/ times) tumor mass weight significantly reduce, respectively 0.5200±0.1172(P<0.001)、0.5254±0.0973(P<0.001)、0.4205±0.1003(P<0.001)、 0.4757 ± 0.0752 (P < 0.001) and 0.3576 ± 0.0659g (P < 0.001).
CD47 antibody low dose group (4 μ g/ times), CD47 antibody middle dose group (20 μ g/ times), CD47 antibody high dose group (100 μ g/ times), Rituximab group (10 μ g/ times) and combination group (10 μ of g/ times+Rituximab of 20 μ of CD47 antibody g/ times) IR value is respectively 60.26%, 59.85%, 67.86%, 63.64% and 72.67%.
Compared with Rituximab g/ group of 10 μ, g/ combination group of 20 μ of CD47 antibody, 10 μ of g/ times+Rituximab the 25th Its gross tumor volume is substantially reduced (579 ± 66vs, 377 ± 45mm3(P < 0.05)), CD47 antibody is shared with Rituximab can Enhance the anti-tumor activity of Rituximab.
5, conclusion
The growth to human lymphoma cell's Raji Nude Mice is administered in CD47 antibody low, middle and high dose groups tail vein There is inhibiting effect, high dose group inhibitory effect is best；CD47 antibody is shared with Rituximab can enhance Rituximab Anti-tumor activity.Tumor-bearing mice can be resistant to drug very well, not have the symptoms such as obvious weight loss.
Sequence table
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<120>purposes of a kind of anti-cd 47 antibody in the drug of preparation treatment lymthoma
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<212> PRT
<213>mouse (Mus musculus)
<220>
<221> DOMAIN
<223>HCDR3 of clone 167
<400> 16
Trp Gly Tyr Leu Gly Arg Ser Ala Met Asp Tyr
1 5 10
<210> 17
<211> 11
<212> PRT
<213>mouse (Mus musculus)
<220>
<221> DOMAIN
<223>LCDR1 of clone 167
<400> 17
Arg Thr Ser Lys Ser Ile Ser Lys Phe Leu Ala
1 5 10
<210> 18
<211> 7
<212> PRT
<213>mouse (Mus musculus)
<220>
<221> DOMAIN
<223>LCDR2 of clone 167
<400> 18
Ser Gly Ser Thr Leu Gln Ser
1 5
<210> 19
<211> 9
<212> PRT
<213>mouse (Mus musculus)
<220>
<221> DOMAIN
<223>LCDR3 of clone 167
<400> 19
Gln Gln His Asn Glu Tyr Pro Trp Thr
1 5
<210> 20
<211> 117
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223>the humanized heavy chain variable region of source of mouse antibody 055
<400> 20
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Glu Ser Gly Asn Thr Lys Tyr Asn Glu Arg Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Gly Asp Val Phe Phe Ala Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 21
<211> 113
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223>the humanization light chain variable region of source of mouse antibody 055
<400> 21
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Thr Ser
20 25 30
Gly Lys Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 22
<211> 120
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223>the humanized heavy chain variable region of source of mouse antibody 167
<400> 22
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Tyr Leu Gly Arg Ser Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 23
<211> 107
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223>the humanization light chain variable region of source of mouse antibody 167
<400> 23
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Lys Ser Ile Ser Lys Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Asn Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 26
<211> 447
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223>hu167-33 sequence of heavy chain
<400> 26
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Tyr Leu Gly Arg Ser Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 27
<211> 214
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223>hu167-33 sequence of light chain
<400> 27
Asp Val Gln Ile Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Lys Ser Ile Ser Lys Phe
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Asn Glu Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 28
<211> 444
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223>hu055-5 sequence of heavy chain
<400> 28
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Asp Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Glu Ser Gly Asn Thr Lys Tyr Asn Glu Arg Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Gly Asp Val Phe Phe Ala Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 29
<211> 220
<212> PRT
<213>artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223>hu055-5 sequence of light chain
<400> 29
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Thr Ser
20 25 30
Gly Lys Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220

Claims (15)

1. the purposes of a kind of anti-cd 47 antibody or its antigen-binding fragment in the drug of preparation treatment lymthoma, wherein described anti- CD47 antibody includes any one or more CDR regions selected from the following:
The area HCDR of antibody heavy chain variable region: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9 and with SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 7, SEQ ID NO:8, SEQ ID NO:9 have the CDR of at least 85% sequence identity；With
The area LCDR of antibody's light chain variable region: SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 and with SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 have the CDR of at least 85% sequence identity.
2. purposes according to claim 1, wherein the antibody heavy chain variable region includes SEQ ID NO:1, SEQ ID HCDR1, HCDR2 and HCDR3 shown in NO:2 and SEQ ID NO:3, or with SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 has the CDR of at least 85% sequence identity；And/or
The antibody's light chain variable region include SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 shown in LCDR1, LCDR2 and LCDR3, or there is at least 85% sequence identity with SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6 CDR。
3. purposes according to claim 1, wherein the antibody heavy chain variable region includes SEQ ID NO:7, SEQ ID HCDR1, HCDR2 and HCDR3 shown in NO:8 and SEQ ID NO:9, or with SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9 has the CDR of at least 85% sequence identity；And/or
The antibody's light chain variable region include SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12 shown in LCDR1, LCDR2 and LCDR3, or there is at least 85% sequence identity with SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12 CDR.
4. purposes according to any one of claims 1 to 3, wherein the antibody includes: weight shown in SEQ ID NO:13 Light chain variable region or its mutant nucleotide sequence shown in chain variable region or its mutant nucleotide sequence and SEQ ID NO:14；Or
The antibody includes: shown in heavy chain variable region shown in SEQ ID NO:15 or its mutant nucleotide sequence and SEQ ID NO:16 Light chain variable region or its mutant nucleotide sequence.
5. purposes according to claim 4, in which:
The mutant nucleotide sequence of light chain variable region shown in SEQ ID NO:14 includes mutation D66E；
The mutant nucleotide sequence of heavy chain variable region shown in SEQ ID NO:13 include mutation selected from the following: R72A, M48I, E46D, V68A, I70L, R38K, R67K, A97S and combinations thereof；It is preferred that R72A, M48I, E46D, V68A, I70L and combinations thereof；
The mutant nucleotide sequence of light chain variable region shown in SEQ ID NO:16 include mutation selected from the following: V58I, I2V, M4I, Q38E, A43T, P44H and combinations thereof；It is preferred that I2V, M4I and combinations thereof；
The mutant nucleotide sequence of heavy chain variable region shown in SEQ ID NO:15 include mutation selected from the following: R72V, M48V, V68A, M70L, T74K, A40R, R38K, R67K and combinations thereof.
6. purposes according to any one of claims 1 to 5, wherein the antibody includes: weight shown in SEQ ID NO:17 Light chain full length sequence or its mutant nucleotide sequence shown in chain full length sequence or its mutant nucleotide sequence and SEQ ID NO:18；Or
The antibody includes: heavy chain full length sequence shown in SEQ ID NO:19 or its mutant nucleotide sequence and SEQ ID NO:20 institute The light chain full length sequence or its mutant nucleotide sequence shown.
7. purposes according to any one of claims 1 to 6, wherein the anti-cd 47 antibody or its antigen-binding fragment and anti- CD20 antibody or its antigen-binding fragment are used in combination.
8. purposes according to claim 7, wherein the anti-CD 20 antibodies be selected from rituximab, obinutuzumab, Tositumomab、ibritumomab tiuxetan、ofatumumab、ocrelizumab、veltuzumab、 Ocaratuzumab, ublituximab and SCT-400.
9. purposes according to any one of claims 1 to 8, wherein the lymthoma is selected from Hodgkin lymphoma and Fei Huoqi Golden lymthoma；Preferably, non-Hodgkin lymphoma includes follicular lymphoma, lymphoma mantle cell, diffuses large B cell lymph Tumor, NK/T cell lymphoma and t cell lymphoma.
10. purposes according to any one of claims 1 to 9, wherein the knot lymthoma received cyclophosphamide, Ah mould Element, vincristine, one or more combined therapies in prednisone.
11. purposes according to any one of claims 1 to 6, wherein the anti-cd 47 antibody or its antigen-binding fragment Dosage be selected from 0.1-50mg/kg, preferably be selected from 0.3mg/kg, 0.5mg/kg, 0.75mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 5mg/kg、10mg/kg、20mg/kg、30mg/kg。
12. purposes according to any one of claims 1 to 6, wherein the anti-cd 47 antibody or its antigen-binding fragment Dosage be selected from 6-3000mg, preferably be selected from 18mg, 30mg, 60mg, 100mg, 150mg, 175mg, 200mg, 300mg, 400mg, 500mg、600mg、1000mg。
13. according to the described in any item purposes of claim 7 to 8, wherein the anti-CD 20 antibodies or its antigen-binding fragment Dosage is selected from 100-500mg/m2, it preferably is selected from 100mg/m2、150mg/m2、200mg/m2、250mg/m2、275mg/m2、300mg/ m2、325mg/m2、350mg/m2、375mg/m2、400mg/m2、450mg/m2、500mg/m2。
14. a kind of medicine package box, include a effective amount of anti-cd 47 antibody described in claim 1-13 any one or its Antigen-binding fragment and a effective amount of anti-CD 20 antibodies or its antigen-binding fragment.
15. a kind of pharmaceutical composition, include a effective amount of anti-cd 47 antibody described in claim 1-13 any one or its Antigen-binding fragment and a effective amount of anti-CD 20 antibodies or its antigen-binding fragment and one or more pharmaceutical excipients Agent, diluent or carrier.
CN201910441395.1A 2018-05-25 2019-05-24 A kind of purposes of anti-cd 47 antibody in the drug of preparation treatment lymthoma Pending CN110526972A (en)

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WO2021139687A1 (en) * 2020-01-09 2021-07-15 信达生物制药(苏州)有限公司 Application of combination of anti-cd47 antibody and anti-cd20 antibody in preparation of drugs for preventing or treating tumors

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Application publication date: 20191203