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CN118108854B - Antiviral composition containing bispecific antibody and application thereof - Google Patents

Antiviral composition containing bispecific antibody and application thereof Download PDF

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CN118108854B
CN118108854B CN202410353263.4A CN202410353263A CN118108854B CN 118108854 B CN118108854 B CN 118108854B CN 202410353263 A CN202410353263 A CN 202410353263A CN 118108854 B CN118108854 B CN 118108854B
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CN118108854A (en
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王勇
易祥
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Guangxi Fleming Biopharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/084—Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • 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
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/10—Plasmid DNA
    • C12N2800/106—Plasmid DNA for vertebrates
    • C12N2800/107—Plasmid DNA for vertebrates for mammalian

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Abstract

The disclosure provides nanobodies and bispecific antibodies, compositions containing the same, and uses thereof. The antibody disclosed by the invention has high binding force with HPV antigen, can effectively reduce proliferation of cervical cancer cells, has obvious curative effect and has unexpected technical effect. The antibody of the invention has good prospect of patent medicine, important clinical value and good market prospect for coping with the current severe cervical cancer high-incidence trend.

Description

Antiviral composition containing bispecific antibody and application thereof
Technical Field
The disclosure relates to the field of biological medicine, and in particular relates to a bispecific antibody, a composition containing the bispecific antibody and application of the bispecific antibody.
Background
The nano antibody is also called a single domain antibody, a VHH antibody or a camelid antibody, is a heavy chain antibody with a natural deletion of a light chain found in camelids such as alpaca, dromedaries such as dromedaries and sharks, and can be designed artificially. As with intact antibodies, nanobodies can selectively bind to specific antigens. Single domain antibodies appear much smaller, typically 12-14kDa, than the 150-160kDa mass of intact antibodies, being the smallest intact antigen binding fragment.
Based on excellent performance, nanobodies have been widely used in research fields such as molecular imaging, diagnosis, tumor immunotherapy, cell therapy, and the like. It is worth mentioning that the nanobody has excellent application value and prospect in central nervous system diseases, circulatory diseases, infectious diseases, tumors and inflammatory diseases (such as acute coronary syndrome, viral infection, cancer and Alzheimer's disease).
HPV infection is caused by human oncological viruses, which are DNA viruses of the oncological family. More than 200 types have been described. One person can infect multiple types of HPV, and it is currently thought that this disease affects only humans.
Cervical cancer is reported to be the fourth most common cancer in women worldwide, with estimated 60.4 tens of thousands of new cases and 34.2 tens of thousands of deaths in year 2020. Statistical data released by the national cancer center 2023 shows that the new cases of cervical cancer in China are 11.93 ten thousand, and the cases of death are 3.72 ten thousand, so that the prevention and control of cervical cancer are serious.
Almost all cervical cancers are caused by HPV. Many HPV types are oncogenic. About 12 HPV types (including types 16, 18, 31 and 45) are referred to as "high-risk" types, because persistent infections are associated with oropharyngeal, laryngeal, vulvar, vaginal, cervical, penile and anal cancers. These cancers all involve sexually transmitted infections of HPV with stratified epithelial tissue. HPV type 16 is the most oncogenic strain, present in about 47% of cervical cancers, and many vaginal and vulvar cancers, anal cancers and head and neck cancers.
Disclosure of Invention
In one aspect of the disclosure, an antibody is provided comprising a sequence as set forth in any one of SEQ ID NOs 1-5, 8, 9.
In some embodiments of the disclosure, the amino acid sequence of the antibody is set forth in any one of SEQ ID NOs 1-5, 8, 9.
In one aspect of the disclosure, an antibody is provided comprising a sequence as set forth in SEQ ID NO. 8 or 9.
In some embodiments of the disclosure, the antibody is a nanobody.
In some embodiments of the disclosure, the antibody is a bispecific nanobody.
In some embodiments of the disclosure, the antibodies comprise a sequence as set forth in SEQ ID NO. 8. In some embodiments of the disclosure, the antibody comprises a sequence as set forth in SEQ ID NO. 9.
In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 8. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 9.
In some embodiments of the present disclosure, an antibody is provided having the amino acid sequence shown in SEQ ID NO. 11 or 12.
In some embodiments of the present disclosure, an antibody is provided, the amino acid sequence of which is shown in SEQ ID NO. 11. In some embodiments of the present disclosure, an antibody is provided, the amino acid sequence of which is shown in SEQ ID NO. 12.
In another aspect of the disclosure, an antibody is provided comprising a sequence as set forth in any one of SEQ ID NOs 1-5.
In some embodiments of the disclosure, the antibodies comprise a sequence as set forth in SEQ ID NO. 1. In some embodiments of the disclosure, the antibodies comprise a sequence as set forth in SEQ ID NO. 2. In some embodiments of the disclosure, the antibody comprises a sequence as set forth in SEQ ID NO. 3. In some embodiments of the disclosure, the antibodies comprise a sequence as set forth in SEQ ID NO. 4. In some embodiments of the disclosure, the antibody comprises a sequence as set forth in SEQ ID NO. 5.
In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown as SEQ ID NO. 1. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 2. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 3. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 4. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 5. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 7.
In some embodiments of the present disclosure, the amino acid sequence of the antibody is obtained by replacing the sequence fragment shown as SEQ ID NO.1 of the sequence shown as SEQ ID NO. 7 with any of SEQ ID NO. 2-5.
In some embodiments of the disclosure, the antibody is any selected from the group consisting of bispecific, trispecific, tetraspecific, dimeric, tetrameric, multimeric or biparatopic antibodies, single chain antibodies, domain antibodies, and any other modified configuration of immunoglobulin molecules comprising an antigen binding site having the desired specificity. In some embodiments of the disclosure, the antibody is any selected from the group consisting of a full length antibody, an intact antibody, an antibody fragment, an antigen binding fragment, and an antigen binding domain.
In some embodiments of the disclosure, the antibody is a recombinant protein.
In another aspect of the disclosure, a polynucleotide encoding an antibody as described in the disclosure is provided.
In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown as SEQ ID NO. 1. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 2. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 3. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown as SEQ ID NO. 4. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown as SEQ ID NO. 5. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown as SEQ ID NO. 7. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown in SEQ ID NO. 8. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown as SEQ ID NO. 9. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown as SEQ ID NO. 11. In some embodiments of the present disclosure, the amino acid sequence of the antibody is shown as SEQ ID NO. 12.
In some embodiments of the disclosure, the polynucleotide comprises modified nucleotides. The modified nucleotides may be used to produce polynucleotides of the present disclosure. Exemplary modified nucleotides are 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5- (carboxyhydroxymethyl) uracil, inosine, N6-isopentenyl adenine, 1-methylguanine, 1-methylinosine, 2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, 2-thiocytosine, 5-methyl-2-thiouracil, carboxymethyl amino methyl-2-thiouracil, 5-carboxymethyl amino methyl uracil, dihydro uracil N6-substituted adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, β -D-mannosyl-quinidine, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-glycolate, 5-methoxycarboxymethyl uracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyl adenine, uracil-5-hydroxyacetic acid (v), huai Butuo glycoside, pseudouracil, quinidine, β -D-galactosyl-quinidine, 3- (3-amino-3-N-2-carboxypropyl) uracil and 2, 6-diaminopurine.
In another aspect of the disclosure, a vector is provided comprising a polynucleotide encoding an antibody as described in the disclosure.
In some embodiments of the disclosure, the vector may be a plasmid vector, a viral vector, a vector for baculovirus expression, a transposon-based vector, or any other vector suitable for introducing the synthetic polynucleotide of the disclosure into a particular organism by any means. The vectors of the present disclosure may be expression vectors for efficient synthesis of antibody proteins in prokaryotic and eukaryotic systems, including but not limited to yeast and mammalian cell cultures.
In some embodiments of the disclosure, the vector is selected from ：pET-23a(+)、pCMV-Myc、pBs、phagescript、PsiX174、pBluescript SK、pBs KS、pNH8a、pNH16a、pNH18a、pKK223-3、pKK233-3、pDR540、pRIT5、pWLneo、pSV2cat、pOG44、PXR1、pSVK3、pBPV、pMSG and pSVL (Pharmacia), pee6.4, pee12.4, pBluescript, pGEX, agt 10, agt 11, agembl 4, λnm1149, λzapii, pEUK-Cl, pMAM, and pMAMneo (Clontech).
In some embodiments of the disclosure, the vector comprises a promoter and an enhancer sequence. Polynucleotides encoding antibodies of the present disclosure may be operably linked to control sequences in a vector to ensure expression of the antibody. In some embodiments of the disclosure, the regulatory elements may include a transcriptional promoter, sequences encoding suitable mRNA ribosome binding sites, and sequences which control termination of transcription and translation. Expression vectors may also include one or more non-transcriptional elements, such as an origin of replication, suitable promoters and enhancers linked to the gene to be expressed, other 5 'or 3' flanking non-transcribed sequences, 5 'or 3' untranslated sequences, polyadenylation sites, splice donor and acceptor sites, or transcription termination sequences. An origin of replication conferring replication in a host may also be incorporated.
Recombinant expression vectors can be designed for transient or stable expression. In addition, recombinant expression vectors can be prepared for constitutive or inducible expression.
In another aspect of the disclosure, a composition is provided comprising an antibody, polynucleotide, or vector as described in the disclosure.
In some embodiments of the disclosure, the composition comprises an antibody as described in the disclosure.
In another aspect of the present disclosure, there is provided a pharmaceutical composition comprising an antibody, polynucleotide or vector as described in the present disclosure, and a pharmaceutically acceptable adjuvant.
In some embodiments of the present disclosure, the pharmaceutical composition comprises an antibody as described in the present disclosure, and a pharmaceutically acceptable excipient.
In some embodiments of the disclosure, the pharmaceutically acceptable excipients include diluents, adjuvants, excipients.
In some embodiments of the present disclosure, the pharmaceutically acceptable excipients include pH adjusting agents and buffers, excipients, stabilizers, thickeners, lubricants, and colorants.
In some embodiments of the present disclosure, the pharmaceutically acceptable excipients include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, buffers, antioxidants, sugars, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants, or emulsifiers.
In another aspect of the disclosure, a kit is provided comprising an antibody as described in the disclosure.
In another aspect of the disclosure, there is provided the use of an antibody as described in the disclosure in the manufacture of an anticancer drug.
In some embodiments of the disclosure, the anti-cancer drug is an anti-cervical cancer drug. In some embodiments of the disclosure, the anti-cancer drug is a drug for treating HPV 16-positive cervical cancer.
The technical scheme of the disclosure has the technical effects that: the antibody disclosed by the invention has high binding force with HPV antigen, can effectively reduce proliferation of cervical cancer cells, has obvious curative effect, is obviously superior to the prior art, and has unexpected technical effect. The antibody of the invention has good prospect of patent medicine, important clinical value and good market prospect for coping with the current severe cervical cancer high-incidence trend.
Detailed Description
The present disclosure is further illustrated by way of examples below, but is not thereby limited to the scope of the examples described. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. Unless otherwise indicated, reagents and materials used in the disclosure were obtained from commercial sources.
Embodiment one: screening of nanobodies
The inventor immunizes 2 alpaca three times through recombinant expressed commercial HPV16 virus E6 protein, then separates peripheral blood lymphocyte of alpaca, extracts total RNA of cell, and then reverse transcribes the total RNA into cDNA. And amplifying the coding sequence of the nano antibody by using the secondary cDNA as a template and using a specific primer. Finally separating the multi-strain nanometer antibody, wherein 2 strains have optimal activity and are named antiE < 6 > -1 and antiE < 6 > -2, and the amino acid sequences of the multi-strain nanometer antibody are respectively shown as SEQ ID NO. 1 and SEQ ID NO. 2.
The inventor uses the same method to immunize another 2 small alpaca three times through the recombinant expressed commercial HPV16 virus E7 protein, and also obtains a plurality of nanometer antibodies, wherein 3 strains of nanometer antibodies have optimal activity and are named antiE7-1, antiE7-2 and antiE7-3, and the amino acid sequences of the nanometer antibodies are respectively shown as SEQ ID NO. 3, SEQ ID NO. 4 and SEQ ID NO. 5.
Embodiment two: expression of nanobodies
The DNA fragment encoding the nano antibody antiE-1 (SEQ ID NO: 1) was synthesized by outsourcing, which was codon optimized for E.coli, and both ends were linked with restriction enzyme EcoRI and XhoI cleavage sites, respectively. The recombinant protein expression vector plasmid antiE-1 (SEQ ID NO: 6) was constructed by cloning into pET-23a (+) plasmid vector by EcoRI and XhoI cleavage. antiE 6A 6-1 recombinant protein (SEQ ID NO: 7) was linked to a His6 tag sequence.
The antiE recombinant protein expression vector plasmid was transformed into competent cells (ThermoFisher) of E.coli BL21 (DE 3) to express the protein. Positive clones were selected and cultured in TB medium at 37 ℃. When the optical density OD of the cultures reached 0.6, induction was performed with 1mM IPTG and incubated overnight at 28 ℃ in shake flasks. The culture was then centrifuged and the pellet was resuspended in lysis buffer and sonicated. Purified by nickel-Sepharose 6FF (Bio-Tool) affinity chromatography and dialyzed in PBS buffer. The nanobodies were then further purified on a Superdex 75 gel chromatography column (Cytiva). Collecting antiE-1 nanometer antibody recombinant protein, and the purity is more than 98.0%. SDS-PAGE results are molecular weight-dependent and single band.
Recombinant proteins of antiE6-2, antiE7-1, antiE7-2 and antiE7-3 nanometer antibodies are prepared by the same method. The amino acid sequence of the recombinant protein of antiE-1 nanometer antibody is limited to the sequence fragment of SEQ ID NO. 1 replaced by SEQ ID NO. 2-5. The purity of these recombinant proteins was >97.5%.
Embodiment III: antigen affinity assay for nanobodies
HPV16E6 protein was processed according to the instructions using NTA chip (Cytiva, BR-1004-07) HY-P72260) is affixed to the chip in an amount of about 100RU. Each E6 antibody prepared by the preparation method described in the previous example was diluted with PBST buffer to give solutions with concentrations of 1,2, 4, 8, 16, 32, 64, 128, 256, 512, 1024, 2048, 4096 and 8192pmol/L, respectively, and the samples were loaded and tested. The results data show equilibrium dissociation constant K D values between each E6 antibody and HPV16E6 protein, as shown in table 1.
TABLE 1 antigen affinity test results for anti-E6 antibodies
Equilibrium dissociation constant K D (Curve fitting value)
AntiE6-1 nanobody 64pM
AntiE6-2 nanobodies 370pM
The same method is adopted by using HPV16E7 proteinHY-P72259) and HPV16E7 protein, the equilibrium dissociation constant K D values between each E7 antibody and HPV16E7 protein are shown in Table 2.
TABLE 2 antigen affinity test results for anti-E7 antibodies
Equilibrium dissociation constant K D (Curve fitting value)
AntiE7-1 nanobody 865pM
AntiE7-2 nanobodies 93pM
AntiE7-3 nanobodies 95pM
Embodiment four: bispecific nanobody, expression and activity assay
The inventor fuses antiE-1 nanometer antibody with antiE7-2 and antiE7-3 nanometer antibody respectively through linker sequence to obtain bispecific nanometer antibodies antiHPV-12 (SEQ ID NO: 8) and antiHPV16-13 (SEQ ID NO: 9).
According to the reference method, the coding sequences of the bispecific nanobodies antiHPV-12 and antiHPV-13 are cloned into a pCMV-Myc plasmid vector through EcoRI and XhoI enzyme digestion sites respectively, so that recombinant plasmids pCMV-Myc-antiHPV-12 (SEQ ID NO: 10) and pCMV-Myc-antiHPV-13 are constructed, and expressed proteins contain Myc tags at the tail ends and are antiHPV16-12 recombinant proteins (SEQ ID NO: 11) and antiHPV16-13 recombinant proteins (SEQ ID NO: 12) respectively.
HPV16 positive cervical epithelial tumor cell line CaSki with a confluency of about 50% and HPV16 negative human cervical squamous carcinoma cell line C33A were prepared. Recombinant plasmids pCMV-Myc-antiHPV-12 and pCMV-Myc-antiHPV-16-13 were transiently transfected into cells using Lipofectamine 2000 (ThermoFisher, 11668019). The negative control group was transfected with pCMV-Myc plasmid.
Myc tags in CaSki and C33A cells were detected 48h after transfection using anti-myc antibody (SinoBiological, 100029-MM 08), and Western blot analysis confirmed the expression of bispecific antibodies.
Cell viability was determined by MTT method 72h after transfection: DEME medium (10% fetal bovine serum) was used for culture in 96-well plates. Mu.l MTT dye was added to each well and incubated in an incubator (5% CO2, 37 ℃) for 4h. Cells were taken and treated with 150 μl DMSO for 15min. The absorbance at 570nm was measured on a microplate reader. The results are shown in Table 3.
AntiHPV16-12 and antiHPV16-13 significantly inhibited proliferation of HPV16 positive CaSki cells (P < 0.01) without affecting proliferation of HPV16 negative C33A cell lines. And antiHPV16-12 activity was significantly better than antiHPV16-13 (P < 0.01).
TABLE 3 inhibition of proliferation of cervical cancer cells
Although the embodiments of the present disclosure have been described above, it will be appreciated that the above embodiments are illustrative and not to be construed as limiting the present disclosure, and that variations, modifications and alternatives to the above embodiments may be made by one of ordinary skill in the art within the scope of the present disclosure.

Claims (9)

1. An antibody comprising a sequence as set forth in any one of SEQ ID NOs 1-5, 8, 9.
2. The antibody of claim 1, wherein the amino acid sequence of the antibody is as set forth in any one of SEQ ID NOs 1 to 5, 8, 9.
3. The antibody of claim 1, wherein the amino acid sequence of the antibody is shown in SEQ ID NO. 8.
4. The antibody of claim 1, wherein the amino acid sequence of the antibody is shown in SEQ ID NO. 11 or 12.
5. A polynucleotide encoding the antibody of any one of claims 1-4.
6. A vector comprising a polynucleotide encoding the antibody of any one of claims 1-4.
7. A composition comprising the antibody of any one of claims 1-4, the polynucleotide of claim 5, or the vector of claim 6.
8. A pharmaceutical composition comprising the antibody of any one of claims 1-4, and a pharmaceutically acceptable adjuvant.
9. Use of the antibody of any one of claims 1-4 in the manufacture of an anti-cancer medicament for the treatment of HPV 16-positive cervical cancer.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108794623A (en) * 2018-07-04 2018-11-13 北京索莱宝科技有限公司 A kind of monoclonal antibody of anti-HPV16 E6 albumen and its application

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EP2108657A1 (en) * 2008-04-08 2009-10-14 DKFZ Deutsches Krebsforschungszentrum Peptides for inhibiting the HPV-E6 oncoprotein
AU2014290288B2 (en) * 2013-07-15 2018-03-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-human papillomavirus 16 E6 T cell receptors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108794623A (en) * 2018-07-04 2018-11-13 北京索莱宝科技有限公司 A kind of monoclonal antibody of anti-HPV16 E6 albumen and its application

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