CN116535511B - Immunohistochemical antibody for detecting PD-L1 and application thereof - Google Patents
Immunohistochemical antibody for detecting PD-L1 and application thereof Download PDFInfo
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Abstract
The present invention relates to an immunohistochemical antibody for detecting PD-L1. The invention also provides nucleic acid encoding the antibody, a vector containing the same, a host cell, an immunohistochemical antibody composition or kit for detecting PD-L1, application and the like. The immunohistochemical antibody for detecting PD-L1 has strong specificity. The antibodies of the invention were more sensitive and less staining of the immunohistochemical background relative to the commercial anti-PD-L1 antibody 22C3. The antibody provided by the invention can be used as an immunohistochemical antibody for detecting PD-L1, can be used for in-vitro detection of PD-L1, is used for preparing an in-vitro diagnostic reagent for detecting PD-L1, and is used for preparing a PD-L1 companion diagnostic immunohistochemical detection product matched with a targeted drug before treatment. The antibody of the invention has wide application prospect in the field of medicine.
Description
Technical Field
The invention relates to the field of disease diagnosis, in particular to the field of concomitant diagnosis of biological drugs, and in particular relates to an immunohistochemical antibody for detecting PD-L1 and application thereof.
Background
PD-L1 (programmed death ligand 1) is a programmed death receptor ligand 1, and PD-1 (programmed cell death, programmed death receptor 1) ligand. PD-1 belongs to a transmembrane protein on a cell membrane, is expressed on immune cells such as T cells and B cells and tumor cells, and researches show that when PD-L1 on the tumor cell membrane is combined with PD-1 on immune cells such as T cells, the tumor cells send out inhibitory signals, so that the T cells cannot recognize and kill the tumor cells, the immune function of the organism is inhibited, and tumors continue to grow and attack wantonly.
The immune checkpoint inhibitor can be combined with PD-1 or PD-L1 to block the control of tumor cells on immune functions, ensure the functions of T cells and other immune cells, and recapture the clearance of T cells on tumors. Thus, if the tumor cells contain a large amount of PD-L1, a tumor patient may benefit from treatment with an immune checkpoint inhibitor. Immunotherapy can enhance the patient's immune system to help it recognize and combat tumor cells, which often has fewer side effects than other treatments.
Immunohistochemistry (IHC) is a study of locating, characterizing and quantifying antigens (polypeptides and proteins) in tissue cells by chemically developing color developing agents (luciferin, enzymes, metal ions, isotopes) of labeled antibodies by applying the basic principle of immunological antigen-antibody reaction, i.e., the principle of specific binding of antigen to antibody.
PD-L1 Immunohistochemical (IHC) detection is a simple and effective method for predicting the curative effect of PD-1 or PD-L1, and is a method for further predicting the curative effect of a PD-L1 inhibitor by detecting the expression level of PD-L1 on the surface of Tumor Cells (TC) or Immune Cells (IC).
Some immunohistochemical antibodies for detection are disclosed in the art. For example, patent document 1 (CN 110531077a, publication No. 2019.12.03) discloses an Mesothelin (MSLN) immunohistochemical detection kit containing MSLN monoclonal antibody 3-2G6. Patent document 2 (CN 111670201a, publication No. 2020.09.15) discloses an antibody for human epidermal growth factor receptor 2 (Her 2) accompanied by diagnostic immunohistochemical detection (IHC) which can avoid false positives of detection results due to deletion of extracellular region when performing immunohistochemical detection of Her2 expression in a sample as a primary antibody. The art discloses diagnostic anti-PD-L1 antibodies, and patent document 3 (CN 109963872B, publication No. 2023.04.11) discloses diagnostic anti-PD-L1 antibodies and uses thereof, which bind with high specificity and reproducibility to epitopes within human PD-L1, useful for assessing PD-L1 expression in tissue samples to aid patient stratification. Patent document 4 (CN 106604933B, publication No. 2021.08.10) discloses an anti-PD-L1 antibody and diagnostic use thereof, the use of the antibody to manufacture a reagent or kit for use in a method of detecting the presence or expression level of PD-L1 in a biological sample from a subject.
Currently, there are five main types of commonly used immunohistochemical detection antibodies for PD-L1: 22C3, 28-8, SP263, SP142 and 73-10. However, in view of the wide application and potentially enormous market demands for PD-1/PD-L1 target immunotherapy, there is a need in the art for other highly specific, sensitive, PD-L1 immunohistochemical antibodies.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an immunohistochemical antibody for detecting PD-L1, which has strong specificity, high sensitivity and lower immunohistochemical background staining, and can be widely used for in-vitro detection of PD-L1, preparation of in-vitro diagnostic reagents for detecting PD-L1 and preparation of a PD-L1 accompanying diagnostic immunohistochemical detection product matched with the target drug before treatment. The invention also provides nucleic acid encoding the antibody, a vector containing the same, a host cell, an immunohistochemical antibody composition or kit for detecting PD-L1, application and the like.
One aspect of the present invention provides an antibody or antigen-binding fragment thereof that binds to PD-L1, wherein the antibody or antigen-binding fragment thereof comprises 3 heavy chain complementarity determining region CDRs and 3 light chain complementarity determining region CDRs, wherein the HCDR1 amino acid sequence is shown as SEQ ID No. 1, the HCDR2 amino acid sequence is shown as SEQ ID No. 2, the HCDR3 amino acid sequence is shown as SEQ ID No. 3, the LCDR1 amino acid sequence is shown as SEQ ID No. 4, the LCDR2 amino acid sequence is shown as SEQ ID No. 5, and the LCDR3 amino acid sequence is shown as SEQ ID No. 6.
Specifically, the CDRs sequences are as follows:
HCDR1：GFTFASSWIH (SEQ ID NO:1)；
HCDR2：AWISPFGGSNYYDDSVKG(SEQ ID NO:2)；
HCDR3：RHWPSSFDY(SEQ ID NO:3)；
LCDR1：RASQSIDTALN(SEQ ID NO:4)；
LCDR2：TASLLQS(SEQ ID NO:5)；
LCDR3：QQDNLTPMT(SEQ ID NO:6)；
the CDRs sequences are determined by the Kabat definition.
Further, the antibody or antigen binding fragment thereof comprises a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO. 7, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO. 8.
Specifically, the variable region sequence is as follows:
heavy chain variable region (VH) sequence:
EVQLVESGGGLVQPGGSLRDSCAASGFTFASSWIHWVRQAPGKGLEWVAWISPFGGSNYYDDSVKGRFTISADTSKNTTYLQMNSLRAEDTAVYYCARRHWPSSFDYWEQGTLVTVSS（SEQ ID NO:7）。
light chain variable region (VL) sequence:
DIQMTQSPSSLSASVGDVVTITCRASQSIDTALNWYQQKPGKKPKLLIYTASLLQSGVPSRFSGSGSGTDFTLTISLLQPEDFATYYCQQDNLTPMTFGQGTKVEIK（SEQ ID NO:8）。
further, the antibody or antigen binding fragment thereof comprises a heavy chain constant region having an amino acid sequence as shown in SEQ ID NO. 17, and a light chain constant region having an amino acid sequence as shown in SEQ ID NO. 18.
Specifically, the constant region sequence is as follows:
heavy chain constant region (CH) sequence:
GQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK（SEQ ID NO:17）。
light chain constant region (CL) sequence:
GDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC（SEQ ID NO:18）。
further, the antibody or antigen binding fragment thereof includes a monoclonal antibody, chimeric antibody, humanized antibody, fab ', F (ab') 2, fv, scFv, or dsFv fragment.
In another aspect, the invention provides an isolated nucleic acid encoding said antibody or antigen binding fragment.
In another aspect, the invention provides a vector comprising said nucleic acid.
In another aspect, the invention provides a host cell comprising said nucleic acid or said vector.
In another aspect, the invention provides an immunohistochemical antibody composition or kit for detecting PD-L1, characterized in that it comprises said antibody or antigen-binding fragment thereof.
Further, the composition or kit further comprises one or more of the following components: antibody diluent, protein protection liquid, surfactant liquid and preservative.
In another aspect, the invention provides an application of the antibody or antigen binding fragment in preparing an immunohistochemical kit for detecting PD-L1 or preparing a PD-L1 companion diagnostic immunohistochemical detection product matched with the target drug before treatment.
In another aspect of the invention, there is provided a method for detecting PD-L1 expression for non-diagnostic purposes, characterized in that a biological sample is detected using the antibody or antigen-binding fragment, or the immunohistochemical antibody composition or kit.
The immunohistochemical antibody for detecting PD-L1 has the following beneficial effects:
(1) According to the invention, through phage display technology, monoclonal anti-PD-L1 antibody HD066 with strong specificity and high sensitivity suitable for immunohistochemical experiments for detecting PD-L1 is finally obtained by screening.
(2) For the specificity of the immunohistochemical antibody, the anti-PD-L1 antibodies HD066 and HD078 have similar specificity with the commercial positive control antibody 22C3, can recognize PD-L1 positive melanoma tissues, but the commercial positive control antibody 22C3 has deeper nonspecific staining.
(3) For the sensitivity of the immunohistochemical antibody, compared with the concentration of 1 mug/ml of a positive control group, the anti-PD-L1 antibody HD066 and HD078 provided by the invention have the advantages that the lower antibody concentration of 0.5 mug/ml is adopted, the positive melanoma tissues of PD-L1 can be still effectively identified, and the sensitivity is higher than that of the commercial positive control anti-PD-L1 antibody 22C3. Also, antibody HD066 was similar in sensitivity to antibody HD078, but antibody HD066 was less background stained.
(4) The antibody HD066 is finally screened and determined to be used as an immunohistochemical antibody for detecting PD-L1, can be widely used for in-vitro detection of PD-L1, is used for preparing an in-vitro diagnostic reagent for detecting PD-L1, is used for preparing a PD-L1 accompanying diagnostic immunohistochemical detection product matched with a targeted drug before treatment, and has wide application prospect in the field of medicines.
Drawings
FIG. 1 is a chart of IHC staining of melanoma tissue by the negative control antibody G3A1.
FIG. 2 is a IHC staining pattern of melanoma tissue with positive control antibody 22C3.
FIG. 3 is a chart of IHC staining of melanoma tissue by antibody HD078 of experimental group 2.
FIG. 4 is a chart of IHC staining of melanoma tissue by antibody HD066 of experimental group 1.
Detailed Description
Reagents and apparatus employed in the examples of the present invention are commercially available in the art, and are commercially available, and examples of sources of the main reagents and apparatus are given below.
Recombinant human PDL1 protein (Aikangde organism, cat No. IRP 002A); protein XPR36 bioanalyzer (Berle); bond RXm automatic IHC & ISH system (manufacturer Leica, model Bond RX); pannoramic Digital Slide Scanner (manufacturer 3DHISTECH, model Pannarac SCAN); manualrotary microtome (manufacturer Leica, model HistoCore MULTICUT); positive control antibody: DAKO/agilent M3653 PD-L1 monoclonal antibody, clone number 22C3 (brand DAKO/agilent, cat number M3653); negative control antibody: mouse monoclonal antibody IgG1 isotype control (CST, catalogNo. 5415), clone number G3A1; secondary anti-antibodies: bond PolymerRefine Detection (manufacturer Leica, cat No. DS 9800).
EXAMPLE 1 isolation of anti-human PD-L1 antibodies
anti-PD-L1 antibodies were isolated from human antibody phage display libraries by in vitro selection. Streptavidin magnetic beads are coated with biotinylated human PD-L1, and anti-PD-L1 specific phages are panning out using magnetic sorting. Steps to remove potential anti-biotin antibodies were added during the selection process. Specific Fab antibodies were initially identified by ELISA using human PD-L1 as antigen. Based on the principle of binding of PD-L1 to its antibodies, 2 clones HD066, HD078 were obtained by magnetic bead screening for subsequent further characterization. Performing first clone screening through DNA fingerprint; clonality was then confirmed by sequencing. The amino acid sequences of the light chain variable region and the heavy chain variable region of the HD066 and HD078 clones are shown in table 1, and the CDRs sequences are defined by the Kabat definition.
TABLE 1 light chain variable region and heavy chain variable region and CDRs amino acid sequences of HD066, HD078 clones
The variable region gene amplification, the overlapping extension of the signal peptide and the variable region, the homologous recombination and the like are carried out by the conventional molecular biology technology, finally, the nucleotide sequence fragment encoding VH in the table 1 is inserted into a vector pCDNA3.4 with the nucleotide sequence encoding the heavy chain constant region amino acid sequence SEQ ID NO. 17 of an antibody, the nucleotide sequence fragment encoding VL is inserted into a vector pCDNA3.4 with the nucleotide sequence encoding the light chain constant region amino acid sequence (SEQ ID NO. 18) of an antibody, the connected vector is transfected into HEK293 cells to be cultured under the conventional condition, after transient expression is carried out for 5 days, the supernatant is purified by Protein A affinity chromatography to obtain an anti-PD-L1 antibody HD066 and an anti-PD-L1 antibody HD078.
Wherein the heavy chain constant region (CH) sequence is as follows:
GQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK（SEQ ID NO:17）。
the light chain constant region (CL) sequence is as follows:
GDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC（SEQ ID NO:18）。
example 2 affinity of anti-PD-L1 antibodies
The affinity of the anti-PD-L1 antibody HD066 and the anti-PD-L1 antibody HD078 for human PD-L1 was studied by Surface Plasmon Resonance (SPR) analysis. Human PD-L1 conjugated to Fc was immobilized on a sensor chip compatible with the Proteon XPR36 biological analyzer (Berle). The anti-PD-L1 antibody HD066, anti-PD-L1 antibody HD078 solution was then flowed onto the chip, the association/dissociation was recorded and analyzed, and the affinity (KD) calculated.
Experimental results show that the KD (M) of the anti-PD-L1 antibody HD066 to human PD-L1 is 1.04×10 -10 anti-PD-L1 antibody HD078 had a KD (M) of 2.59X10 for human PD-L1 -9 。
Example 3: immunohistochemical experiment procedure
The instrument is adopted: bond RXm automatic IHC & ISH system (manufacturer Leica, model RX), pannoramic Digital Slide Scanner (manufacturer 3DHISTECH, model pannarac SCAN), manual rotary microtome (manufacturer Leica, model HistoCore MULTICUT).
Positive control antibody: DAKO/agilent M3653 PD-L1 monoclonal antibody, clone No. 22C3 (brand DAKO/agilent, cat No. M3653).
Negative control antibody: the mouse monoclonal antibody IgG1 isotype control (CST, catalogNo. 5415), clone number G3A1. Secondary anti-antibodies: bond Polymer Refine Detection (manufacturer Leica, cat No. DS 9800).
Preparation using an Immunohistochemical (IHC) assay protocol conventional in the art
IHC assay procedures are known in the art and generally comprise 1) dewaxing and hydration, 2) cell permeation and blocking, 3) antigen retrieval, 4) serum blocking, 5) primary antibody incubation, 6) secondary antibody incubation, 7) slice development, 8) counterstaining and sealing.
Example 4: PD-L1 positive tumor tissue screening
Tumor specimens including mesothelioma, melanoma, pancreatic cancer, lung cancer tumor samples were prepared. The specimen is fixed in formalin solution within 30 minutes of the separation, then gradient ethanol dehydration is carried out, the dehydrated tissue is placed in xylene to be transparent, the tissue is immersed in melted low-melting-point paraffin, paraffin embedding is carried out, after the paraffin blocks are solidified, the tissue is cut into slices with the thickness of 3-5 mu m, and a glass slide coated with polylysine is used for picking up the tissue and then a bleaching and drying instrument is used for drying.
Immunohistochemical experiment steps: the tissue slices were baked at 65 ℃ for 1 hour, then subjected to dewaxing treatment in xylene for 10 minutes, then subjected to gradient ethanol hydration, specifically operated such that the dewaxed slices were immersed in absolute ethanol for 5 minutes, 95% ethanol for 5 minutes, 75% ethanol for 5 minutes, and finally immersed in distilled water. The hydrated sections were subjected to antigen retrieval followed by soaking in medium PBST.
The liquid surrounding the tissue on the sections was removed, fresh 3% peroxidase blocking solution was added to the delineation area, and incubated at 37℃for 10 minutes to eliminate peroxidase activity in the tissue, and the sections were washed 2 times with PBST.
Positive control antibody 22C3 solution, negative control antibody G3A1 were added and incubated at 37℃for 60 min, and the sections were washed 2 times with PBST. The slicing results show that melanoma is a positive tumor tissue with strong positive expression of PD-L1. Subsequent experiments will employ melanoma tissues for screening and validation of the PD-L1 immunohistochemical diagnostic antibodies of the invention.
Example 5: PD-L1 immunohistochemical diagnosis antibody screening and verification
The immunohistochemical experimental procedure in example 4 was used, positive control antibody 22C3 solution, negative control antibody G3A1, experimental group 1 antibody HD066 and experimental group 2 antibody HD078 were set for the experiment, different antibody concentrations were selected, 2. Mu.g/ml, 1. Mu.g/ml and 0.5. Mu.g/ml, the antibody concentration which can bind to the target PD-L1 positive cancer tissue was selected, and the background staining was relatively moderate, and finally the antibody concentration of 1. Mu.g/ml or 0.5. Mu.g/ml was selected.
The procedure is as in example 4, using 1. Mu.g/ml positive control antibody 22C3 solution, 1. Mu.g/ml negative control antibody G3A1, 0.5. Mu.g/ml Experimental group 1 antibody HD066, 0.5. Mu.g/ml Experimental group 2 antibody HD078 for immunohistochemical analysis of melanoma tissue.
The experimental results are shown in fig. 1-4, wherein fig. 1 is a staining chart of melanoma tissue IHC of the negative control antibody G3A1, fig. 2 is a staining chart of melanoma tissue IHC of the positive control antibody 22C3, fig. 3 is a staining chart of melanoma tissue IHC of the experimental group 2 antibody HD078, and fig. 4 is a staining chart of melanoma tissue IHC of the experimental group 1 antibody HD066.
For the immunohistochemical staining pattern results described above, the experimental group 1 antibody HD066 and the experimental group 2 antibody HD078, which had similar specificity to the commercial positive control antibody 22C3, both recognized PD-L1 positive melanoma tissue, but the commercial positive control antibody 22C3 was stained more deeply in non-specificity.
From the perspective of sensitivity analysis of the immunohistochemical antibodies, compared with the concentration of 1 mug/ml of a positive control group, the concentration of the antibody HD066 of the experimental group 1 and the concentration of the antibody HD078 of the experimental group 2 are lower by 0.5 mug/ml, the positive melanoma tissues of PD-L1 can be still effectively identified, and the sensitivity is higher than that of the commercial positive control antibody 22C3. In addition, group 1 antibody HD066 was similarly sensitive to group 2 antibody HD078, but the background staining of group 1 antibody HD066 was less.
Therefore, the antibody HD066 of the experimental group 1 is finally screened and determined to be used as an immunohistochemical antibody for detecting PD-L1, can be widely used for in vitro detection of PD-L1, is used for preparing an in vitro diagnostic reagent for detecting PD-L1, and is used for preparing a matched PD-L1 accompanying diagnostic immunohistochemical detection product before targeted drug treatment.
The above examples of the present disclosure are merely examples for clearly illustrating the present disclosure and are not limiting of the embodiments of the present disclosure. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modifications, equivalent substitutions, improvements, etc. that fall within the spirit and principles of the present disclosure are intended to be included within the scope of the claims of the present disclosure.
Claims (11)
1. An antibody or antigen-binding fragment thereof that binds PD-L1, wherein the antibody or antigen-binding fragment thereof comprises 3 heavy chain complementarity determining region CDRs and 3 light chain complementarity determining region CDRs, wherein the HCDR1 amino acid sequence is shown in SEQ ID No. 1, the HCDR2 amino acid sequence is shown in SEQ ID No. 2, the HCDR3 amino acid sequence is shown in SEQ ID No. 3, the LCDR1 amino acid sequence is shown in SEQ ID No. 4, the LCDR2 amino acid sequence is shown in SEQ ID No. 5, and the LCDR3 amino acid sequence is shown in SEQ ID No. 6.
2. The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID No. 7, and a light chain variable region having an amino acid sequence as set forth in SEQ ID No. 8.
3. The antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region having an amino acid sequence as set forth in SEQ ID No. 17, and a light chain constant region having an amino acid sequence as set forth in SEQ ID No. 18.
4. The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a monoclonal antibody, chimeric antibody, humanized antibody, fab ', F (ab') 2, fv, scFv, or dsFv fragment.
5. An isolated nucleic acid encoding the antibody or antigen-binding fragment of any one of claims 1-4.
6. A recombinant vector comprising the nucleic acid of claim 5.
7. A recombinant host cell comprising the nucleic acid of claim 5 or the recombinant vector of claim 6.
8. An immunohistochemical antibody composition or kit for detecting PD-L1, comprising the antibody or antigen-binding fragment thereof of any one of claims 1-4.
9. The immunohistochemical antibody composition or kit according to claim 8, wherein the composition or kit further comprises one or more of the following components: antibody diluent, protein protection liquid, surfactant liquid and preservative.
10. Use of an antibody or antigen binding fragment according to any one of claims 1-4 for the preparation of an immunohistochemical kit for detection of PD-L1 and/or for the preparation of a pre-treatment kit for targeted drug-associated diagnostic immunohistochemical detection product for PD-L1.
11. A method for detecting PD-L1 expression for non-diagnostic purposes, characterized in that an isolated biological sample is detected using the antibody or antigen-binding fragment of any one of claims 1-4, or the immunohistochemical antibody composition or kit of any one of claims 8-9.
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