WO2022002019A1 - 抗cd70抗体及其应用 - Google Patents
抗cd70抗体及其应用 Download PDFInfo
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- WO2022002019A1 WO2022002019A1 PCT/CN2021/102998 CN2021102998W WO2022002019A1 WO 2022002019 A1 WO2022002019 A1 WO 2022002019A1 CN 2021102998 W CN2021102998 W CN 2021102998W WO 2022002019 A1 WO2022002019 A1 WO 2022002019A1
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Images
Classifications
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- C07K2317/734—Complement-dependent cytotoxicity [CDC]
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Definitions
- the present disclosure belongs to the field of biomedicine, and particularly relates to an antibody that binds to CD70 and its application.
- CD70 is a cell surface antigen, a member of the tumor necrosis factor (TNF) family, a type II membrane protein containing 193 amino acids and a molecular weight of about 50kD. In vivo, it interacts with its receptor CD27 in a homotrimeric form, and then the intracellular domain of CD27 binds to tumor necrosis factor receptor-associated factors (TRAF), such as TRAF2 and TRAF5, to activate NF ⁇ B and JNK pathways that ultimately lead to pro-survival and proliferative signals.
- TRAF2 and TRAF5 tumor necrosis factor receptor-associated factors
- CD70-induced CD27 signaling results in increased generation and activation of CD27-expressing regulatory T cells.
- CD70 also promotes tumor growth by evading immune surveillance by inducing regulatory T cells.
- CD70 is transiently expressed on activated T cells, B cells and dendritic cells, but hardly expressed on non-lymphoid normal tissues.
- CD70 is highly expressed in a variety of hematological and solid tumors, such as B-cell lymphoma, renal cancer, and breast cancer, and is negatively correlated with prognosis.
- CD27 is co-expressed with CD70 in hematological tumors, and the combination of the two leads to the cleavage of the extracellular domain of CD27 to form soluble CD27 (sCD27), which can be used as a diagnostic biomarker.
- the present disclosure provides a novel anti-CD70 antibody.
- the anti-CD70 antibodies described in this disclosure include anti-CD70 full-length antibodies and antigen-binding fragments thereof.
- the present disclosure provides an anti-CD70 antibody comprising a heavy chain variable region and a light chain variable region, wherein:
- the heavy chain variable region comprises HCDR1 and HCDR3 as set forth in SEQ ID NO: 9 and SEQ ID NO: 11, respectively, and HCDR2 as set forth in SEQ ID NO: 10 or SEQ ID NO: 42;
- the The light chain variable region comprises LCDR1 and LCDR3 as set forth in SEQ ID NO: 12 and SEQ ID NO: 14, respectively, and LCDR2 as set forth in SEQ ID NO: 13 or SEQ ID NO: 43;
- the heavy chain variable region comprises HCDR1 and HCDR3 as set forth in SEQ ID NO: 15 and SEQ ID NO: 17, respectively, and HCDR2 as set forth in SEQ ID NO: 16 or SEQ ID NO: 54;
- the The light chain variable region comprises LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, respectively; or
- the heavy chain variable region comprises HCDR1 and HCDR3 as shown in SEQ ID NO: 21 and SEQ ID NO: 23, respectively, and HCDR2 as shown in SEQ ID NO: 22 or SEQ ID NO: 71;
- the The light chain variable region comprises LCDR1 and LCDR3 as set forth in SEQ ID NO:24 and SEQ ID NO:25, respectively, and LCDR2 as set forth in SEQ ID NO:13 or SEQ ID NO:43.
- the anti-CD70 antibodies of the present disclosure comprise a heavy chain variable region and a light chain variable region, wherein,
- the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO:9, SEQ ID NO:10 and SEQ ID NO:11, respectively, and the light chain variable region comprises SEQ ID NO:1, respectively: 12. LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 13 and SEQ ID NO: 14; or
- the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:9, SEQ ID NO:42 and SEQ ID NO:11, respectively, and the light chain variable region comprises HCDR1, respectively, as SEQ ID NO:11: 12. LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 43 and SEQ ID NO: 14; or
- the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO: 15, SEQ ID NO: 16 and SEQ ID NO: 17, respectively; the light chain variable region comprises SEQ ID NO: 17, respectively; 18. LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID NO: 19 and SEQ ID NO: 20; or
- the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO: 15, SEQ ID NO: 54 and SEQ ID NO: 17, respectively; the light chain variable region comprises SEQ ID NO: 17, respectively; 18. LCDR1, LCDR2 and LCDR3 as set forth in SEQ ID NO: 19 and SEQ ID NO: 20; or
- the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO: 21, SEQ ID NO: 22 and SEQ ID NO: 23, respectively; the light chain variable region comprises SEQ ID NO: 23, respectively: 24.
- the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO: 21, SEQ ID NO: 71 and SEQ ID NO: 23, respectively; the light chain variable region comprises SEQ ID NO: 24. LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:43 and SEQ ID NO:25.
- the aforementioned anti-CD70 antibody is a murine antibody, a chimeric antibody, or a humanized antibody; in some embodiments, the aforementioned anti-CD70 antibody is a full-length antibody or an antigen-binding fragment thereof. In some embodiments, the antigen-binding fragment is selected from the group consisting of: Fab, F(ab') 2 , F(ab) 2 , Fd, Fv, dsFv, scFv, and diabodies thereof.
- the aforementioned anti-CD70 antibody is a humanized antibody comprising a framework region of a human antibody or a framework region variant of a human antibody relative to the light chain of a human antibody
- the framework regions and/or the heavy chain framework regions have up to 11 amino acid backmutations, respectively.
- the heavy chain framework region of the antibody comprises one or more amino acid backmutations selected from the group consisting of 4M, 37I, 38K, 48I, 67A, 69L, 71A, 73R, 78A, 80L, and 94T, And/or the light chain framework region of the antibody comprises one or more amino acid back mutations selected from 5S and 70N; in some embodiments, the light chain framework region of the antibody comprises 38R, 43S , 69R, 70Q and 71Y one or more amino acid back-mutations, and/or the heavy chain framework region of the antibody comprises one or more amino acids selected from 2I, 24T, 46K, 72E and 82aN backmutations; in some embodiments, the antibody comprises one or more amino acid backmutations on the heavy chain framework region selected from 27D, 30P, 37L, 38K, 48I, 66K, 67A, 69L, and 82aN, And/or the light chain framework region of the antibody comprises a 49S amino acid back mutation;
- the anti-CD70 antibody comprises a heavy chain framework region variant of a human antibody comprising, relative to the heavy chain framework region of the human antibody, selected from the group consisting of 4M, 37I, 38K, 48I, 67A, 69L, 71A, 73R one or more amino acid back-mutations in , 78A, 80L and 94T, and/or the anti-CD70 antibody comprises a light chain framework region variant of a human antibody comprising a light chain framework region variant selected from the group consisting of 5S relative to the light chain framework region of the human antibody and one or more amino acid backmutations in 70N; in some embodiments, the anti-CD70 antibody comprises a light chain framework region variant of a human antibody comprising a light chain framework region variant selected from the group consisting of 38R, One or more amino acid back-mutations in 43S, 69R, 70Q and 71Y, and/or the anti-CD70 antibody comprises a variant of the heavy chain framework region of a human antibody comprising a
- the humanized antibody comprises a light chain variable region and a heavy chain variable region selected from the group consisting of a), b) or c) below:
- the humanized antibody comprises:
- variable region comprises a heavy chain framework region variant of a human antibody, which relative to the heavy chain framework region of a human antibody comprises a group selected from the group consisting of 4M, 37I, 38K, 48I, 67A, 69L, 71A, 73R, 78A, 80L and 94T
- the light chain variable region comprises a light chain framework region variant of a human antibody comprising one or more selected from the group consisting of 5S and 70N relative to the light chain
- a heavy chain variable region comprising HCDR1 and HCDR3 as set forth in SEQ ID NO: 15 and SEQ ID NO: 17, respectively, and HCDR2 as set forth in SEQ ID NO: 16 or SEQ ID NO: 54; and a light A chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, respectively; and the light chain variable region comprises the light chain framework of a human antibody Region variants comprising one or more amino acid backmutations selected from the group consisting of 38R, 43S, 69R, 70Q and 71Y relative to the light chain framework region of a human antibody, and/or the heavy chain variable region comprising a human antibody A variant of the heavy chain framework region comprising one or more amino acid backmutations selected from the group consisting of 2I, 24T, 46K, 72E and 82aN relative to the heavy chain framework region of a human antibody; or
- variable region comprises a heavy chain framework region variant of a human antibody comprising one or more selected from the group consisting of 27D, 30P, 37L, 38K, 48I, 66K, 67A, 69L and 82aN relative to the heavy chain framework region of the human antibody Multiple amino acid backmutations, and/or the light chain variable region comprises a light chain framework region variant of a human antibody comprising a 49S amino acid backmutation relative to the light chain framework region of the human antibody.
- the mutation site corresponds to the Kab
- the heavy chain variable region of the aforementioned anti-CD70 antibody is selected from the group consisting of 4M, 37I, 38K, 48I, 67A, 69L, 71A, SEQ ID NO: 26 or SEQ ID NO: 34.
- a heavy chain variable region in which one or more amino acids in 73R, 78A, 80L, and 94T are backmutated, and the light chain variable region has a selection based on SEQ ID NO:32 or SEQ ID NO:40.
- the aforementioned anti-CD70 antibody comprises a heavy chain variable region and a light chain variable region, wherein:
- the amino acid sequence of the heavy chain variable region has at least 90%, 91% with SEQ ID NO: 3, 26, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38 or 39, respectively , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, and/or the amino acid sequence of the light chain variable region and SEQ ID NO: 4, 32, 33, 40 or 41 have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, respectively;
- the amino acid sequence of the variable region of the heavy chain has at least 90%, 91%, 92%, 93%, 94%, 95% of the amino acid sequence of SEQ ID NO: 5, 44, 45, 46, 51, 52 or 53, respectively , 96%, 97%, 98%, 99% or 100% sequence identity
- the amino acid sequence of the light chain variable region has at least SEQ ID NO: 6, 47, 48, 49 or 50, respectively 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity; or
- the amino acid sequence of the heavy chain variable region has at least 90%, 91% with SEQ ID NO: 7, 55, 56, 57, 58, 59, 60, 63, 64, 65, 66, 67 or 68, respectively , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, and/or the amino acid sequence of the light chain variable region and SEQ ID NO: 8, 61, 62, 69 or 70 have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, respectively.
- the aforementioned anti-CD70 antibodies comprise heavy chain variable region and light chain variable region combinations as set forth in Table 1, Table 2, and Table 3 below:
- variable region of the heavy chain of the antibody is SEQ ID NO: 26 in the same row
- variable region of the light chain is SEQ ID NO: 40 in the same column
- variable region of the heavy chain of the antibody is SEQ ID NO: 44 in the same row
- variable region of the light chain is SEQ ID NO: 47 in the same column
- variable region of the heavy chain of the antibody is SEQ ID NO: 55 in the same row
- variable region of the light chain is SEQ ID NO: 69 in the same column, and so on.
- the aforementioned anti-CD70 antibody comprises a heavy chain variable region and a light chain variable region, wherein:
- the heavy chain variable region the amino acid sequence of which is shown in SEQ ID NO: 26, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38 or 39; and the light chain may be A variable region whose amino acid sequence is shown in SEQ ID NO: 32, 33, 40 or 41; or
- the heavy chain variable region the amino acid sequence of which is shown in SEQ ID NO: 55, 56, 57, 58, 59, 60, 63, 64, 65, 66, 67 or 68; and the light chain can be The variable region, the amino acid sequence of which is shown in SEQ ID NO: 61, 62, 69 or 70.
- the aforementioned anti-CD70 antibody comprises a heavy chain variable region and a light chain variable region as shown below:
- the aforementioned anti-CD70 antibody comprises an antibody heavy chain constant region and a light chain constant region; preferably, the heavy chain constant region is selected from the group consisting of human IgGl, IgG2, IgG3 and IgG4 constant regions and conventional variants thereof,
- the light chain constant region is selected from the group consisting of human antibody kappa and lambda chain constant regions and conventional variants thereof; more preferably, the antibody comprises a heavy chain constant region as shown in SEQ ID NO:72 and a heavy chain constant region as shown in SEQ ID NO:73 Light chain constant region shown.
- the aforementioned anti-CD70 antibody comprises:
- the aforementioned anti-CD70 antibody comprises:
- the present disclosure also provides an isolated anti-CD70 antibody, wherein the antibody competes with the anti-CD70 antibody of any of the foregoing for binding to human CD70, a human CD70 epitope, monkey CD70, or monkey CD70 antigenic epitopes. In some embodiments, the antibody binds the same epitope on human CD70 as the anti-CD70 antibody of any of the foregoing.
- the anti-CD70 antibody of any of the preceding wherein the anti-CD70 antibody is a hypofucosylated antibody; in some embodiments, the hypofucosylated anti-CD70 antibody Are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the antibody heavy chains are free of fucose sugars Modified antibodies.
- the hypofucosylated anti-CD70 antibody is an antibody whose heavy chain is at least 95%, 96%, 97%, 98%, 99%, or 100% unmodified by fucosylation.
- the aforementioned anti-CD70 antibody is an IgG1 antibody whose 100% heavy chain is not modified by fucosylated glycosylation (also referred to as afucosylated IgG1 antibody).
- the anti-CD70 antibody of any one of the preceding, the anti-CD70 antibody has at least one of the following characteristics:
- the anti-CD70 antibody is less than 1 x 10-8 M, preferably less than 1 x 10 -9 M, or less than 1 x 10 -10 M, or less than 6 x 10 -11 M, or less than 5 x 10 -11 M, or a KD value of less than 4 ⁇ 10 ⁇ 11 M, or less than 3 ⁇ 10 ⁇ 11 M, binds to human CD70 as determined by surface plasmon resonance; for example, as described in Test Example 1 of the present disclosure method to detect;
- the anti-CD70 antibody can bind to both human CD70 antigen and monkey CD70 antigen, but not to mouse CD70 antigen;
- the anti-CD70 antibody can inhibit CD70-induced CD27 signaling, preferably, the anti-CD70 antibody inhibits the maximum percentage inhibition (Imax(%)) of IL-8 secretion by human CD27-expressing cells (eg, HT1080/CD27 cells) Greater than or equal to 72%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, 99% or 100%; more preferably greater than or equal to 90%, 91%, 93% or 98%, the IL-8 secretion is detected by the Elisa method, for example detected by the method described in Test Example 5 of the present disclosure;
- the anti-CD70 antibody has one or more of the following effector functions: antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cytotoxicity to cells expressing human CD70 Cell-mediated phagocytosis (ADCP); preferably, the anti-CD70 antibody has a maximal lysis rate greater than or equal to 70%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 95%, or 100 %; more preferably greater than or equal to 74%, 78%, 84% or 86%; in some scenarios, CDC effector function is detected by the method described in Test Example 7 of the present disclosure; and
- the anti-CD70 antibody can be internalized by cells expressing human CD70, preferably, the maximum lysis rate of cell internalization lysis is greater than or equal to 70%, 75%, 80%, 85%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%; more preferably greater than or equal to 96% or 97%; in some embodiments, cellular internalization passes the test cases of the present disclosure 10 methods for detection.
- the present disclosure also provides a nucleic acid molecule encoding the anti-CD70 antibody of any of the foregoing.
- the present disclosure also provides a host cell comprising the aforementioned nucleic acid molecule.
- the host cell can be selected from prokaryotic cells and eukaryotic cells, preferably eukaryotic cells, more preferably mammalian cells, preferably excluding human mammalian cells, wherein the mammalian cells include but are not limited to CHO, 293, NSO and gene editing in mammalian cells can alter the glycosylation modification of the antibody or its antigen-binding fragment, thereby altering the ADCC function of the antibody or its antigen-binding fragment, for example, knockout genes such as Fut8 or GnT-III for Glycosylation modification.
- the present disclosure also provides a method for preparing the aforementioned anti-CD70 antibody, the method comprising the steps of culturing the aforementioned host cell, and then purifying and recovering the antibody.
- the present disclosure also provides an immunoconjugate comprising the anti-CD70 antibody of any of the foregoing and an effector molecule coupled to the anti-CD70 antibody; preferably, the The effector molecule is selected from the group consisting of radioisotopes, antineoplastic agents, immunomodulators, biological response modifiers, lectins, cytotoxic drugs, chromophores, fluorophores, chemiluminescent compounds, enzymes, metal ions, and any combination thereof.
- the present disclosure also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the anti-CD70 antibody of any of the foregoing, or the foregoing nucleic acid molecule, or the foregoing immunoconjugate, and a or more pharmaceutically acceptable carriers, diluents or excipients.
- the present disclosure also provides a method for immunodetection or determination of CD70, the method comprising the step of contacting the anti-CD70 antibody of any of the foregoing with a subject or a sample from the subject .
- the present disclosure also provides a kit comprising the anti-CD70 antibody or immunoconjugate of any of the foregoing.
- the present disclosure also provides a method of preventing or treating a disease or disorder, the method comprising administering to a subject a therapeutically effective amount of the anti-CD70 antibody of any of the foregoing, or the foregoing nucleic acid molecule , or the aforementioned pharmaceutical composition, or the aforementioned immunoconjugate.
- the present disclosure also provides the anti-CD70 antibody described in any of the foregoing, or the foregoing nucleic acid molecule, or the foregoing pharmaceutical composition, or the foregoing immunoconjugate prepared for use in preventing or treating a disease or use in medicines for disorders.
- the present disclosure provides the anti-CD70 antibody of any of the foregoing, or the foregoing nucleic acid molecule, or the foregoing pharmaceutical composition, or the foregoing immunoconjugate, as a medicament for use in To prevent or treat a disease or condition.
- the disease or disorder of any of the foregoing is a CD70-related disease or disorder.
- the disease or disorder is a disease or disorder in which high CD70 expression is detrimental to the subject.
- the disease or disorder is a tumor, an autoimmune disease, or an infectious disease.
- the tumor is selected from the group consisting of: head and neck squamous cell carcinoma, head and neck cancer, brain cancer, glioma, glioblastoma multiforme, neuroblastoma, central nervous system Systemic cancer, neuroendocrine tumor, throat cancer, nasopharyngeal cancer, esophageal cancer, thyroid cancer, malignant pleural mesothelioma, lung cancer, breast cancer, liver cancer, hepatobiliary cancer, pancreatic cancer, gastric cancer, gastrointestinal cancer, intestinal cancer, colon cancer cancer, colorectal cancer, kidney cancer, clear cell renal cell carcinoma, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, melanoma, leukemia, lymphoma, bone cancer, Chondrosarcoma, myeloma, multiple myeloma, myelodysplastic syndrome, Keukenberg's tumor, myeloproliferative
- the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, joint psoriasis, psoriasis, dermatitis, systemic scleroderma, systemic scleroderma and sclerosis, inflammatory Intestinal disease (IBD), Crohn's disease, ulcerative colitis, respiratory distress syndrome, meningitis, encephalitis, uveitis, glomerulonephritis, eczema, asthma, arteriosclerosis, leukocyte adhesion deficiency, multiple sclerosis Symptoms of immune-mediated thrombocytopenia (eg, acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura idiopathic thrombocytopenic purpura), hemolytic anemia, myasthenia gravis, lupus
- the disease or disorder is: acute myeloid leukemia, myelodysplastic syndrome, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, renal cell carcinoma, metastatic renal cell carcinoma, rheumatoid arthritis, and psoriasis.
- the aforementioned therapeutically effective amount of the composition in a unit dose contains 0.1-3000 mg of the aforementioned anti-CD70 antibody, or the aforementioned nucleic acid molecule, or the aforementioned immunoconjugate, or the aforementioned pharmaceutical composition.
- the treatment further comprises administering to the subject a therapeutically effective amount of a second therapeutic agent.
- Figure 1A and Figure 1B show the experimental results of anti-CD70 antibody binding to CD70-positive 786-O cells;
- Figure 1A shows the experimental results of anti-CD70 antibody binding to CD70-positive 786-O cells, and
- Figure 1B is a non-fucosylated antibody Figure of the experimental results of CD70 antibody binding to CD70-positive 786-O cells.
- Figures 2A and 2B show the experimental results of anti-CD70 antibody binding to CD70-positive Raji cells, wherein Figure 2A is the experimental results of anti-CD70 antibody binding to CD70-positive Raji cells, and Figure 2B is the binding of afucosylated anti-CD70 antibody to CD70-positive Experimental results of Raji cells.
- Figure 3 shows the results of ELISA experiments of huB7002 binding to human, monkey and mouse CD70 proteins.
- Figure 4 shows the results of ELISA experiments of huB1010 binding to human, monkey and mouse CD70 proteins.
- Figure 5 shows the results of ELISA experiments of huF4011 binding to human, monkey and mouse CD70 proteins.
- Figure 6 shows the experimental results of anti-CD70 antibody blocking CD27 binding to CD70 positive cells.
- Figure 7 shows the results of experiments in which afucosylated anti-CD70 antibodies blocked CD27 binding to CD70 positive cells.
- Figure 8 shows the results of the inhibition experiment of anti-CD70 antibody on IL-8 secretion of HT1080/CD27 cells.
- Figure 9 shows the results of the inhibition experiment of afucosylated anti-CD70 antibody on IL-8 secretion by HT1080/CD27 cells.
- Figure 10 shows the experimental results of anti-CD70 antibody on ADCC (NK92) of 786-O cells in vitro.
- FIG 11 shows the experimental results of anti-CD70 antibody on ADCC (PBMC) of 786-O cells in vitro.
- Figure 12 shows the experimental results of anti-CD70 antibody on Raji cell CDC in vitro.
- Figure 13 shows the experimental results of in vitro CDC of Raji cells by afucosylated anti-CD70 antibody.
- Figures 14A and 14B show the experimental results of in vitro ADCP of anti-CD70 antibody on 786-O and Raji cells, wherein Figure 14A is a graph of the ADCP experimental results of anti-CD70 antibody on 786-O cells, and Figure 14B is a graph of anti-CD70 antibody on Raji cells The results of ADCP experiments on cells.
- Figure 15 shows the experimental results of the inhibition of Treg cells by anti-CD70 antibodies in vitro.
- Figure 16 shows the results of internalization experiments of anti-CD70 antibodies in 786-O cells.
- Figure 17 shows the results of in vivo efficacy experiments of anti-CD70 antibodies in mouse Raji model.
- Figure 18 shows the results of in vivo efficacy experiments of afucosylated anti-CD70 antibodies in the mouse Raji model.
- antibody in this disclosure is used in the broadest sense and encompasses a variety of antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), full length antibodies or antigen binding thereof Fragments (also referred to as "antigen-binding portions”) so long as they exhibit the desired antigen-binding activity.
- Natural full-length antibodies are immunoglobulins (Ig) comprising at least two heavy chains and two light chains interconnected by disulfide bonds. The amino acid composition and sequence of the immunoglobulin heavy chain constant region are different, so their antigenicity is also different.
- immunoglobulins can be divided into five classes, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, whose corresponding heavy chains are ⁇ , ⁇ , and ⁇ chains, respectively. , alpha chains, and epsilon chains.
- the same type of Ig can be divided into different subclasses according to the difference in the amino acid composition of the hinge region and the number and position of disulfide bonds in the heavy chain.
- IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
- Light chains are classified into kappa chains or lambda chains by the difference in the constant region.
- Each of the five classes of Ig can have a kappa chain or a lambda chain.
- Each heavy chain consists of a heavy chain variable region (abbreviated as VH) and a heavy chain constant region (abbreviated as CH).
- the heavy chain constant region contains three domains, CH1, CH2 and CH3.
- Each light chain consists of a light chain variable region (abbreviated as VL) and a light chain constant region (abbreviated as CL).
- the heavy and light chain variable regions include hypervariable regions (also called complementarity determining regions, abbreviated as CDRs or HVRs) and framework regions (also called framework regions, abbreviated as FRs) with relatively conserved sequences.
- CDRs complementarity determining regions
- FRs framework regions
- Each VL and VH consists of 3 CDRs and 4 FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
- the three CDR regions of the light chain are referred to as LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain are referred to as HCDR1, HCDR2, and HCDR3.
- Antibodies of the present disclosure include murine antibodies, chimeric antibodies, and humanized antibodies.
- murine antibody in this disclosure is a murine monoclonal antibody directed against an antigen (eg, human CD70) prepared according to knowledge and skill in the art. For example, subjects are injected with the CD70 antigen, and hybridomas expressing antibodies with the desired sequence or functional properties are isolated.
- the murine anti-CD70 antibody or antigen-binding fragment thereof may further comprise a light chain constant region of a murine ⁇ , ⁇ chain or a variant thereof, or further comprise a murine IgG1 , the heavy chain constant region of IgG2, IgG3 or variants thereof.
- chimeric antibody is an antibody obtained by fusing the variable region of a murine antibody with the constant region of a human antibody, which can alleviate the immune response induced by the murine antibody.
- a chimeric antibody first create a hybridoma that secretes a mouse-specific monoclonal antibody, then clone the variable region gene from the mouse hybridoma cell, and then clone the constant region gene of the human antibody as needed, and then clone the mouse variable region gene from the mouse hybridoma cell.
- the region gene and the human constant region gene are connected to form a chimeric gene and then inserted into an expression vector, and finally the chimeric antibody molecule is expressed in a eukaryotic system or a prokaryotic system.
- the antibody light chain of the chimeric antibody further comprises a light chain constant region of a human kappa, lambda chain or a variant thereof.
- the antibody heavy chain of the CD70 chimeric antibody further comprises the heavy chain constant region of human IgG1, IgG2, IgG3, IgG4 or a variant thereof, preferably comprises a human IgG1, IgG2 or IgG4 heavy chain constant region, or uses amino acid mutation (eg L234A and/or L235A mutation, and/or S228P mutation, 265A and/or 297A) IgG1, IgG2 or IgG4 variants.
- amino acid mutation eg L234A and/or L235A mutation, and/or S228P mutation, 265A and/or 297A
- humanized antibody also known as CDR-grafted antibody, refers to the grafting of murine CDR sequences into a human antibody variable region framework, i.e. a different type of human germline antibody antibodies produced in framework sequences.
- the heterologous reaction induced by chimeric antibodies can be overcome because they carry a large amount of murine protein components.
- framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
- the germline DNA sequences of human heavy and light chain variable region genes can be obtained in the "VBase" human germline sequence database, and in Kabat, E.A. et al., 1991 Sequences of Proteins of Immunological Interest, 5th edition.
- the minimum reverse mutation or back mutation can be performed on the framework sequence of the variable region of the human antibody to maintain or enhance the activity.
- the humanized antibodies of the present disclosure also include humanized antibodies that have been further subjected to affinity maturation mutation of the CDRs by yeast display.
- the antibody or antigen-binding fragment thereof may further comprise a light chain constant region of human or murine ⁇ , ⁇ chains or variants thereof, or further comprise human or murine IgG1 , heavy chain constant regions of IgG2, IgG3, IgG4 or variants thereof; may comprise human IgG1, IgG2 or IgG4 heavy chain constant regions, or use amino acid mutations (e.g. L234A and/or L235A mutation, and/or S228P mutation, 265A and/or IgG1, IgG2 or IgG4 variants of 297A).
- amino acid mutations e.g. L234A and/or L235A mutation, and/or S228P mutation, 265A and/or IgG1, IgG2 or IgG4 variants of 297A.
- inventions of the human antibody heavy chain constant region and the human antibody light chain constant region mentioned in the present disclosure refer to the human-derived heavy chain constant regions disclosed in the prior art that do not alter the structure and function of the antibody variable region or variants of the light chain constant region
- exemplary variants include IgG1, IgG2, IgG3 or IgG4 heavy chain constant region variants with site-directed reengineering and amino acid substitutions of the heavy chain constant region, specifically replacing YTE as known in the art Mutations, L234A and/or L235A mutations, S228P mutations, 265A (eg D265A) and/or 297A (eg N297A), and/or mutations to obtain a knob-into-hole structure (so that the antibody heavy chain has knob-Fc and hole- Fc combination), these mutations have been shown to confer novel properties of the antibody without altering the function of the variable region of the antibody.
- Human antibody (HuMAb), "human antibody”, “fully human antibody”, “fully human antibody” are used interchangeably and can be an antibody derived from a human or an antibody obtained from a transgenic organism,
- the transgenic organism is "engineered” to produce specific human antibodies in response to antigenic stimulation and can be produced by any method known in the art.
- elemental elements of human heavy and light chain loci are introduced into cell lines of organisms derived from embryonic stem cell lines in which endogenous heavy and light chain loci are targeted to destruction.
- Transgenic organisms can synthesize human antibodies specific for human antigens, and the organisms can be used to generate human antibody-secreting hybridomas.
- a human antibody can also be one in which the heavy and light chains are encoded by nucleotide sequences derived from one or more human DNA sources.
- Fully human antibodies can also be constructed by gene or chromosomal transfection methods and phage display techniques, or by in vitro activated B cells, all of which are known in the art.
- full-length antibody intact antibody
- complete antibody completely antibody
- whole antibody whole antibody
- antibodies of the present disclosure include “full-length antibodies” and “antigen-binding fragments” thereof.
- the full-length antibody of the present disclosure includes a full-length antibody formed by the combination of light and heavy chain variable regions in Table 1, Table 2, and Table 3, respectively, linked to the light and heavy chain constant regions.
- Those skilled in the art can select light chain constant regions and heavy chain constant regions derived from different antibodies according to actual needs, such as light chain constant regions and heavy chain constant regions derived from human antibodies.
- the different light chain variable regions and heavy chain variable regions in Table 1, Table 2 and Table 3 can be combined to form single chain antibodies (scFv), Fab or other antigen binding fragments comprising scFv or Fab.
- antigen-binding fragment or “functional fragment” or “antigen-binding portion” refers to one or more fragments of an intact antibody that retain the ability to specifically bind an antigen (eg, CD70). Fragments of full-length antibodies have been shown to perform the antigen-binding function of antibodies.
- binding fragments encompassed by the term "antigen-binding fragment” include: (i) Fab fragments, a monovalent fragment consisting of VL, VH, CL and CH1 domains; (ii) F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge on the hinge region, (iii) an Fd fragment consisting of VH and CH1 domains; (iv) a VH and Fv fragment composed of VL domains; (v) dsFv, a stable antigen-binding fragment formed by VH and VL via interchain disulfide bonds; (vi) diabodies and bispecific antibodies comprising scFv, dsFv, Fab and other fragments and multispecific antibodies.
- Antigen binding moieties can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.
- Antibodies can be of different isotypes, eg, IgG (eg, IgGl, IgG2, IgG3, or IgG4 subtype), IgAl, IgA2, IgD, IgE, or IgM antibodies.
- amino acid difference or “amino acid mutation” refers to an amino acid change or mutation in a variant protein or polypeptide compared to the original protein or polypeptide, including 1, 2, 3, or Insertion, deletion or substitution of more amino acids.
- antibody framework or "FR region” refers to the portion of a variable domain VL or VH that serves as a scaffold for the antigen binding loops (CDRs) of the variable domain. Essentially, it is a variable domain without CDRs.
- CDR complementarity determining region
- HCDR1, HCDR2, HCDR3 three CDRs in each heavy chain variable region and three CDRs (LCDR1, LCDR2, LCDR3) in each light chain variable region.
- LCDR1, LCDR2, LCDR3 three CDRs in each light chain variable region.
- the amino acid sequence boundaries of CDRs can be determined using any of a variety of well-known schemes, including the "Kabat” numbering convention (see Kabat et al.
- VH variable domain
- VL variable domain
- CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50 -56 (LCDR2) and 89-97 (LCDR3).
- CDR amino acids in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2) and 95-102 (HCDR3); and amino acids in VL Residue numbers are 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3).
- the CDRs are defined by amino acid residues 26-35 in human VH (HCDR1 ), 50-65 (HCDR2) and 95-102 (HCDR3) and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3) in human VL.
- VH The CDR amino acid residue numbers in VL are approximately 26-35 (CDR1), 51-57 (CDR2) and 93-102 (CDR3), and the CDR amino acid residue numbers in VL are approximately 27-32 (CDR1), 50-52 (CDR2) and 89-97 (CDR3).
- the CDR regions of the antibody can be determined using the program IMGT/DomainGap Align.
- the CDR amino acids in VH are numbered 26-32 (HCDR1), 50-58 ( HCDR2) and 95-102 (HCDR3); and the amino acid residues in VL are numbered 24-34 (LCDR1), 50-56 (LCDR2 ) and 89-97 (LCDR3).
- the antibody variable region and CDR sequences of the present disclosure correspond to the "Kabat" numbering convention.
- epitopes refers to a site on an antigen to which an antibody specifically binds (eg, a specific site on a CD70 molecule).
- Epitopes typically include at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 contiguous or non-contiguous amino acids in a unique spatial conformation. See, eg, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, G.E. Morris, Ed. (1996).
- the terms “specifically binds”, “selectively binds”, “selectively binds” and “specifically binds” refer to the binding of an antibody to a predetermined epitope on an antigen.
- the antibody is less than about 10 -8 M, e.g. less than about 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M or smaller affinity (KD) binding.
- KD refers to the dissociation equilibrium constant for a particular antibody-antigen interaction.
- the antibodies of the present disclosure bind CD70 with a dissociation equilibrium constant (KD) of less than about 10-8 M, eg, less than about 10-9 M or 10-10 M, using surface plasmon resonance (SPR) technology Measured in a Biacore T200 instrument.
- SPR surface plasmon resonance
- the term “compete” in the context of antigen-binding proteins competing for the same epitope (eg, neutralizing antigen-binding proteins or neutralizing antibodies), it means competition between antigen-binding proteins, as determined by the following assay:
- the antigen binding protein eg, antibody or immunologically functional fragment thereof
- the antigen binding protein prevents or inhibits (eg reduces) the interaction of a reference antigen binding protein (eg ligand or reference antibody) with a common antigen (eg CD70 antigen or specific binding of its fragments).
- RIA solid-phase direct or indirect radioimmunoassay
- EIA solid-phase direct or indirect enzyme immunoassay
- Sandwich competition assay see, eg, Stahli et al., 1983, Methods in Enzymology 9:242-253
- solid-phase direct biotin-avidin EIA see, eg, Kirkland et al., 1986, J. Immunol. 137:3614-3619
- solid phase Direct Labeling Assay Solid Phase Direct Labeling Sandwich Assay (see e.g.
- Solid Phase Direct Labeling with I-125 Label RIA see, eg, Morel et al., 1988, Molec. Immunol. 25:7-15
- solid-phase direct biotin-avidin EIA see, eg, Cheung, et al., 1990, Virology 176:546-552
- directly labeled RIA Methyl et al., 1990, Scand. J. Immunol. 32:77-82
- the assay involves the use of purified antigen bound to a solid surface or cell bearing either an unlabeled test antigen binding protein and a labeled reference antigen binding protein.
- Antigen-binding proteins identified by competitive assays include: antigen-binding proteins that bind to the same epitope as the reference antigen-binding protein; and antigen-binding proteins that bind to adjacent epitopes sufficiently close to the binding epitope of the reference antigen-binding protein protein, the two epitopes sterically prevent each other from binding. Additional details regarding methods for determining competitive binding are provided in the Examples herein.
- a competing antigen binding protein when present in excess, it will inhibit (eg decrease) by at least 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70% -75% or 75% or more specific binding of the reference antigen binding protein to a common antigen. In certain instances, binding is inhibited by at least 80-85%, 85-90%, 90-95%, 95-97%, or 97% or more.
- nucleic acid molecule refers to DNA molecules and RNA molecules. Nucleic acid molecules may be single-stranded or double-stranded, preferably double-stranded DNA or single-stranded mRNA or modified mRNA. A nucleic acid is "operably linked" when it is placed in a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the coding sequence.
- amino acid sequence identity means that when aligning amino acid sequences (gaps are introduced where necessary to achieve maximum percent sequence identity, and any conservative substitutions are not considered part of sequence identity), in a first sequence with a second sequence The percentage of amino acid residues in which the amino acid residues are identical.
- alignment can be accomplished in a variety of ways known in the art, eg, using software such as BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR).
- One skilled in the art can determine parameters suitable for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
- fucosylated or "fucosylated” or “fucosylated modification” refers to the presence of a fucose residue within the oligosaccharide attached to the peptide chain of an antibody. Fucosylation is a common process of post-translational modification of glycoproteins. Representative enzyme genes related to core fucosylation include GMD (GDP-mannose 4,6-dehydratase) gene and Fut8 (fut8, FUT8) , ⁇ -1,6-fucosyltransferase) gene, the core fucosylation level can be effectively regulated by inhibiting the expression of these two genes or constructing Fut8 knockout CHO host cells (YAMANE-OHNUKI et al.
- fucosylated antibodies comprise in the N-oligosaccharide of the Fc region, at a core N-acetylglucosamine (GlcNAc) residue (eg, position Asn297 of a human IgG1 Fc (corresponding to the EU numbering convention)) Alpha-1,6-fucose.
- GlcNAc N-acetylglucosamine
- an antibody that is "hypofucosylated” refers to an antibody in which the carbohydrate structure attached to the Fc region has a low glycosylation modification of fucose; "afucosylated” or “afucosylated” “refers to an antibody in which the carbohydrate structure attached to the Fc region lacks the glycosylation modification of fucose.
- Antibody fucosylation levels can be determined by methods known in the art for all oligosaccharides to determine the percentage of fucosylated oligosaccharides. Methods known in the art for determining fucosylation include, but are not limited to, gel electrophoresis, liquid chromatography, mass spectrometry, and the like.
- the level of fucosylation of the antibody is determined by hydrophilic interaction chromatography (or hydrophilic interaction liquid chromatography, HILIC), eg by treatment of the sample with peptide-N-glycanase F to denature To cleave N-linked glycans, the N-linked glycans were then analyzed for fucose content.
- hydrophilic interaction chromatography or hydrophilic interaction liquid chromatography, HILIC
- the hypofucosylated antibodies of the present disclosure are antibodies in which at least 80% of the heavy chains are not modified by glycosylation of fucose, eg, at least 80-95%, 90-95% %, 95-100%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the antibody heavy chain is fucose free Glycosylation modification.
- fucose eg. at least 80-95%, 90-95% %, 95-100%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the antibody heavy chain is fucose free Glycosylation modification.
- fucose eg.g, at least 80-95%, 90-95% %, 95-100%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the antibody heavy chain is fucos
- Hypofucosylated or afucosylated antibodies can be prepared by methods well known in the art. Prepared, for example, by adding, removing or deleting one or more carbohydrate moieties present on the antibody, eg, by cleavage of fucose residues of the antibody using fucosidase (see Tarentino et al. (1975) Biochem. 14:5516). Antibodies with reduced fucosylation can also be prepared by altering the glycosylation composition by altering the level of glycosylation, for example by modifying the glycan module attached to each Fc fragment at residue N297 (Natsume et al. (2009) Drug Des. Devel. Ther. 3:7).
- Hypofucosylated or afucosylated antibodies can also be expressed without altering the sequence of the antibody, e.g., by cells that alter the glycosylation pattern of the antibody, including, e.g., by genetically engineered glycosylation engineering.
- Various glycosylated engineered cells have been disclosed in the art, for example, cells lacking the fucosyltransferase gene (FUT8, ( ⁇ -(1,6)fucosyltransferase) cell lines Ms704, Ms705, and Ms709, etc.
- carrying an enzyme encoding an enzyme that uses GDP-6-deoxy-D-lyxo-4-hexose as a substrate can also produce hypofucosylated or afucosylated antibodies (see US Pat. No. 8,642,292).
- the afucosylated antibody was prepared by the method described in Example 5.
- ADCC antibody-dependent cell-mediated cytotoxicity
- FcR-expressing non-specific cytotoxic cells eg, natural killer (NK) cells, neutrophils, and macrophages
- NK cells Primary cells that regulate ADCC
- monocytes express FcyRI, FcyRII and FCYRIII.
- ADCC assays can be performed (such as described by Clynes et al. (PNASUSA 95:652-656 (1998)), US Pat. Nos. US5500362, US5821337, etc.).
- the ADCC is detected by the method of Test Example 6 of the present disclosure.
- ADCP antibody-dependent cellular phagocytosis
- phagocytic cells eg, macrophages, neutrophils, and dendritic cells
- Internalized antibody-coated target cells or virions are contained in vesicles called phagosomes, which then fuse with one or more lysosomes to form phagolysosomes.
- ADCP can be assessed by in vitro cytotoxicity assays and videomicroscopy using macrophages as effector cells (eg, van Bij et al. Journal of Hepatology Vol 53, Issue 4, October 2010, pp. 677–685 ).
- the ADCP is detected by the method of Test Example 8 of the present disclosure.
- CDC complement-dependent cytotoxicity
- in vitro assays eg, using normal human serum as a complement source for CDC
- C1q concentration series e.g., C1q concentration series
- the assay can be performed by an assay as described by Romeuf et al. (Romeuf et al., Br J Haematol. 2008 Mar; 140(6):635-43).
- the CDC is detected by the method of Test Example 7 of the present disclosure.
- conjugate refers to a new type of drug in which a ligand is linked to a biologically active drug through a stable linking unit.
- antibody drug conjugate antibody drug conjugate, ADC
- ADC antibody drug conjugate
- the antibody can be conjugated to the drug either directly or via a linker.
- the average number of drug moieties per antibody which can range, for example, from about 0 to about 20 drug moieties per antibody, in some embodiments 1 to about 10 drug moieties per antibody, in certain embodiments is 1 to about 8 drug moieties per antibody.
- Compositions of mixtures of antibody-drug conjugates of the present disclosure wherein the average drug loading per antibody is from about 2 to about 5 or from about 3 to about 4.
- an immunoconjugate disclosed herein can be an antibody attached to an effector molecule, wherein the antibody can be an antibody comprising a heavy chain and a light chain.
- the antibody may be an antibody fragment, such as a Fab, Fab', F(ab')2, scFv, dsFv, ds-scFv, dimer, minibody, diabody, bispecific antibody fragment, Multimers, and any combination thereof.
- the effector molecule can be a radioisotope, antineoplastic agent, immunomodulatory agent, biological response modifier, lectin, cytotoxic drug, chromophore, fluorophore, chemiluminescent compound, enzyme, metal ions, and any combination thereof.
- the antibodies or antibody fragments described in this disclosure can be coupled to effector molecules by any means.
- the antibody or antibody fragment can be attached to the toxin by chemical or recombinant means.
- Chemical means for preparing fusions or conjugates are known in the art and can be used to prepare immunoconjugates.
- the method for conjugating the antibody or antibody fragment and the toxin must be capable of linking the antibody to the toxin without interfering with the ability of the antibody or antibody fragment to bind to the target molecule.
- cytotoxic drug refers to a substance that inhibits or prevents the function of cells and/or causes cell death or destruction. Including toxins, chemotherapy drugs and other compounds that can be used to kill tumor cells.
- toxin refers to any substance capable of having a deleterious effect on the growth or proliferation of cells, which may be small molecule toxins from bacteria, fungi, plants or animals and their derivatives, including camptothecin derivatives such as ixatib Kang, maytansinoids and derivatives thereof (CN101573384) such as DM1, DM3, DM4, auristatin F (AF) and derivatives thereof, such as MMAF, MMAE, 3024 (WO 2016/127790 A1, compound 7), diphtheria Toxins, exotoxins, ricin (ricin) A chain, abrin (abrin) A chain, modeccin, ⁇ -brucellin (sarcin), aleutites fordii toxin, carnation (dianthin) ) Toxin, Pokeweed (Phytolaca americana) Toxin (PAPI, PAPII and PAP-S), Momordica charantia inhibitor, curcin, crotin, Soa
- chemotherapeutic drug is a chemical compound that can be used to treat tumors. This definition also includes antihormonal agents that act to modulate, reduce, block or inhibit the effects of hormones that promote cancer growth, and are often in the form of systemic or systemic therapy. They can themselves be hormones.
- chemotherapeutic drugs include alkylating agents such as thiotepa; cyclosphamide (CYTOXAN TM ); alkyl sulfonates such as busulfan, improsulfan and piperidine piposulfan; aziridines such as benaodopa, carboquone, meturedopa and uredopa; aziridine and methylamelamine include Altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil , naphthalene mustard, cholophosphamide, estramustine, ifosfamide, mechlorethamine, oxazolam hydrochloride; melphalan, new Nitrogen mustard (novembichin), cholesteryl phenylacetate mustard, prednimustine, trofosfamide, uracil mustard; nitrosureas such
- anti-hormonal agents that modulate or inhibit the effect of hormones on tumors, such as anti-estrogen agents including tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole , 4-hydroxytamoxifen, trioxifene (trioxifene), keoxifene, LY117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide (flutamide), nilutamide ( nilutamide), bicalutamide, leuprolide and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.
- anti-estrogen agents including tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole , 4-hydroxytamoxifen, trioxifene (trioxifene), keoxifene, LY117018, onapristone, and torem
- both the antibody and the toxin are proteins and can be conjugated using techniques well known in the art.
- crosslinkers There are hundreds of crosslinkers disclosed in the art that can couple two proteins. Crosslinkers are generally selected based on reactive functional groups available or inserted on the antibody or toxin. Additionally, if no reactive groups are present, a photoactivatable crosslinker can be used. In some cases, it may be desirable to include a spacer between the antibody and the toxin.
- Crosslinking agents known in the art include homobifunctional agents: glutaraldehyde, dimethyl adipimide, and bis(diazobenzidine), and heterobifunctional agents: m-maleimide Benzoyl-N-hydroxysuccinimide and sulfo-m-maleimidobenzoyl-N-hydroxysuccinimide.
- Crosslinkers that can be used to couple effector molecules to antibody fragments include, for example, TPCH (S-(2-thiopyridyl)-L-cysteine hydrazide) and TPMPH (S-(2-thiopyridyl) ) mercapto-propionic hydrazide).
- TPCH and TPMPH react on the carbohydrate portion of the glycoprotein that has previously been oxidized by mild periodate treatment, thereby forming a hydrazone bond between the hydrazide portion of the crosslinker and the periodate-generated aldehyde.
- Heterobifunctional crosslinkers GMBS N-( ⁇ -maleimidobutyryloxy)-succinimide
- SMCC succinimidyl 4-(N-maleimido- Methyl)cyclohexane
- GMBS N-( ⁇ -maleimidobutyryloxy)-succinimide
- SMCC succinimidyl 4-(N-maleimido- Methyl)cyclohexane
- a cross-linking agent can be used to introduce a long spacer arm between the components, such as 3-(2-pyridyldithio)propionic acid n - Succinimidyl ester (SPDP).
- SPDP 3-(2-pyridyldithio)propionic acid n - Succinimidyl ester
- expression vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
- the vector is a "plasmid,” which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated.
- the vector is a viral vector in which additional DNA segments can be ligated into the viral genome.
- the vectors disclosed herein are capable of autonomous replication in the host cells into which they have been introduced (eg, bacterial vectors and episomal mammalian vectors with a bacterial origin of replication) or may integrate into the host cell's genome after introduction into the host cell, thereby following The host genome replicates together (eg, a non-episomal mammalian vector).
- mice can be immunized with human CD70 or a fragment thereof, and the resulting antibody can be renatured, purified, and amino acid sequenced using conventional methods.
- Antigen-binding fragments can likewise be prepared by conventional methods.
- the disclosed antibodies or antigen-binding fragments are genetically engineered to add one or more human FR regions to non-human CDR regions.
- Human FR germline sequences can be obtained by aligning the IMGT human antibody variable region germline gene database with MOE software, from the website of ImMunoGeneTics (IMGT) at http://imgt.cines.fr, or from the Journal of Immunoglobulins, 2001 ISBN012441351 get.
- IMGT ImMunoGeneTics
- host cell refers to a cell into which an expression vector has been introduced.
- Host cells can include bacterial, microbial, plant or animal cells.
- Bacteria susceptible to transformation include members of the enterobacteriaceae family, such as strains of Escherichia coli or Salmonella; Bacillaceae such as Bacillus subtilis; Pneumococcus; Streptococcus and Haemophilus influenzae.
- Suitable microorganisms include Saccharomyces cerevisiae and Pichia pastoris.
- Suitable animal host cell lines include CHO (Chinese Hamster Ovary cell line), 293 cells and NSO cells. To obtain afucosylated antibodies, Glu1 and Fut8 gene knockout host cells can be used, including but not limited to Glu1 and Fut8 gene knockout CHOK1 cells.
- the engineered antibodies or antigen-binding fragments of the present disclosure can be prepared and purified using conventional methods.
- cDNA sequences encoding heavy and light chains can be cloned and recombined into a GS expression vector.
- the recombinant immunoglobulin expression vector can stably transfect CHO cells.
- mammalian-like expression systems lead to glycosylation of the antibody, especially at the highly conserved N-terminal site of the Fc region.
- Stable clones were obtained by expressing antibodies that specifically bind human CD70. Positive clones were expanded in serum-free medium in bioreactors for antibody production.
- the antibody-secreted culture medium can be purified by conventional techniques.
- a or G Sepharose FF column with adjusted buffer. Non-specifically bound components are washed away. The bound antibody was eluted by pH gradient method, and the antibody fragments were detected by SDS-PAGE and collected. Antibodies can be filtered and concentrated by conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves, ion exchange. The obtained product should be frozen immediately, eg -70°C, or lyophilized.
- administering when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to exogenous drugs, therapeutic agents, diagnostic agents, or compositions Contact with animals, humans, subjects, cells, tissues, organs or biological fluids.
- administering can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods.
- Treatment of cells includes contact of reagents with cells, and contact of reagents with fluids, wherein the fluids are in contact with cells.
- administering also mean in vitro and ex vivo treatment of, eg, cells by an agent, diagnostic, binding composition, or by another cell.
- Treatment as it applies to human, veterinary or research subjects, refers to therapeutic treatment, prophylactic or preventive measures, research and diagnostic applications.
- Treatment means administering an internal or external therapeutic agent, eg, a composition comprising any of the binding compounds of the present disclosure, to a patient having one or more disease symptoms for which the therapeutic agent is known to have Therapeutic effect.
- a therapeutic agent is administered in a patient or population to be treated in an amount effective to alleviate one or more symptoms of a disease, to induce regression of such symptoms or to inhibit progression of such symptoms to any clinically measured degree.
- the amount of a therapeutic agent effective to relieve symptoms of any particular disease can vary depending on factors such as the patient's disease state, age and weight, and the ability of the drug to produce the desired effect in the patient.
- Whether symptoms of a disease have been alleviated can be assessed by any clinical test commonly used by doctors or other health care professionals to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (eg, methods of treatment or articles of manufacture) may be ineffective in alleviating symptoms of each target disease, the method of The U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test determine that it should reduce symptoms of the target disease in a statistically significant number of patients.
- H test Kruskal-Wallis test
- Jonckheere-Terpstra test Jonckheere-Terpstra test
- Wilcoxon test determine that it should reduce symptoms of the target disease in a statistically significant number of patients.
- Constant modification or “conservative substitution or substitution” refers to the replacement of amino acids in a protein by other amino acids with similar characteristics (eg, charge, side chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.) such that frequent Changes are made without altering the biological activity of the protein.
- Those skilled in the art are aware that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., 224, (4th ed.).
- substitution of structurally or functionally similar amino acids is unlikely to disrupt biological activity. Exemplary conservative substitutions are as follows:
- Trp(W) Tyr Phe Tyr(Y) Trp; Phe Val(V) Ile; Leu
- an “effective amount” or “effective dose” refers to the amount of a drug, compound, or pharmaceutical composition necessary to obtain any one or more beneficial or desired therapeutic results.
- beneficial or desired results include elimination or reduction of risk, reduction in severity, or delay in onset of disorders, including biochemical, tissue academic and/or behavioral symptoms.
- beneficial or desired outcomes include clinical outcomes, such as reducing the incidence or amelioration of one or more symptoms of the various target antigen-related disorders of the present disclosure, reducing the amount of other agents required to treat the disorder dose, enhances the efficacy of another agent, and/or delays the progression of a disorder associated with the target antigen of the present disclosure in a patient.
- Exogenous refers to a substance produced outside an organism, cell, or human body, as the case may be.
- Endogenous refers to a substance produced in a cell, organism, or human body as the case may be.
- Homology refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. Two DNA molecules are homologous when a position in the two compared sequences is occupied by the same base or amino acid monomer subunit, for example if each position is occupied by an adenine, then the molecules are homologous at that position . The percent homology between the two sequences is a function of the number of matches or homologous positions shared by the two sequences divided by the number of positions compared x 100.
- sequences when sequences are optimally aligned, two sequences are 60% homologous if 6 matches or homology at 10 positions in the two sequences; if 95 matches at 100 positions in the two sequences or homologous, then the two sequences are 95% homologous.
- comparisons are made when aligning two sequences to give the greatest percent homology.
- the comparison can be performed by the BLAST algorithm, where the parameters of the algorithm are chosen to give the maximum match between the respective sequences over the entire length of the respective reference sequences.
- the following references refer to BLAST algorithms frequently used in sequence analysis: BLAST Algorithm (BLAST ALGORITHMS): Altschul, SF et al., (1990) J. Mol. Biol.
- the expressions "cell”, “cell line” and “cell culture” are used interchangeably and all such designations include progeny.
- the words “transformants” and “transformed cells” include primary test cells and cultures derived therefrom, regardless of the number of transfers. It should also be understood that, due to deliberate or unintentional mutations, all progeny may not be exactly the same in terms of DNA content. Mutant progeny that have the same function or biological activity as screened in the original transformed cell are included. Where a different name is meant, it is clear from the context.
- Polymerase chain reaction or "PCR” as used herein refers to a procedure or technique in which traces of a specified portion of nucleic acid, RNA and/or DNA are amplified as described in, eg, US Pat. No. 4,683,195. Generally, sequence information from the end of the target region or beyond is required to allow the design of oligonucleotide primers; these primers are identical or similar in sequence to the corresponding strand of the template to be amplified. The 5'-terminal nucleotides of the two primers can be identical to the ends of the material to be amplified.
- PCR can be used to amplify specific RNA sequences, specific DNA sequences from total genomic DNA and cDNA, phage or plasmid sequences transcribed from total cellular RNA, and the like. See generally Mullis et al. (1987) Cold Spring Harbor Symp. Ouant. Biol. 51:263; Erlich ed., (1989) PCR TECHNOLOGY (Stockton Press, N.Y.).
- PCR as used herein is considered to be one example, but not the only example, of a nucleic acid polymerase reaction method for amplifying a nucleic acid test sample, which method includes the use of known nucleic acids and nucleic acid polymerases as primers to amplify or Generate a specific portion of nucleic acid.
- isolated refers to a purified state, and in this case means that the named molecule is substantially free of other biomolecules, such as nucleic acids, proteins, lipids, carbohydrates, or other materials, such as cell debris and growth media. Generally, the term “isolated” is not intended to mean the complete absence of these materials or the absence of water, buffers, or salts, unless they are present in amounts that significantly interfere with the experimental or therapeutic use of the compounds as described herein.
- “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable Carriers and Excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
- pharmaceutically acceptable carrier refers to any inactive substance suitable for use in a formulation for the delivery of a drug such as an anti-CD70 antibody or antigen-binding fragment described herein.
- the carrier can be an antiadherent, binder, coating, disintegrant, filler or diluent, preservative (eg, antioxidant, antibacterial or antifungal), sweetener, absorption delaying agent, wetting agent agents, emulsifiers, buffers, etc.
- suitable pharmaceutically acceptable carriers include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.) dextrose, vegetable oils (eg, olive oil), saline, buffers, buffered saline, and the like Osmotic agents such as sugars, polyols, sorbitol and sodium chloride.
- the present disclosure includes an agent for treating a disease associated with a target antigen (eg, CD70) positive cell comprising the anti-CD70 antibody or antigen-binding fragment thereof of the present disclosure as an active ingredient.
- the active ingredient is administered to a subject in a therapeutically effective amount to treat a disease associated with CD70 positive cells in the subject.
- the therapeutically effective amount is a unit dose of the composition containing 0.1-3000 mg of an antibody that specifically binds to human CD70 as previously described.
- the disease or disorder associated with CD70 in the present disclosure is not limited as long as it is a disease or disorder associated with CD70.
- the molecules of the present disclosure are very useful for some of the following diseases or disorders that express CD70: eg, rheumatoid arthritis, autoimmune demyelinating diseases (eg, multiple sclerosis, allergy encephalomyelitis), endocrine eye disease, uveretinitis, systemic lupus erythematosus, myasthenia gravis, Grave's disease, glomerulonephritis, autoimmune hepatological disease, inflammatory bowel disease (eg, Crohn's disease) disease, ulcerative colitis, celiac disease), anaphylaxis, allergic reactions, Sjogren's syndrome, type I diabetes, primary biliary cirrhosis, Wegener's granulomatosis, fibromyalgia, polymyositis , dermatomyositis
- the molecules of the present disclosure are useful for some of the following CD70-expressing diseases (eg, cancer), including kidney cancer (eg, renal cell carcinoma), breast cancer, brain tumors, chronic or acute leukemia (including acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia), lymphomas (eg, Hodgkin lymphoma and non-Hodgkin lymphoma, lymphocytic lymphoma, primary CNS lymphoma tumor, T-cell lymphoma), nasopharyngeal cancer, melanoma (e.g., metastatic malignant melanoma), prostate cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck , skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anus, stomach cancer, testicular cancer, uterine cancer, fallopian
- pairs of molecules of the present disclosure are characterized by the presence of tumor cells expressing CD70, including, for example, renal cell carcinoma (RCC) such as clear cell RCC, glioblastoma, breast cancer, brain tumor, Nasopharyngeal (nasopharyngal) carcinoma, non-Hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Burkitt lymphoma, anaplastic large cell lymphoma (ALCL), multiple myeloma, cutaneous T-cell lymphoma, nodular cleft cell lymphoma, lymphocytic lymphoma, peripheral T-cell lymphoma, Lennert lymphoma, immunoblastic lymphoma, T-cell leukemia/lymphoma (ATLL) , adult T-cell leukemia (T-ALL), centroblastic/centrocytic (cb/cc) follicular lymphomas cancers
- the present disclosure relates to methods for immunodetection or assay of a target antigen (eg CD70), reagents for immunodetection or assay of a target antigen (eg CD70), for immunodetection or assay of cells expressing a target antigen (eg CD70)
- a method and a diagnostic agent for diagnosing a disease associated with a target antigen (eg, CD70) positive cell comprising the present disclosure that specifically recognizes the target antigen (eg, human CD70) and binds to the amino acid sequence of the extracellular region or its three-dimensional structure the antibody or antibody fragment as the active ingredient.
- the method for detecting or determining the amount of the target antigen can be any known method.
- the target antigen eg, CD70
- the method for detecting or determining the amount of the target antigen can be any known method.
- immunoassays or assays can be any known method.
- An immunodetection or assay method is a method for detecting or measuring the amount of antibody or antigen using labeled antigen or antibody.
- immunodetection or assay methods include radioactive substance-labeled immunoantibody methods (RIA), enzyme immunoassays (EIA or ELISA), fluorescent immunoassays (FIA), luminescence immunoassays, Western blotting, physicochemical methods Wait.
- CD70-positive cells eg, high-expressing CD70 cells
- Diseases associated with CD70-positive cells can be diagnosed by detecting or assaying CD70-expressing cells with the antibodies or antibody fragments of the present disclosure.
- immunodetection methods In order to detect the cells expressing the polypeptide, known immunodetection methods can be used, and preferably, immunoprecipitation methods, fluorescent cell staining methods, immunohistochemical staining methods, and the like are used. In addition, a fluorescent antibody staining method using the FMAT8100HTS system (Applied Biosystem) and the like can be used.
- the biological sample for detecting or measuring the target antigen eg CD70
- the target antigen eg CD70
- cells expressing the target antigen eg CD70
- tissue cells blood, plasma , serum, pancreatic juice, urine, feces, tissue fluid or culture fluid.
- the diagnostic agent containing the monoclonal antibody or antibody fragment thereof of the present disclosure may also contain a reagent for performing an antigen-antibody reaction or a reagent for detecting a reaction.
- Reagents for performing antigen-antibody reactions include buffers, salts, and the like.
- Reagents for detection include those commonly used in immunodetection or assay methods, such as a labeled secondary antibody that recognizes the monoclonal antibody, its antibody fragment or its conjugate, and a substrate corresponding to the label, and the like.
- the amino acid sequence of the antigen and detection protein used in the present disclosure was designed, and different tags such as His tag or Fc were optionally fused on the basis of the CD70 protein. Wait. They were respectively cloned into pTT5 vector (Biovector, CAT#102762), transiently expressed in 293 cells, and purified to obtain the antigen and detection protein of the present disclosure.
- His-tagged CD70 protein extracellular domain (abbreviation: His-TNC-CD70) sequence, as a detection reagent;
- the underlined part is the 6 ⁇ His tag
- the italic part is the TNC tag
- the rest is the extracellular domain of CD70 protein.
- the underlined part is the Human-IgG1-Fc part, and the ununderlined part is the CD70 protein extracellular domain.
- the cell expression supernatant samples were centrifuged at high speed to remove impurities, the buffer was replaced with PBS, and imidazole was added to a final concentration of 5 mM. Equilibrate the nickel column with 5 mM imidazole in PBS and rinse 2-5 column volumes. The replaced cell supernatant sample was applied to a Ni Sepharose excel column (GE, 17-3712-02). The column was rinsed with 5 mM imidazole in PBS until the A280 reading dropped to baseline. Then, the column was washed with PBS+10mM imidazole to remove non-specifically bound impurity proteins, and the effluent was collected.
- Ni Sepharose excel column GE, 17-3712-02
- the target protein was eluted with a PBS solution containing 300 mM imidazole, and the elution peaks were collected.
- the collected eluate was concentrated and further purified by gel chromatography Superdex200 (GE, 28-9893-35), and the mobile phase was PBS. Aggregate peaks were removed and eluted peaks were collected.
- the obtained protein was identified as correct by electrophoresis, peptide map and LC-MS. His-tagged His-TNC-CD70 was obtained and used as a detection reagent for the antibody of the present disclosure.
- the cell expression supernatant samples were centrifuged at high speed to remove impurities, and the supernatant was subjected to MabSelect Sure (GE, 17-5438-01) affinity chromatography.
- the MabSelect Sure column was first regenerated with 0.2M NaOH, rinsed with pure water and equilibrated with PBS. After combining the supernatants, washed with PBS until the A280 reading dropped to the baseline.
- the target protein was eluted with 0.1M acetate buffer at pH 3.5 and neutralized with 1M Tris-HCl.
- the eluted samples were properly concentrated and further purified by gel chromatography Superdex200 (GE, 28-9893-35) equilibrated with PBS, and then concentrated to an appropriate concentration in the receiving tube where the target protein was collected.
- This method was used to purify the CD70-Fc fusion protein, and this method can also be used to purify the antibody proteins of this disclosure.
- Anti-human CD70 antibodies were produced by immunizing mice.
- Balb/c white mice were used in the experiment, female, 6-8 weeks old (Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., animal production license number: SCXK (Beijing) 2012-0001).
- Breeding environment SPF grade. After the mice were purchased, they were reared in a laboratory environment for 1 week, regulated by a 12/12 hour light/dark cycle, the temperature was 20-25°C, and the humidity was 40-60%. The acclimated mice were immunized according to the following protocol.
- the protein antigen was emulsified and then inoculated, and the cell antigen was resuspended in a phosphate buffer solution for inoculation.
- the inoculation time was 0, 14, 28, 42, 56 and 70 days
- blood was collected on the 21st, 49th and 82nd days
- the antibody titer in the mouse serum was determined by ELISA method. Mice with high antibody titers in serum and titers tending to a plateau were selected, and their spleens were used to establish immune pools.
- the primers for constructing the library were designed and synthesized according to the IMGT database (Goldwisdom Corporation). Through three rounds of PCR reactions, single-chain antibody fragments were obtained. All PCR reactions used LA Tag (Takara Cat No. RR02MB).
- the first round of PCR uses cDNA as the template to amplify the heavy chain variable region and light chain variable region sequences respectively; the second round of PCR uses the first round product as the template, and the 5' end of the heavy chain variable region and the light chain variable region are amplified.
- the Sfi1 restriction site sequence was introduced at the 3' end of the variable region, and a linker sequence was introduced at the 3' end of the heavy chain variable region and the 5' end of the light chain variable region;
- the variable region and the variable region of the light chain are used together as a template, and bridging PCR is performed to obtain a single-chain antibody fragment with the variable region of the heavy chain in the front and the variable region of the light chain behind.
- the single-chain antibody fragment and the transformed library building vector pCantab5E were digested with Sfi1 (NEB Cat No.#R0123L), and electrophoresed with Gel Extraction Kit (Omega Cat No. D2500-02) was used for purification and recovery. Then use T4 DNA ligase (NEB Cat No.#M0202L) to ligate at 16°C for 16-18 hours, then use the above kit for purification and recovery, and finally eluate with deionized water. 1 ⁇ g of the ligation product was mixed with one electrotransformation competent TG1 (Lucigen Cat No.
- the phage library (1 ⁇ 10 12 to 1 ⁇ 10 13 /pfu) was suspended in 1 mL of 2% MPBS (PBS containing 2% nonfat dry milk), and 100 ⁇ L was added M-280 Streptavidin (Invitrogen Cat No. 11206D), placed on a turntable with repeated inversion, and sealed at room temperature for 1 hour. Place the tube on the magnetic rack for 2 minutes, remove the Dynabeads, and transfer the phage library to a new tube. 2 ⁇ g/mL of biotin-labeled His-TNC-CD70 was added to the blocked phage library and placed on a turntable for 1 hour.
- M-280 Streptavidin Invitrogen Cat No. 11206D
- Dynabeads were suspended in 1 mL of 2% MPBS, placed on a turntable and repeatedly turned, and blocked at room temperature for 1 hour. Place the tube on a magnetic stand for 2 minutes and aspirate the blocking solution. The blocked Dynabeads were added to the phage library and the His-TNC-CD70 mixture, and placed on a turntable for 15 minutes. Place the tube on a magnetic stand for 2 minutes and aspirate the mixture. Dynabeads were eluted with 1 mL of PBST (PBS containing 0.1% Tween-20), then 0.5 mL of 1 mg/mL trypsin (Sigma Cat No.
- PBST PBS containing 0.1% Tween-20
- T1426-250MG T1426-250MG was added, and the cells were placed on a turntable and incubated for 15 minutes.
- the eluted phages were directly infected with log-phase E. coli TG1, and the titer was determined, amplified and concentrated for the next round of panning.
- the concentration of biotin-labeled human His-TNC-CD70 was reduced to 1 ⁇ g/mL, and the number of PBST washings was increased to 15 times.
- the eluted phages were infected with Escherichia coli TG1 and plated, and single clones were randomly picked for phage ELISA.
- the clones were seeded in 96-well deep-well plates (Nunc Cat No. 260251) and cultured at 37°C for 16-18 hours. A small amount was inoculated into another 96-well deep-well plate until the OD600 reached about 0.5, and M13K07 helper phage (NEB Cat No.N0315S) was added for packaging. The cells were removed by centrifugation at 4000g for 10 minutes, and the culture medium was aspirated for human CD70 binding ELISA detection. The positive clones were frozen and preserved in time and sent to a sequencing company for sequencing. The amino acid sequences corresponding to the DNA sequences of positive clones B1, B7, and F4 were measured as follows:
- the sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, the underline is the CDR sequence determined according to the Kabat numbering system, and the italics is the FR sequence.
- the heavy chain and light chain CDR region sequences of murine antibodies B1, B7, and F4 are shown in Table 5 below:
- CDRs in the table are CDRs determined according to the Kabat numbering system
- the human His-TNC-CD70 protein was diluted to a concentration of 2 ⁇ g/mL with PBS buffer pH 7.4, added to a 96-well microtiter plate (Corning, Cat No. CLS3590-100EA) at a volume of 100 ⁇ L/well, and incubated at 4°C. Place in refrigerator for 16-18 hours. After discarding the liquid, 200 ⁇ L/well of blocking solution of 5% nonfat milk powder (Sangon Biotech, Product No. A600669-0250) diluted with PBS was added, and incubated in a 37°C incubator for 2 hours for blocking.
- PBST buffer pH 7.4 PBS containing 0.1% tween-20
- MPBS pH 7.4 PBS containing 2% skim milk powder
- the heavy and light chain variable region germline genes with high homology to B1, B7 and F4 were selected as templates respectively.
- the CDRs of the source antibody were respectively grafted into the corresponding human template to form variable region sequences in the order of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
- the CDR amino acid residues in the following specific examples are identified and annotated by the Kabat numbering system.
- the humanized light chain templates of murine antibody B1 are IGKV4-1*01 and IGKJ4*01, and the humanized heavy chain templates are IGHV1-46*01 and IGHJ1*01, and the CDRs of murine antibody B1 were transplanted into them respectively.
- the amino acid of the FR part of the humanized antibody is further modified by back mutation, wherein the FR part of the light chain includes one or more back mutations in 5S or 70N (wherein the position of the back mutation site is numbered according to Kabat.
- the FR part of the heavy chain includes one or more back mutations in 4M, 37I, 38K, 48I, 67A, 69L, 71A, 73R, 78A, 80L, 94T (wherein the position of the back mutation site is according to Kabat Numbering rules are determined), the back mutation design of the humanized antibody of antibody B1 is shown in Table 7 below:
- Graft represents the CDR of murine antibody implanted into the human germline FR region; the position of the back mutation site is determined according to the Kabat numbering system, such as "T5S", which means that the 5th T is mutated to S according to the Kabat numbering system.
- B1 humanized antibody light chain variable region/heavy chain variable region sequences are as follows:
- the individual amino acids of the CDR portion of the light chain variable region and the heavy chain variable region were modified, wherein the amino acid sequence of HCDR2 was modified from DIYPGNGDASYNQKFRD (as shown in SEQ ID NO: 10) to DIYPGTGDASYNQKFRD (as shown in SEQ ID NO: 10) 42), the amino acid sequence of LCDR2 was transformed by LASNLES (as shown in SEQ ID NO: 13) into: LADNLES (as shown in SEQ ID NO: 43), after the transformation, the B1 humanized antibody light chain variable region/heavy
- the chain variable region sequence is as follows:
- the sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 in sequence
- the italic in the sequence is the FR sequence
- the underline is the CDR sequence determined according to the Kabat numbering system.
- the humanized light chain templates of mouse antibody B7 are IGKV27-1*01 and IGKJ4*01, and the humanized heavy chain templates are IGHV7-4-1*02 and IGHJ6*01.
- the CDRs of mouse antibody B7 were transplanted respectively into its human template, and then back-mutate the amino acids of the FR portion of the humanized antibody, wherein the light chain FR portion includes one or more back-mutations in 38R, 43S, 69R, 70Q or 71Y (wherein the back The position of the mutation site is determined according to the Kabat numbering rule), and the FR part of the heavy chain includes one or more back mutations in 2I, 24T, 46K, 72E, 82aN (the position of the back mutation site is determined according to the Kabat numbering rule) ).
- the back-mutation design of the humanized antibody variable region of antibody B7 is shown in Table 8 below:
- Grafted represents the CDR of murine antibody implanted into the human germline FR region; the position of the mutation site is determined according to the Kabat numbering system, such as "S82a N” means according to the Kabat numbering system, the 82a (also called 82A) position S is mutated is N.
- B7 humanized antibody light/heavy chain variable region sequences are as follows:
- the individual amino acids of the CDR portion of the heavy chain variable region were also modified, wherein the amino acid sequence of HCDR2 was modified from the original WINTYTGEPTYADDFKG (as shown in SEQ ID NO: 16) to: WINTYTGEPTYADEFKG (as shown in SEQ ID NO: 54) ), the sequence of the heavy chain variable region of the B7 humanized antibody after the transformation is as follows:
- the sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 in sequence
- the italic in the sequence is the FR sequence
- the underline is the CDR sequence determined according to the Kabat numbering system.
- the humanized light chain templates of murine antibody F4 are IGKV4-1*01 and IGKJ2*01, and the humanized heavy chain templates are IGHV1-69*08 and IGHJ1*01, and the CDRs of murine antibody F4 were transplanted into them respectively.
- the amino acid of the FR part of the humanized antibody is further modified by back mutation, wherein the FR part of the light chain includes a back mutation of 49S (where the position of the back mutation site is determined according to the Kabat numbering rule), and the FR part of the heavy chain includes a back mutation of 49S.
- Grafted means that the CDR of murine antibody is implanted into the human germline FR region; the position of the back mutation site is determined according to the Kabat numbering rule.
- S82a N means mutating S to N at position 82a (also called 82A) according to the Kabat numbering system
- the individual amino acids of the CDR parts of the light chain variable region and the heavy chain variable region were also modified, wherein the amino acid sequence of HCDR2 was modified from the original AIFPGNGETSYNQNFKG (SEQ ID NO: 22) to: AIFPGTGETSYNQNFKG (such as SEQ ID NO: 71), the amino acid sequence of LCDR2 was transformed from the original LASNLES (SEQ ID NO: 13) to: LADNLES (as shown in SEQ ID NO: 43)
- the sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 in sequence
- the italic in the sequence is the FR sequence
- the underline is the CDR sequence determined according to the Kabat numbering system.
- the heavy chain constant region of the antibody can be selected from the heavy chain constant regions of human IgGl, IgG2, IgG3, IgG4, or variants thereof, and the light chain constant regions can be selected from the light chain constant regions of human kappa, lambda chains or variants thereof.
- the antibody heavy chain constant region is selected from the human IgG1 heavy chain constant region shown in SEQ ID NO: 72, and the light chain constant region is selected from the human light chain constant region shown in SEQ ID NO: 73 .
- the carboxy terminus of the variable region of the heavy chain of the previously screened murine antibodies B1, B7, and F4 was connected to the amino terminus of the constant region of the human heavy chain as shown in SEQ ID NO: 72, and the carboxy terminus of the variable region of the variable region of the light chain of the murine antibody was linked.
- the chimeric antibody of B1, B7, and F4 is represented as CHB1, CHB7, and CHF4, respectively.
- huB1001 indicates that the heavy chain variable region is huB1VH1 (SEQ ID NO: 26), the light chain variable region is huB1VL1-1 (SEQ ID NO: 40), and the heavy chain constant region is SEQ ID NO: : 72, the light chain constant region is the humanized antibody shown in SEQ ID NO: 73, and so on.
- huB7001 indicates that the heavy chain variable region is huB7VH1 (SEQ ID NO: 44), the light chain variable region is huB7VL1 (SEQ ID NO: 47), and the heavy chain constant region is SEQ ID NO: 72 As shown, the light chain constant region is the humanized antibody shown in SEQ ID NO: 73, and so on.
- huF4001 indicates that the heavy chain variable region is huF4VH1 (SEQ ID NO: 55), the light chain variable region is huF4VL1-1 (SEQ ID NO: 69), and the heavy chain constant region is such as SEQ ID NO: 69 : 72, the light chain constant region is the humanized antibody shown in SEQ ID NO: 73, and so on.
- Exemplary humanized antibody light/heavy chain full-length sequences are as follows:
- the underlined part is the antibody variable region sequence
- the ununderlined part is the antibody constant region sequence
- monkey CD70-Fc Sequence of monkey CD70 protein extracellular domain and Human-IgG1-Fc fusion protein (abbreviation: monkey CD70-Fc):
- the underlined part is the Human-IgG1-Fc part, and the ununderlined part is the extracellular domain of the monkey CD70 protein
- mouse CD70-Fc Sequence of mouse CD70 protein extracellular domain and Human-IgG1-Fc fusion protein
- the underlined part is the Human-IgG1-Fc part
- the ununderlined part is the mouse CD70 protein extracellular domain human CD27 and Human-IgG1-Fc fusion protein (abbreviation: CD27-Fc) sequence:
- the underlined part is the Human-IgG1-Fc part
- the ununderlined part is the human CD27 part
- the italicized part is the linker sequence
- a double-gene vector encoding the heavy chain and light chain amino acid sequences of CD70 antibody was constructed, and the double-gene vector was stably transfected by electroporation using an electroporator (BioRad) to knock out CHOK1 (ECACC, Cat#85051005) -1VL, Lot#12G006), the electroporated cells were ice-bathed for 5 min, and then transferred to pre-warmed cells containing 1% SP4 (CAT#BESP1076E, Lonza) + 0.5% Anti-Clumping agent (CAT#01-0057DG, Gibco) Gently mix in CD CHO medium (CAT# 10743-029, Gibco), and culture in a cell shaker (36.5°C, 6.0% CO 2 , 120 rpm, 80% relative humidity).
- the cells were counted and plated in a minipool (micro cell pool), 2000 cells per well were seeded into 96-well cell culture plates, and 100 ⁇ L of 0.5% ACF supplement (CAT#3820, STEMCELL) was added to each well. Technologies) + 0.5% Anti-Clumping agent CD CHO medium to start the screening of minipool; observe the cell formation after the 14th day of plating, and after the cell coverage is greater than 30%, the protein expression in the supernatant is determined by the Octet-based method.
- the cell population with better expression was transferred from 96-well cell plate to 24-well cell plate, and cultured in 1mL CD CHO medium containing 25 ⁇ M MSX (CAT#M5379-500MG, SIGMA) + 0.5% Anti-Clumping agent, pressurized After 14 days of screening, the Octet-based method was used to determine the protein expression in the supernatant of the minipool cell population, and the cell population with better expression was transferred into a 125 mL cell culture flask, and placed in a cell culture shaker for culture (shaker culture conditions are: 36.5°C, 6.0% CO 2 , 80% relative humidity, 120 rpm); after culturing for 2-3 days, the cells were sampled and counted, and the cells were passaged by the dilution method until the cells were in the exponential growth phase, and then the cell lines were subjected to Fed-Batch culture.
- shaker culture conditions are: 36.5°C, 6.0% CO 2 , 80% relative humidity, 120 rpm
- afucosylated humanized antibodies are represented by the suffix "(afuc)", for example: huB7002(afuc), huB1010(afuc), huF4011(afuc) and 41D12(afuc) represent huB7002(afuc), Afucosylated antibodies to huB1010, huF4011 and 41D12.
- Test Example 1 Biacore detection of anti-CD70 antibody affinity experiment
- Human Fc capture molecules were covalently coupled to a CM5 biosensor chip (CAT#BR-1005-30, GE) according to the method described in the instructions of the human Fc capture kit (CAT#BR-1008-39, GE). , so as to affinity capture the antibody to be tested. Then, the human His-TNC-CD70 antigen (as shown in SEQ ID NO: 1) was flowed on the surface of the chip, and the reaction signal was detected in real time by the Biacore T200 instrument, thereby obtaining the binding and dissociation curves. After each cycle of dissociation in the experiment, the biochip was washed and regenerated with the regeneration solution prepared in the human Fc capture kit (GE). The data fitting model adopts 1:1 Model. The experimental results are shown in Table 13:
- the experimental results show that the anti-CD70 antibody of the present disclosure has high affinity to human CD70 antigen.
- the experimental results show that the anti-CD70 antibodies of the present disclosure can effectively bind to CD70-positive cells, and huB7002 and its afucosylated antibodies huB7002 (afuc) and huB1010 and their afucosylated antibodies huB1010 (afuc)
- the binding capacity was stronger than that of the positive control.
- Test Example 3 ELISA experiment of anti-CD70 antibody binding to human, monkey and mouse CD70 protein
- the binding capacity of the anti-CD70 antibody was detected by the amount of binding of the antibody to the CD70 antigen protein immobilized on the ELISA plate.
- Human CD70-Fc (as shown in SEQ ID NO: 2), monkey CD70-Fc (as shown in SEQ ID NO: 82) and mouse CD70-Fc (as shown in SEQ ID NO: 83) were coated at 1 ⁇ g/mL ), blocked after incubation.
- the experimental results show that the anti-CD70 antibodies of the present disclosure can all bind to human CD70 antigen and monkey CD70 antigen, but not to mouse CD70 antigen.
- Test Example 4 Experiment in which anti-CD70 antibody blocks CD27 binding to CD70 positive cells
- the cell blocking activity of anti-CD70 antibody was detected by flow cytometry. After blocking 1 ⁇ 10 6 cells/mL CHO-S cells (Invitrogen, R80007) expressing human full-length CD70 with 1% BSA PBS buffer, anti-CD70 antibody samples diluted at different concentrations and biotin-labeled CD27-Fc were added (as shown in SEQ ID NO: 84) and incubated for 1 h. After two washes, Alexa Fluor 488-streptavidin (Invitrogen, CAT#S11223) was added and incubated for 1 h. After two washes, the fluorescence signal values were read using a flow cytometer. The experimental results are shown in Figures 6 and 7.
- the experimental results show that the anti-CD70 antibody of the present disclosure has the ability to block the binding of CD27 to CD70-positive cells.
- CD27 cells will secrete IL-8.
- the effect of anti-CD70 antibody on the level of CD70-induced CD27 signaling was detected by detecting the secretion of IL-8 by CD27-expressing cells.
- HT1080/CD27 cells HT1080 cells expressing human full-length CD27 (ATCC, CCL-121) were collected, resuspended in RPMI1640 containing 10% FBS, and the cells were diluted to 2 ⁇ 10 6 cells/mL.
- U266 cells and different concentrations of antibodies were added in a ratio of 1:1 to 96-well plates (Corning, CAT#3599) by adding 50 ⁇ L each, and incubated for 60 minutes (37°C). , 5% CO 2 ), 50 ⁇ L of HT1080/CD27 cells were added.
- CD70 antibody inhibits CD70/CD27 binding-mediated IL-8 secretion assay
- Imax is the maximum inhibition rate of anti-CD70 antibody inhibiting the secretion of IL-8 by CD27 cells
- the experimental results show that the anti-CD70 antibody of the present disclosure has better inhibitory ability on IL-8 secretion of HT1080/CD27 cells than the control antibodies 41D12 and 41D12(afuc). It is indicated that the anti-CD70 antibody of the present disclosure can effectively inhibit CD70-induced CD27 signaling by blocking CD70/CD27 binding.
- Test Example 6 Experiment of anti-CD70 antibody on ADCC of 786-O cells in vitro
- 786-O-Luc cells (luciferase-expressing 786-O cells (ATCC, CCL-86)) were collected and incubated with Assay Buffer in MEM ⁇ (Gibco, CAT#12561-056) basal medium (containing 2 mM L-Glutamine) 12.5% fetal bovine serum (Gibco, CAT#10099-141), 12.5% horse serum (Biyuntian, CAT#C0262), 0.2mM inositol (SIGMA, CAT#I7508), 0.02mM folic acid (SIGMA, CAT#) F8758), 0.1mM 2-mercaptoethanol (MERCK, CAT#M6250-10ML) and 200U/mL recombinant human IL-2 (Peprotech, CAT#200-02-100) were resuspended, and the cells were diluted to 2 ⁇ 10 5 cells/ mL.
- MEM ⁇ Gibco, CAT#12561-056
- NK92 cells (Nanjing Kebai, CBP60980) were collected, resuspended in Assay buffer, and the cells were diluted to 1 ⁇ 10 6 cells/mL.
- 786-O-Luc cells were collected, resuspended in RPMI 1640 medium (Gibco, CAT#11875119) containing 10% ultra-low IgG fetal bovine serum (Gibco, CAT#1921005PJ), and the cells were diluted to 1 ⁇ 10 5 cells/mL .
- PBMC Peripheral blood mononuclear cells
- the experimental results show that the anti-CD70 antibody of the present disclosure has a strong effect on ADCC of 786-O cells in vitro, and the afucosylated humanized antibody significantly improves the effect of ADCC.
- Test Example 7 Experiment of anti-CD70 antibody on Raji cell in vitro CDC
- Raji cells (ATCC, CCL-86) were collected and resuspended, and the cells were resuspended at 1 ⁇ 10 6 cells/mL in phenol red-free RPMI 1640 containing 10% ultra-low IgG fetal bovine serum (Gibco, CAT#1921005PJ). base (Gibco, CAT# 11835-030). Subsequently, the cells at 5 ⁇ 10 4 cells / hole (50 ⁇ L / well) were plated in 96-well plates (Corning, CAT # 3903). Then, 50 ⁇ L of different concentrations of antibodies were added.
- Test Example 8 Experiment of anti-CD70 antibody on ADCP in vitro of 786-O and Raji cells
- PBMCs peripheral blood mononuclear cells
- PBMCs peripheral blood mononuclear cells
- CD14 + monocytes were sorted using CD14 magnetic beads (Miltenyi Biotec, CAT#130-050-201).
- Monocytes were differentiated by culturing for 7 days in RPMI 1640 medium (Gibco, CAT#11875119) containing 10% FBS (Gibco, CAT#10091148) and 50 ng/mL M-CSF (Peprotech, CAT#300-25) for 7 days become macrophages. Macrophages were collected by scraping the macrophages with a cell scraper on the day of the experiment.
- CFSE carboxyfluorescein diacetate succinimidyl ester
- the experimental results show that the anti-CD70 antibody of the present disclosure has a good in vitro ADCP effect on 786-O cells and Raji cells.
- Test Example 9 In vitro inhibition experiment of anti-CD70 antibody on Treg cells
- PBMC Peripheral blood mononuclear cells
- U266 cells and PBMCs were added at a ratio of 1:1 to 96-well plates (U bottom plate, corning, CAT#3788) in 50 ⁇ L each, followed by 25 ⁇ L of different concentrations of antibodies and 25 ⁇ L of anti-CD3 (final concentration of 3ug/mL) ( ebioscience, CAT#16-0037-85) and anti-CD28 (ebioscience, CAT#16-0289-85) antibody were incubated for 48 h (37°C, 5% CO 2 ), and the cells were collected in 1.5 mL ep tubes (Axygen, CAT).
- the experimental results show that the anti-CD70 antibody of the present disclosure has a good ability to inhibit Treg cells in vitro.
- 786-O-Luc cells (786-O cells expressing luciferase (ATCC, CRL-1932)) were harvested and treated with RPMI 1640 medium (Gibco) containing 10% ultra-low IgG fetal bovine serum (Gibco, CAT#1921005PJ). , CAT#11875119), resuspend and dilute the cells to 2 ⁇ 10 4 cells/mL. Subsequently, cells were plated in 96-well plates (Corning, CAT #3903) at 1000 cells/well (50 ⁇ L/well). It was incubated for 16 hours (37 °C, 5% CO 2 ).
- the RPMI 1640 medium containing 10% ultra-low IgG fetal bovine serum was used to prepare 4 times the concentration of DT3C (Fragment A of diphtheria toxin and the 3C fragment of group G Streptococcus were fused, and its molar concentration was 6 times the molar concentration of the antibody. ).
- Use the same medium to prepare 4 times the concentration of antibody mix DT3C and antibody at a volume of 1:1, and incubate at room temperature for 30 min. Concentration gradient dilutions were then performed. The diluted antibody was added to the cells at a ratio of 1:1, 50 ⁇ L/well. Incubated for 3 days (37 °C, 5% CO 2 ).
- the experimental results show that the anti-CD70 antibody of the present disclosure can be internalized by 786-O cells, and the maximum cleavage rate of cell internalization lysis exceeds 96%.
- Test Example 11 In vivo efficacy experiment of anti-CD70 antibody in mouse Raji model
- mice purchased from Viton Lever
- bioluminescent substrate 15 mg/mL
- mice were intraperitoneally injected with bioluminescent substrate (15 mg/mL), injected at a volume of 10 mL/kg, anesthetized with isoflurane, and photographed and imaged by a small animal imaging system 10 minutes after injection, and the body weight and bioluminescent signal (Total Flux ) value is too large or too small
- the mice are randomly divided into 4 groups according to the bioluminescence signal, including the negative control IgG (IgG protein irrelevant to the CD70 target, the dose of 30 mg/kg) group, the positive control 41D12 (the dose of 10mg/kg), huB7002 (administration dose 10mg/kg), huF4011-10 (administration dose 10mg/kg), 8 animals
- Photographs were imaged twice a week, body weights were weighed, and data were recorded.
- Excel statistical software was used to record the data, the bioluminescence signal value was Total Flux (unit, p/s), and the mean value was calculated by avg; SD value was calculated by STDEV; SEM value was calculated by STDEV/SQRT (number of animals in each group);
- GraphPad was used Prism software was used for graphing, and Two-way ANOVA was used for statistical analysis of the data.
- T/C(%) (T-T0)/(C-C0) ⁇ 100, where T and C are the tumor photons in the treatment group and control group at the end of the experiment; T0 and C0 are at the beginning of the experiment of tumor photons.
- TGI (%) 100-T/C (%).
- the anti-CD70 antibody at a dose of 10 mg/kg could significantly inhibit the growth of tumor cells in the Luc-Raji tumor model (p ⁇ 0.001), and the tumor inhibition rate of huB7002 was as high as 81%.
- the tumor inhibition rate of 41D12 was only 63%.
- mice purchased from Viton Lever
- Luc-Raji cells luciferase-expressing Raji cells (ATCC, CCL-86)
- CB17 SCID mice purchased from Viton Lever
- Each mouse was intraperitoneally injected with bioluminescent substrate (15 mg/mL), injected at a volume of 10 mL/kg, anesthetized with isoflurane, and photographed and imaged by a small animal imaging system 10 minutes after injection, and the body weight and bioluminescent signal (Total Flux ) value is too large or too small, the mice are randomly divided into groups according to the bioluminescence signal, 8 mice in each group, and the antibody is administered by intraperitoneal injection on the day of grouping (negative control is IgG-type protein irrelevant to the target), administered twice, Dosing on days 1 and 3. Images were taken on days 7 and 14, body weights were weighed, and data were recorded. The experimental results are shown in Figure 18.
- the experimental results showed that compared with the negative control IgG group, the afucosylated antibody group could significantly inhibit the growth of tumor (p ⁇ 0.001).
- the tumor inhibition rates of huB1010(afuc) at doses of 1.5, 5, and 15 mg/kg were 82%, 85%, and 84%, respectively.
- the tumor inhibition rates were 87%, 85%, and 82%, respectively.
- each administration group still had high tumor inhibitory activity.
- huB1010 (afuc) 5mg/kg dose The tumor inhibition rate of the group was still 68% on the 14th day. There was no dose effect in each dose group, indicating that even the 1.5 mg/kg dose was sufficient to sufficiently inhibit tumor growth.
- Test Example 12 Anti-CD70 Antibody Pharmacokinetic Experiment in Vivo
- mice Male SD rats (purchased from Viton Lever) 3 rats/group were administered intravenously at a dose of 3mpk.
- the administration group was administered 5min (min means minutes) before and after administration, and 8h (h means minutes) hours), 1d (d means day), 2d, 4d, 7d, 10d, 14d, 21d, 28d, collect 0.15 mL of whole blood without anticoagulation, place the blood at 4°C for 30 min, centrifuge at 1000g for 15 min, and take the supernatant. (serum) in EP tubes and stored at -80°C.
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Abstract
Description
原始残基 | 保守取代 |
Ala(A) | Gly;Ser |
Arg(R) | Lys;His |
Asn(N) | Gln;His;Asp |
Asp(D) | Glu;Asn |
Cys(C) | Ser;Ala;Val |
Gln(Q) | Asn;Glu |
Glu(E) | Asp;Gln |
Gly(G) | Ala |
His(H) | Asn;Gln |
Ile(I) | Leu;Val |
Leu(L) | Ile;Val |
Lys(K) | Arg;His |
Met(M) | Leu;Ile;Tyr |
Phe(F) | Tyr;Met;Leu |
Pro(P) | Ala |
Ser(S) | Thr |
Thr(T) | Ser |
Trp(W) | Tyr;Phe |
Tyr(Y) | Trp;Phe |
Val(V) | Ile;Leu |
抗体 | 酶标仪OD450nm处读值 |
B1 | 1.16 |
F4 | 1.09 |
B7 | 1.97 |
可变区 | huB1VL1-1 | huB1VL2-1 | huB1VL1 | huB1VL2 |
huB1VH1 | huB1001 | huB1015 | huB1025 | huB1037 |
huB1VH2 | huB1002 | huB1016 | huB1026 | huB1038 |
huB1VH3 | huB1003 | huB1017 | huB1027 | huB1039 |
huB1VH4 | huB1004 | huB1018 | huB1028 | huB1040 |
huB1VH5 | huB1005 | huB1019 | huB1029 | huB1041 |
huB1VH6 | huB1006 | huB1007 | huB1030 | huB1042 |
huB1VH1-1 | huB1009 | huB1008 | huB1031 | huB1043 |
huB1VH2-1 | huB1010 | huB1020 | huB1032 | huB1044 |
huB1VH3-1 | huB1011 | huB1021 | huB1033 | huB1045 |
huB1VH4-1 | huB1012 | huB1022 | huB1034 | huB1046 |
huB1VH5-1 | huB1013 | huB1023 | huB1035 | huB1047 |
huB1VH6-1 | huB1014 | huB1024 | huB1036 | huB1048 |
可变区 | huB7VL1 | huB7VL2 | huB7VL3 | huB7VL4 |
huB7VH1 | huB7001 | huB7007 | huB7013 | huB7019 |
huB7VH1-1 | huB7002 | huB7008 | huB7014 | huB7020 |
huB7VH2 | huB7003 | huB7009 | huB7015 | huB7021 |
huB7VH2-1 | huB7004 | huB7010 | huB7016 | huB7022 |
huB7VH3 | huB7005 | huB7011 | huB7017 | huB7023 |
huB7VH3-1 | huB7006 | huB7012 | huB7018 | huB7024 |
可变区 | huF4VL1-1 | huF4VL2-1 | huF4VL1 | huF4VL2 |
huF4VH1 | huF4001 | huF4014 | huF4025 | huF4037 |
huF4VH2 | huF4002 | huF4015 | huF4026 | huF4038 |
huF4VH3 | huF4003 | huF4016 | huF4027 | huF4039 |
huF4VH4 | huF4004 | huF4017 | huF4028 | huF4040 |
huF4VH5 | huF4005 | huF4018 | huF4029 | huF4041 |
huF4VH6 | huF4006 | huF4019 | huF4030 | huF4042 |
huF4VH1-1 | huF4007 | huF4020 | huF4031 | huF4043 |
huF4VH2-1 | huF4008 | huF4021 | huF4032 | huF4044 |
huF4VH3-1 | huF4009 | huF4011 | huF4033 | huF4045 |
huF4VH4-1 | huF4010 | huF4022 | huF4034 | huF4046 |
huF4VH5-1 | huF4012 | huF4023 | huF4035 | huF4047 |
huF4VH6-1 | huF4013 | huF4024 | huF4036 | huF4048 |
抗体 | ka(1/Ms) | kd(1/s) | KD(M) |
CHB1 | 2.26E+06 | 7.54E-05 | 3.34E-11 |
CHF4 | 2.23E+06 | 8.37E-05 | 3.75E-11 |
CHB7 | 5.66E+06 | 1.70E-04 | 3.00E-11 |
huF4025 | 2.15E+06 | 8.68E-05 | 4.03E-11 |
huF4026 | 2.44E+06 | 9.56E-05 | 3.92E-11 |
huF4027 | 2.73E+06 | 9.13E-05 | 3.35E-11 |
huF4028 | 2.56E+06 | 1.06E-04 | 4.12E-11 |
huF4009 | 2.51E+06 | 1.14E-04 | 4.55E-11 |
huF4011 | 3.12E+06 | 1.45E-04 | 4.65E-11 |
huB1025 | 3.33E+06 | 1.54E-04 | 4.62E-11 |
huB1026 | 1.91E+06 | 9.62E-05 | 5.03E-11 |
huB1037 | 3.93E+06 | 1.60E-04 | 4.07E-11 |
huB1038 | 1.80E+06 | 1.01E-04 | 5.61E-11 |
huB1010 | 3.67E+06 | 1.30E-04 | 3.55E-11 |
huB7002 | 6.09E+06 | 1.74E-04 | 2.86E-11 |
huB7004 | 5.58E+06 | 1.57E-04 | 2.82E-11 |
huB7006 | 6.41E+06 | 1.58E-04 | 2.46E-11 |
huB7008 | 4.87E+06 | 1.69E-04 | 3.47E-11 |
huB7010 | 4.36E+06 | 1.72E-04 | 3.96E-11 |
huB7012 | 5.99E+06 | 1.54E-04 | 2.57E-11 |
huB7014 | 4.92E+06 | 1.82E-04 | 3.71E-11 |
huB7016 | 4.43E+06 | 1.85E-04 | 4.18E-11 |
huB7018 | 4.12E+06 | 1.91E-04 | 4.64E-11 |
huB7020 | 5.76E+06 | 1.59E-04 | 2.76E-11 |
huB7022 | 4.41E+06 | 1.95E-04 | 4.42E-11 |
huB7024 | 4.41E+06 | 2.05E-04 | 4.64E-11 |
抗体 | IC50(ng/mL) | Imax(%) |
huB7002(afuc) | 19.8 | 91.7 |
huF4011(afuc) | 13.0 | 92.3 |
huB7002 | 21.0 | 98.7 |
huF4011 | 14.2 | 93.8 |
41D12 | 23.3 | 70.9 |
41D12(afuc) | 24.2 | 71.1 |
huB7002(afuc) | huB7002 | huB1010(afuc) | huB1010 | huF4011(afuc) | |
EC50(ng/mL) | 0.11 | 8.32 | 0.07 | 7.21 | 0.08 |
最大裂解(%) | 89.79 | 78.10 | 92.03 | 82.03 | 90.29 |
抗体 | huB7002(afuc) | huB7002 | 41D12(afuc) |
EC50(nM) | 8.65 | 13.26 | 55.46 |
最大裂解% | 96.45 | 97.18 | 63.59 |
分组 | 总发光(p/s) | 抑瘤率 | p |
D0 | SEM | D14 | SEM | TGI(%) | (vs blank) | |
IgG-30mg/kg | 1.33E+07 | 2.00E+06 | 4.73E+09 | 6.64E+08 | - | - |
41D12-10mg/kg | 1.33E+07 | 2.05E+06 | 1.75E+09 | 3.81E+08 | 63% | p<0.001 |
huB7002-10mg/kg | 1.34E+07 | 2.07E+06 | 8.92E+08 | 2.32E+08 | 81% | p<0.001 |
huF4011-10mg/kg | 1.33E+07 | 2.25E+06 | 1.11E+09 | 4.28E+08 | 77% | p<0.001 |
huB7002 | huB1010 | 41D12 | |
t1/2(d) | 17.2 | 16.2 | 13.3 |
Cmax(ug/mL) | 58.4 | 60.6 | 57.6 |
AUC 0-t(ug/mL*h) | 7568 | 9444 | 7005 |
AUC 0-∞(ug/mL*h) | 10788 | 13401 | 8851 |
CL(mL/day/kg) | 6.7 | 5.4 | 8.2 |
MRT 0-∞(h) | 549.1 | 542.3 | 413.3 |
Claims (16)
- 一种抗CD70抗体,其包含重链可变区和轻链可变区,其中:i)所述重链可变区包含分别如SEQ ID NO:15和SEQ ID NO:17所示的HCDR1和HCDR3,以及如SEQ ID NO:54或SEQ ID NO:16所示的HCDR2;所述轻链可变区包含分别如SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20所示的LCDR1、LCDR2和LCDR3;ii)所述重链可变区包含分别如SEQ ID NO:9和SEQ ID NO:11所示的HCDR1和HCDR3,以及如SEQ ID NO:10或SEQ ID NO:42所示的HCDR2;所述轻链可变区包含分别如SEQ ID NO:12和SEQ ID NO:14所示的LCDR1和LCDR3,以及如SEQ ID NO:13或SEQ ID NO:43所示的LCDR2;或iii)所述重链可变区包含分别如SEQ ID NO:21和SEQ ID NO:23所示的HCDR1和HCDR3,以及如SEQ ID NO:22或SEQ ID NO:71所示的HCDR2;所述轻链可变区包含分别如SEQ ID NO:24和SEQ ID NO:25所示的LCDR1和LCDR3,以及如SEQ ID NO:13或SEQ ID NO:43所示的LCDR2;优选地,i)所述重链可变区包含分别如SEQ ID NO:15、SEQ ID NO:54和SEQ ID NO:17所示的HCDR1、HCDR2和HCDR3,所述轻链可变区包含分别如SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20所示的LCDR1、LCDR2和LCDR3;ii)所述重链可变区包含分别如SEQ ID NO:9、SEQ ID NO:42和SEQ ID NO:11所示的HCDR1、HCDR2和HCDR3,所述轻链可变区包含分别如SEQ ID NO:12、SEQ ID NO:43和SEQ ID NO:14所示的LCDR1、LCDR2和LCDR3;或iii)所述重链可变区包含分别如SEQ ID NO:21、SEQ ID NO:71和SEQ ID NO:23所示的HCDR1、HCDR2和HCDR3,所述轻链可变区包含分别如SEQ ID NO:24、SEQ ID NO:43和SEQ ID NO:25所示的LCDR1、LCDR2和LCDR3。
- 根据权利要求1所述的抗CD70抗体,其中所述抗CD70抗体是鼠源抗体、嵌合抗体或人源化抗体。
- 根据权利要求1或2所述的抗CD70抗体,其中所述抗CD70抗体为人源化抗体,所述人源化抗体包含人抗体的框架区或人抗体的框架区变体,所述框架区变体相对于人抗体的轻链框架区和/或重链框架区分别具有至多11个氨基酸的回复突变;优选地,所述人源化抗体包含:a)重链可变区,其包含分别如SEQ ID NO:15和SEQ ID NO:17所示的HCDR1和HCDR3,以及如SEQ ID NO:54或SEQ ID NO:16所示的HCDR2;和轻链可变区,其包含分别如SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20所示的 LCDR1、LCDR2和LCDR3;且所述轻链可变区包含人抗体的轻链框架区变体,其相对于人抗体的轻链框架区包含选自38R、43S、69R、70Q和71Y中的一个或更多个氨基酸回复突变,和/或所述重链可变区包含人抗体的重链框架区变体,其相对于人抗体的重链框架区包含选自2I、24T、46K、72E和82a N中的一个或更多个氨基酸回复突变;或b)重链可变区,其包含分别如SEQ ID NO:9和SEQ ID NO:11所示的HCDR1和HCDR3,以及如SEQ ID NO:10或SEQ ID NO:42所示的HCDR2;和轻链可变区,其包含分别如SEQ ID NO:12和SEQ ID NO:14所示的LCDR1和LCDR3,以及如SEQ ID NO:13或SEQ ID NO:43所示的LCDR2;且所述重链可变区包含人抗体的重链框架区变体,其相对于人抗体的重链框架区包含选自4M、37I、38K、48I、67A、69L、71A、73R、78A、80L和94T中的一个或更多个氨基酸回复突变;和/或所述轻链可变区包含人抗体的轻链框架区变体,其相对于人抗体的轻链框架区包含选自5S和70N中的一个或更多个氨基酸回复突变;或c)重链可变区,其包含分别如SEQ ID NO:21和SEQ ID NO:23所示的HCDR1和HCDR3,以及如SEQ ID NO:22或SEQ ID NO:71所示的HCDR2;和轻链可变区,其包含分别如SEQ ID NO:24和SEQ ID NO:25所示的LCDR1和LCDR3,以及如SEQ ID NO:13或SEQ ID NO:43所示的LCDR2;且所述重链可变区包含人抗体的重链框架区变体,其相对于人抗体的重链框架区包含选自27D、30P、37L、38K、48I、66K、67A、69L和82a N中的一个或更多个氨基酸回复突变,和/或所述轻链可变区包含人抗体的轻链框架区变体,其相对于人抗体的轻链框架区包含49S氨基酸回复突变。
- 根据权利要求1或2所述的抗CD70抗体,其包含重链可变区和轻链可变区,其中:d)所述重链可变区,其氨基酸序列与SEQ ID NO:5、44、45、46、51、52或53具有至少90%的序列同一性,和/或所述轻链可变区,其氨基酸序列与SEQ ID NO:6、47、48、49或50具有至少90%的序列同一性;或e)所述重链可变区,其氨基酸序列与SEQ ID NO:3、26、27、28、29、30、31、34、35、36、37、38或39具有至少90%的序列同一性,和/或所述轻链可变区,其氨基酸序列与SEQ ID NO:4、32、33、40或41具有至少90%的序列同一性;或f)所述重链可变区,其氨基酸序列与SEQ ID NO:7、55、56、57、58、59、60、63、64、65、66、67或68具有至少90%的序列同一性,和/或所述轻链可变区,其氨基酸序列与SEQ ID NO:8、61、62、69或70具有至少90%的序列同一性;优选地,所述的抗CD70抗体包含重链可变区和轻链可变区,其中:g)所述重链可变区如SEQ ID NO:44、45、46、51、52或53所示;和所述轻链可变区序列如SEQ ID NO:47、48、49或50所示;或h)所述重链可变区如SEQ ID NO:26、27、28、29、30、31、34、35、36、37、38或39所示;和所述轻链可变区如SEQ ID NO:32、33、40或41所示;或i)所述重链可变区如SEQ ID NO:5所示;和所述轻链可变区如SEQ ID NO:6所示;或j)所述重链可变区如SEQ ID NO:3所示;和所述轻链可变区如SEQ ID NO:4所示;或k)所述重链可变区如SEQ ID NO:7所示;和所述轻链可变区如SEQ ID NO:8所示;或l)所述重链可变区如SEQ ID NO:55、56、57、58、59、60、63、64、65、66、67或68所示;和所述轻链可变区如SEQ ID NO:61、62、69或70所示;更优选地,所述抗CD70抗体包含如下所示的重链可变区和轻链可变区:n)所述重链可变区如SEQ ID NO:51所示;和所述轻链可变区如SEQ ID NO:47所示;或o)所述重链可变区如SEQ ID NO:35所示;和所述轻链可变区如SEQ ID NO:40所示;或p)所述重链可变区如SEQ ID NO:65所示;和所述轻链可变区如SEQ ID NO:70所示。
- 根据权利要求1至4中任一项所述的抗CD70抗体,其中所述抗CD70抗体包含抗体重链恒定区和轻链恒定区;优选地,所述重链恒定区选自人IgG1、IgG2、IgG3和IgG4恒定区及其常规变体,所述轻链恒定区选自人抗体κ和λ链恒定区及其常规变体;更优选地,所述抗体包含如SEQ ID NO:72所示的重链恒定区和如SEQ ID NO:73所示的轻链恒定区。
- 根据权利要求1至5中任一项所述的抗CD70抗体,其包含:q)与SEQ ID NO:74具有至少85%序列同一性的重链,和/或与SEQ ID NO:75具有至少85%序列同一性的轻链;或r)与SEQ ID NO:76具有至少85%序列同一性的重链,和/或与SEQ ID NO:77具有至少85%同一性的轻链;或s)与SEQ ID NO:78具有至少85%序列同一性的重链,和/或与SEQ ID NO:79具有至少85%同一性的轻链;优选地,所述的抗CD70抗体包含:t)如SEQ ID NO:74所示的重链和如SEQ ID NO:75所示的轻链;或u)如SEQ ID NO:76所示的重链和如SEQ ID NO:77所示的轻链;或v)如SEQ ID NO:78所示的重链和如SEQ ID NO:79所示的轻链。
- 一种分离的抗CD70抗体,其中所述抗CD70抗体与权利要求1至6中任一项所述的抗CD70抗体竞争性结合人CD70或猴CD70。
- 根据权利要求1至7中任一项所述的抗CD70抗体,其中所述的抗CD70抗体为低岩藻糖基化抗体;优选地,所述低岩藻糖基化抗体为至少80%、85%、90%、95%或100%的抗体重链未被岩藻糖糖基化修饰的抗体;更优选地,所述抗体为100%的抗体重链未被岩藻糖糖基化修饰的IgG1抗体。
- 根据权利要求1至8中任一项所述的抗CD70抗体,所述抗CD70抗体具有以下特征中的至少一种:A.所述抗CD70抗体以小于1×10 -8M,优选小于1×10 -9M,或小于1×10 -10M,或小于6×10 -11M的KD值与人CD70结合,所述KD值通过表面等离子共振技术测定;B.所述抗CD70抗体既能与人CD70抗原结合,也能与猴CD70抗原结合,但不与小鼠CD70抗原结合;C.所述抗CD70抗体能抑制CD70诱导的CD27信号传导,优选地,所述抗CD70抗体抑制表达人CD27细胞分泌IL-8的最大抑制百分比大于72%、90%、91%、93%或98%;D.所述抗CD70抗体具有以下的一个或更多个效应子功能:对表达人CD70细胞的抗体依赖性细胞介导的细胞毒性、补体依赖性细胞毒性和抗体依赖性细胞介导的吞噬作用;或E.所述抗CD70抗体能被表达人CD70的细胞内化。
- 核酸分子,其编码权利要求1至9中任一项所述的抗CD70抗体。
- 宿主细胞,其包含权利要求10所述的核酸分子,优选地,所述宿主细胞为微生物、植物或动物细胞宿主细胞;更优选地,所述宿主细胞为敲除了Glul和Fut8基因的宿主细胞。
- 一种药物组合物,其含有治疗有效量的根据权利要求1至9中任一项所述的抗CD70抗体,或根据权利要求10所述的核酸分子,以及一种或更多种药学上可接受的载体、稀释剂或赋形剂。
- 一种免疫偶联物,其包含:权利要求1至9中任一项所述的抗CD70抗体 和效应分子,其中,所述效应分子偶联至所述抗CD70抗体;优选地,所述效应分子选自由放射性同位素、抗肿瘤剂、免疫调节剂、生物反应修饰剂、凝集素、细胞毒性药物、发色团、荧光团、化学发光化合物、酶和金属离子组成的组中的一种或更多种。
- 一种用于免疫检测或测定CD70的方法,所述方法包括使权利要求1至9中任一项所述的抗CD70抗体接触受试者或来自受试者的样品的步骤。
- 一种试剂盒,其包含根据权利要求1至9中任一项所述的抗CD70抗体、或根据权利要求13所述的免疫偶联物。
- 一种预防或治疗疾病或病症的方法,所述方法包括向受试者施用治疗有效量的以下物质:A.权利要求1至9中任一项所述的抗CD70抗体,B.权利要求10所述的核酸分子,C.权利要求12所述的药物组合物,或D.权利要求13所述的免疫偶联物,其中所述疾病或病症优选为肿瘤、自身免疫性疾病或感染性疾病;优选地,所述疾病或病症为与CD70有关的疾病或病症。
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AU2021298632A AU2021298632A1 (en) | 2020-06-30 | 2021-06-29 | Anti-CD70 antibody and application thereof |
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WO2024040195A1 (en) | 2022-08-17 | 2024-02-22 | Capstan Therapeutics, Inc. | Conditioning for in vivo immune cell engineering |
WO2024054992A1 (en) | 2022-09-09 | 2024-03-14 | Bristol-Myers Squibb Company | Methods of separating chelator |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024040195A1 (en) | 2022-08-17 | 2024-02-22 | Capstan Therapeutics, Inc. | Conditioning for in vivo immune cell engineering |
WO2024040194A1 (en) | 2022-08-17 | 2024-02-22 | Capstan Therapeutics, Inc. | Conditioning for in vivo immune cell engineering |
WO2024054992A1 (en) | 2022-09-09 | 2024-03-14 | Bristol-Myers Squibb Company | Methods of separating chelator |
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EP4173638A1 (en) | 2023-05-03 |
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