CN111375059B - anti-GITR antibody pharmaceutical composition and application thereof - Google Patents
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- CN111375059B CN111375059B CN201911374084.4A CN201911374084A CN111375059B CN 111375059 B CN111375059 B CN 111375059B CN 201911374084 A CN201911374084 A CN 201911374084A CN 111375059 B CN111375059 B CN 111375059B
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- SPRBJFWIUVWXBT-UHFFFAOYSA-K tripotassium 2-hydroxypropane-1,2,3-tricarboxylate 2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [K+].[K+].[K+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O SPRBJFWIUVWXBT-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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- C07K—PEPTIDES
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- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Abstract
The invention relates to an anti-GITR antibody pharmaceutical composition and application thereof. In particular, the present invention relates to a pharmaceutical composition comprising an anti-GITR antibody or antigen-binding fragment thereof and a buffer. Further, the pharmaceutical composition further comprises a sugar and a nonionic surfactant. The pharmaceutical compositions of the present invention exhibit high antibody stability.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing an anti-GITR antibody and application of the pharmaceutical composition as a medicine.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Tumors, one of the biggest healthy killers, are a serious challenge to human society for a long time. Traditional therapies such as surgery, chemotherapy and radiation therapy often have little effect in treating disseminated solid tumors. Tumor immunotherapy is a continuous hot spot in the field of tumor therapy at present, and makes full use of and mobilizes killer T cells in tumor patients to kill tumors, so that the tumor immunotherapy is probably the most effective and safe way for treating tumors. Such therapies have now shown good application prospects for the treatment of several different types of cancer, including disseminated metastatic tumors.
In addition to the need for providing a first signal to T cells via presentation of MHC-antigen peptides by Antigen Presenting Cells (APCs), activation of T cells in humans employs a two-signaling system, which requires a series of co-stimulatory molecules to provide a second signal to generate a normal immune response in T cells. This dual signal pathway system plays a vital role in the balance of the immune system in vivo, and it tightly regulates the body's different immune responses to self and non-self antigens. Absence of the second signal provided by the co-stimulatory molecule will result in a non-response or loss of a sustained specific immune response of the T cell, resulting in tolerance. Thus, this second signaling pathway plays a very critical regulatory role throughout the immune response of the body.
GITR (glucocorticoid-induced TNFR-related protein, also known as TNFRSF 18) is a transmembrane protein consisting of 228 amino acids, having a 19 amino acid signal sequence, 134 amino acids extracellular domain with 3 cysteine-rich motifs, 23 amino acid transmembrane segment, and 52 amino acid intracellular domain, wherein the intracellular domain has high homology with the intracellular domains of mouse and human TNFR, 4-1BB, and CD 27. GITR belongs to the superfamily of Tumor Necrosis Factor Receptors (TNFR), is expressed in many components of the innate and adaptive immune systems, and has only minimal expression in a variety of normal tissues including breast, prostate, brain, heart, kidney, liver, salivary gland, spleen, stomach, thymus and uterus.
GITR is constitutively present on non-activated T cells and binds to another transmembrane protein called GITR ligand (GITRL). After T cell activation, GITR expression increases, triggering co-activates effector T lymphocytes (Teff), and modulates regulatory T cell (Treg) activity. GITR is activated by GITRL expressed primarily on APC, delivering a signal through its intracellular domain, triggering NF-kB activation by TRAF2/NIK pathway. This activation process can increase resistance to tumor and viral infections, and is involved in autoimmune and inflammatory processes, including enhancing the response to infection and tumor by NK cell coactivation mechanisms.
Patent publications on anti-GITR antibodies are currently seen, for example WO2006105021, WO2011028683, WO2011028683, WO2013039954, WO2015184099, WO2015187835, WO2015031667, WO2016054638, WO2017087678, WO2017068186, etc. However, until now, there is no GITR antibody in clinical use, and there is still a need to develop new anti-GITR antibodies suitable for clinical use.
However, antibody drugs have a large molecular weight and a complex structure, and are easily degraded, polymerized, or subjected to undesired chemical modification, and thus are unstable. In order to make antibodies suitable for administration and maintain stability during storage and subsequent use, the study of stable formulations of antibody drugs is particularly important.
Disclosure of Invention
In one aspect, the invention provides a pharmaceutical composition comprising an anti-GITR antibody, or antigen-binding fragment thereof, and a buffer selected from a histidine buffer or an acetate buffer.
In an alternative embodiment, the acetate buffer is a sodium acetate-acetate buffer having a pH of about 5.0 to 6.0, preferably a pH of about 5.0 to 5.5, and preferably a pH of about 5.5 to 6.0. In non-limiting embodiments, the acetate buffer is an acetic acid-sodium acetate buffer having a pH of about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0, preferably an acetic acid-sodium acetate buffer having a pH of about 5.5. The histidine buffer is a histidine-hydrochloric acid buffer or a histidine-acetic acid buffer having a pH of about 5.5 to 6.5, preferably a pH of about 5.5 to 6.0, and preferably a pH of about 6.0 to 6.5. In non-limiting embodiments, the histidine buffer is a histidine-hydrochloric acid buffer or a histidine-acetic acid buffer at a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4 or 6.5, preferably a histidine-acetic acid buffer at a pH of about 6.0 or about 5.8.
In an alternative embodiment, the buffer concentration is about 5mM to 40mM, preferably about 5mM to 35mM, preferably about 5mM to 30mM, preferably about 5mM to 25mM, preferably about 5mM to 20mM, preferably about 5mM to 15mM, preferably about 5mM to 10mM, preferably about 10mM to 40mM, preferably about 10mM to 35mM, preferably about 10mM to 30mM, preferably about 10mM to 25mM, preferably about 10mM to 20mM, preferably about 10mM to 15mM, preferably about 15mM to 40mM, preferably about 15mM to 35mM, preferably about 15mM to 30mM, preferably about 15mM to 25mM, preferably about 15mM to 20mM, preferably about 20mM to 40mM, preferably about 20mM to 35mM, preferably about 20mM to 30mM, preferably about 20mM to 25mM, preferably about 25mM to 30mM, preferably about 35 mM. In non-limiting examples, the buffer concentration is about 5mM, 7mM, 8mM, 9mM, 10mM, 12mM, 14mM, 16mM, 18mM, 20mM, 22mM, 24mM, 26mM, 28mM, 30mM, 35mM, or 40mM, more preferably about 10mM.
In an alternative embodiment, the concentration of the anti-GITR antibody or antigen-binding fragment thereof in the above-described pharmaceutical composition is about 0.5mg/ml to 100mg/ml, preferably about 10mg/ml to 90mg/ml, preferably about 10mg/ml to 80mg/ml, preferably about 10mg/ml to 70mg/ml, preferably about 10mg/ml to 60mg/ml, preferably about 10mg/ml to 50mg/ml, preferably about 10mg/ml to 40mg/ml, preferably about 10mg/ml to 30mg/ml, preferably about 10mg/ml to 20mg/ml, preferably about 20mg/ml to 100mg/ml, preferably about 20mg/ml to 90mg/ml, preferably about 20mg/ml to 70mg/ml, preferably about 60mg/ml, preferably about 40mg to 40mg/ml, preferably about 30mg to 30mg/ml, preferably about 40mg to 40mg/ml, preferably about 30mg to 30mg/ml, preferably about 30mg to 90mg/ml, preferably about 30mg to 80mg/ml, preferably about 30mg to 30mg/ml, preferably about 30mg to 40mg/ml, preferably about 40mg to about 60 mg/ml. Preferably about 40mg/ml to 60mg/ml, preferably about 40mg/ml to 50mg/ml, preferably about 50mg/ml to 100mg/ml, preferably about 50mg/ml to 90mg/ml, preferably about 50mg/ml to 80mg/ml, preferably about 50mg/ml to 70mg/ml, preferably about 50mg/ml to 60mg/ml, preferably about 60mg/ml to 100mg/ml, preferably about 60mg/ml to 90mg/ml, preferably about 60mg/ml to 80mg/ml, preferably about 60mg/ml to 70mg/ml, preferably about 70mg/ml to 100mg/ml, preferably about 70mg/ml to 90mg/ml, preferably about 70mg/ml to 80mg/ml, preferably about 80mg/ml to 100mg/ml, preferably about 80mg/ml to 90mg/ml, preferably about 90mg/ml to 90mg/ml, preferably about 60mg/ml to 80 mg/ml. In non-limiting examples, the anti-GITR antibody or antigen-binding fragment thereof is at a concentration of about 0.5mg/ml, 1mg/ml, 10mg/ml, 20mg/ml, 30mg/ml, 40mg/ml, 50mg/ml, 60mg/ml, 70mg/ml, 80mg/ml, 90mg/ml, or 100mg/ml, most preferably about 50mg/ml.
In an alternative embodiment, the above pharmaceutical composition further comprises a sugar, preferably from trehalose or sucrose, most preferably sucrose. In some embodiments, the sugar concentration is about 70mg/ml to 150mg/ml, preferably about 70mg/ml to 140mg/ml, preferably about 70mg/ml to 130mg/ml, preferably about 70mg/ml to 120mg/ml, preferably about 70mg/ml to 110mg/ml, preferably about 70mg/ml to 100mg/ml, preferably about 70mg/ml to 90mg/ml, preferably about 70mg/ml to 80mg/ml, preferably about 80mg/ml to 140mg/ml, preferably about 80mg/ml to 130mg/ml, preferably about 80mg/ml to 120mg/ml, preferably about 80mg/ml to 110mg/ml, preferably about 80mg/ml to 100mg/ml, preferably about 80mg/ml to 90mg/ml, preferably about 90mg/ml to 140mg/ml, preferably about 90mg/ml to 130mg/ml, preferably about 90mg to 130mg/ml, preferably about 130mg to 120mg/ml, preferably about 130mg to 100mg/ml, preferably about 90mg to 130mg/ml, preferably about 100mg to 100 mg/ml. In non-limiting examples, the sugar concentration is about 70mg/ml, 75mg/ml, 80mg/ml, 85mg/ml, 90mg/ml, 100mg/ml, 110mg/ml, 120mg/ml, 130mg/ml, 140mg/ml, or 150mg/ml, more preferably about 80mg/ml.
In alternative embodiments, the above pharmaceutical composition further comprises a surfactant, wherein the surfactant may be selected from polysorbate 20, polysorbate 80, polyhydroxyene, triton, sodium dodecyl sulfonate, sodium lauryl sulfonate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauramidopropyl-betaine, cocamidopropyl-betaine, oleamidopropyl-betaine, myristamidopropyl-dimethylamine, palmitamidopropyl-betaine, isostearamidopropyl-betaine, myristamidopropyl-dimethylamine, palmitamidopropyl-dimethylamine, stearamidopropyl-dimethylamine, methyl cocoa-sodium, methyl-macrogol, sodium taurate, copolymer of ethylene glycol, polypropylene glycol, and the like. The surfactant is preferably a polysorbate, more preferably polysorbate 80; in some embodiments, the surfactant is present at a concentration of about 0.2mg/ml to about 0.8mg/ml, preferably about 0.2mg/ml to about 0.7mg/ml, preferably about 0.2mg/ml to about 0.6mg/ml, preferably about 0.2mg/ml to about 0.5mg/ml, preferably about 0.2mg/ml to about 0.4mg/ml, preferably about 0.2mg/ml to about 0.3mg/ml, preferably about 0.3mg/ml to about 0.7mg/ml, preferably about 0.3mg/ml to about 0.6mg/ml, preferably about 0.3mg/ml to about 0.5mg/ml, preferably about 0.3mg/ml to about 0.4mg/ml, preferably about 0.4mg/ml to about 0.7mg/ml, preferably about 0.4mg/ml to about 0.6mg/ml, preferably about 0.4mg/ml to about 0.5mg/ml, preferably about 0.5mg to about 0.6mg/ml, preferably about 0.3mg/ml to about 0.5 mg/ml. In non-limiting examples, the surfactant concentration is about 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, or 0.8mg/ml, more preferably about 0.4mg/ml.
In an alternative embodiment, the pharmaceutical composition comprises: (a) about 0.5 to 100mg/ml of an anti-GITR antibody or antigen-binding fragment thereof, (b) about 5 to 40mM histidine salt buffer or acetate buffer, (c) about 70 to 150mg/ml sucrose, and (d) about 0.2mg/ml to 0.8mg/ml polysorbate.
In an alternative embodiment, the above pharmaceutical composition comprises: (a) about 40 to 60mg/ml of an anti-GITR antibody or antigen-binding fragment thereof, (b) about 10 to 30mM of a sodium acetate-acetate buffer having a pH of about 5.0 to 6.0, or a histidine-hydrochloric acid buffer or histidine-acetic acid buffer having a pH of about 5.5 to 6.5, (c) about 70 to 90mg/ml of sucrose, and (d) about 0.2mg/ml to 0.6mg/ml of polysorbate 80.
In an alternative embodiment, the above pharmaceutical composition comprises: about 10mM histidine-acetic buffer, pH about 6.0 or about 5.8, about 50mg/ml anti-GITR antibody, about 80mg/ml sucrose, and about 0.4mg/ml polysorbate 80.
In alternative embodiments, the anti-GITR antibody or antigen-binding fragment thereof in the above pharmaceutical composition is a murine antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, or a humanized antibody or antigen-binding fragment thereof.
In an alternative embodiment, the anti-GITR antibody or antigen-binding fragment thereof in the above pharmaceutical composition is a murine antibody or antigen-binding fragment thereof, or a chimeric antibody or antigen-binding fragment thereof, selected from the antibodies or antigen-binding fragments thereof as set forth in any one of (a) to (D) below:
(A) An anti-GITR antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region LCVR is sequence SEQ ID No. 5 and the heavy chain variable region HCVR is sequence SEQ ID No. 4;
(B) An anti-GITR antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region LCVR is SEQ ID No. 7 and the heavy chain variable region HCVR is SEQ ID NO:6, preparing a base material;
(C) An anti-GITR antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region LCVR is SEQ ID No. 9 and the heavy chain variable region HCVR is SEQ ID NO:8, 8;
(D) An anti-GITR antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region LCVR is SEQ ID No. 11 and the heavy chain variable region HCVR is SEQ ID NO:10.
in an alternative embodiment, the anti-GITR antibody or antigen-binding fragment thereof in the above pharmaceutical composition is a humanized antibody or antigen-binding fragment thereof, which is obtained by humanized engineering the above antibody; preferably, the FR region sequence on the light chain variable region of said humanized antibody is derived from the human germline light chain IGKV 4-1X 01 sequence shown in SEQ ID NO. 13 or a variant thereof, or from the human germline light chain IGKV 3-11X 01 sequence shown in SEQ ID NO. 15 or a variant thereof; the FR region sequence on the heavy chain variable region is derived from the human germline heavy chain IGHV3-48 x 03 sequence shown as SEQ ID NO. 12 or a variant thereof, or from the human germline heavy chain IGHV1-2 x 02 sequence shown as SEQ ID NO. 14 or a variant thereof; preferably, the variant is a back mutation having 1-10 amino acids in the sequence shown as SEQ ID NO. 12, 13, 14 or 15.
In an alternative embodiment, the anti-GITR antibody or antigen-binding fragment thereof in the above pharmaceutical composition comprises:
(A) The sequence is shown in SEQ ID NO: 16. 17 or 18, and/or a heavy chain variable region having a sequence as set forth in SEQ ID NO: 19. 20 or 21, and a light chain variable region shown in seq id no; or (b)
(B) The sequence is shown in SEQ ID NO: 22. 23 or 24, and/or a heavy chain variable region having a sequence as set forth in SEQ ID NO: 25. 26 or 27.
In an alternative embodiment, the anti-GITR antibody or antigen-binding fragment thereof in the above pharmaceutical composition comprises:
(A) The sequence is shown in SEQ ID NO:17, and a heavy chain variable region having the sequence set forth in SEQ ID NO:20, and a light chain variable region shown in seq id no; or (b)
(B) The sequence is shown in SEQ ID NO:23, and a heavy chain variable region having the sequence set forth in SEQ ID NO: 26.
In alternative embodiments, the anti-GITR antibody or antigen-binding fragment thereof described in the above pharmaceutical composition further comprises a constant region; preferably, the antibody heavy chain constant region is derived from a human IgG1, igG2, igG3, or IgG4 or mutated sequence thereof, and the light chain constant region is derived from a human kappa, lambda chain, or mutated sequence thereof.
In an alternative embodiment, the anti-GITR antibody or antigen-binding fragment thereof described in the above pharmaceutical composition comprises:
(A) The sequence is shown in SEQ ID NO:28, and the sequence set forth in SEQ ID NO:29, and a light chain full-length sequence shown in seq id no; or (b)
(B) The sequence is shown in SEQ ID NO:30, and the sequence is shown as SEQ ID NO: 31.
In one embodiment, the above pharmaceutical composition comprises: 10mM histidine-HCl buffer at about pH 6.0 and 50mg/ml anti-GITR antibody.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM histidine-HCl buffer at about pH 6.5 and 50mg/ml anti-GITR antibody.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM acetic acid-sodium acetate buffer, about pH 5.5, 80mg/ml sucrose and 50mg/ml anti-GITR antibody.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM acetic acid-sodium acetate buffer, about pH 5.5, 80mg/ml sucrose, 50mg/ml anti-GITR antibody and 0.2mg/ml polysorbate 80.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM acetic acid-sodium acetate buffer, about pH 5.5, 80mg/ml sucrose sugar, 50mg/ml anti-GITR antibody, and 0.4mg/ml polysorbate 80.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM acetic acid-sodium acetate buffer, about pH 5.5, 80mg/ml sucrose, 50mg/ml anti-GITR antibody and 0.6mg/ml polysorbate 80.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM acetic acid-sodium acetate buffer, about pH 5.5, 80mg/ml sucrose, 0.5mg/ml anti-GITR antibody, and 0.4mg/ml polysorbate 80.
In yet another embodiment, the above pharmaceutical composition comprises: 20mM histidine-acetic buffer, about pH 6.0, 80mg/ml sucrose and 50mg/ml anti-GITR antibody.
In yet another embodiment, the above pharmaceutical composition comprises: 30mM histidine-acetic buffer, about pH 6.0, 80mg/ml sucrose and 50mg/ml anti-GITR antibody.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM histidine-acetic buffer, about pH 6.1, 80mg/ml sucrose and 50mg/ml anti-GITR antibody.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM histidine-acetic buffer, about pH 6.0, 80mg/ml sucrose, 40mg/ml anti-GITR antibody and 0.4mg/ml polysorbate 80.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM histidine-acetic buffer, about pH 6.0, 80mg/ml sucrose, 60mg/ml anti-GITR antibody and 0.4mg/ml polysorbate 80.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM histidine-acetic buffer, about pH 6.5, 80mg/ml sucrose, 50mg/ml anti-GITR antibody and 0.4mg/ml polysorbate 80.
In yet another embodiment, the above pharmaceutical composition comprises: 10mM histidine-acetic buffer, about pH 5.5, 80mg/ml sucrose, 50mg/ml anti-GITR antibody and 0.4mg/ml polysorbate 80.
In another aspect, the invention features a method of preparing the above pharmaceutical composition, the method including the step of mixing an anti-GITR antibody, or antigen-binding fragment thereof, with a pharmaceutically acceptable excipient.
In another aspect, the invention features a lyophilized formulation comprising an anti-GITR antibody or antigen-binding fragment thereof, obtained by lyophilizing the pharmaceutical composition described above.
In another aspect, the invention features a reconstituted solution comprising an anti-GITR antibody or antigen-binding fragment thereof, the reconstituted solution being prepared by reconstitution of a lyophilized formulation as described above.
In another aspect, the invention features a lyophilized formulation comprising an anti-GITR antibody or antigen-binding fragment thereof, which is reconstituted to form the pharmaceutical composition described above.
In another aspect, the invention discloses an article of manufacture comprising a container containing the pharmaceutical composition, lyophilized formulation, or reconstituted solution described above.
In another aspect, the invention discloses the above pharmaceutical composition, lyophilized formulation, reconstituted solution or formulation as a medicament. Preferably, the medicament is useful for treating GITR or GITRL mediated diseases or conditions; preferably, the medicament is useful for treating cancer, preferably selected from the group consisting of: melanoma, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, liver cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer, cervical cancer, multiple myeloma, leukemia, lymphoma, gall bladder cancer, and glioblastoma.
In another aspect, the invention discloses the use of the above pharmaceutical composition, lyophilized formulation, reconstituted solution or formulation in the manufacture of a medicament for treating GITR or GITRL mediated diseases or conditions; wherein the disease or condition is preferably cancer; preferably, the cancer is selected from: melanoma, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, liver cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer, cervical cancer, multiple myeloma, leukemia, lymphoma, gall bladder cancer, and glioblastoma.
In another aspect, the invention features a method of treating and preventing a GITR or GITRL-mediated disease or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of the foregoing pharmaceutical composition, lyophilized formulation, reconstituted solution or formulation; wherein the disease or condition is preferably cancer; preferably, the cancer is selected from: melanoma, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, liver cancer, gastric cancer, colorectal cancer, bladder cancer, esophageal cancer, cervical cancer, multiple myeloma, leukemia, lymphoma, gall bladder cancer, and glioblastoma.
Drawings
FIG. 1 is an in vitro cell activity test of murine anti-GITR antibodies, showing that each antibody tested can effectively stimulate secretion of its cytokine IL-2. The functional strength of each antibody was assessed by stimulating IL-2 secretion concentration.
FIG. 2 is an in vitro cell activity test of humanized anti-GITR antibody, showing that both antibodies hu18F10 and hu8A11 to be tested can effectively stimulate secretion of cytokine IL-2, whose functional strength is equivalent to or stronger than that of the reference antibody BMAB.
FIG. 3 is a graph showing tumor growth curves of NCG mice bearing melanoma on A375 grafts co-transplanted with human PBMC.
FIG. 4 is a graph showing the change in body weight of NCG mice co-transplanted with human PBMC with A375-transplanted melanoma.
Detailed Description
1. Terminology
In order that the invention may be more readily understood, certain technical and scientific terms are defined below. Unless clearly defined otherwise herein in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
"buffer" refers to a buffer that is resistant to pH changes by the action of its acid-base conjugated components. Examples of buffers to control the pH in the appropriate range include acetate, succinate, gluconate, histidine, oxalate, lactate, phosphate, citrate, tartrate, fumarate, glycylglycine and other organic acid buffers.
A "histidine buffer" is a buffer comprising histidine ions. Examples of histidine buffers include histidine-hydrochloric acid, histidine-acetic acid, histidine-phosphate, histidine-sulfate, and the like buffers, preferably histidine-hydrochloric acid buffers. The histidine-acetic acid buffer is prepared from histidine and acetic acid or histidine and histidine-acetate.
A "citrate buffer" is a buffer that includes citrate ions. Examples of citrate buffers include citric acid-sodium citrate, citric acid-potassium citrate, citric acid-calcium citrate, citric acid-magnesium citrate, and the like. A preferred citrate buffer is citric acid-sodium citrate.
A "succinate buffer" is a buffer that includes succinate ions. Examples of succinate buffers include sodium succinate, potassium succinate, calcium succinate, and the like. The preferred succinate buffer is sodium succinate-succinate.
An "acetate buffer" is a buffer that includes acetate ions. Examples of acetate buffers include acetic acid-sodium acetate, histidine acetate, acetic acid-potassium acetate, calcium acetate, acetic acid-magnesium acetate, and the like. The preferred acetate buffer is acetic acid-sodium acetate.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to maintain the stability of the active ingredients of the antibody, promote the administration to organisms, and facilitate the absorption of the active ingredients so as to exert biological activity. As used herein, the terms "pharmaceutical composition" and "formulation" are not intended to be mutually exclusive.
The pharmaceutical composition of the present invention is in the form of a solution, wherein the solvent is water unless otherwise specified.
By "lyophilized formulation" is meant a pharmaceutical composition in liquid or solution form or a formulation or pharmaceutical composition obtained after a vacuum freeze-drying step of a liquid or solution formulation.
The terms "about," "approximately" or "substantially comprise," as used herein, mean that the value is within an acceptable error range for the particular value being determined by one of ordinary skill in the art, which value depends in part on how the measurement or determination is made (i.e., the limits of the measurement system). For example, "about" in each implementation in the art may mean within 1 or exceeding a standard deviation of 1. Alternatively, "about," "about," or "substantially comprising" may mean a range of up to 20%. Furthermore, the term may mean at most one order of magnitude or at most 5 times the value, especially for biological systems or processes. Unless otherwise indicated, when a particular value is found in this application and in the claims, the meaning of "about", "about" or "substantially comprising" should be assumed to be within the acceptable error of that particular value.
The pharmaceutical composition provided by the invention can achieve a stable effect: a pharmaceutical composition wherein the antibody substantially retains its physical and/or chemical stability and/or biological activity after storage, preferably the pharmaceutical composition substantially retains its physical and chemical stability and its biological activity after storage. The shelf life is generally selected based on the predetermined shelf life of the pharmaceutical composition. There are a number of analytical techniques for measuring protein stability that measure stability after storage at a selected temperature for a selected period of time.
A stable pharmaceutical antibody formulation is one in which no significant change is observed in the following cases: the storage is at refrigeration temperature (2-8 ℃) for at least 3 months, preferably 6 months, more preferably 1 year, and even more preferably up to 2 years. In addition, stable liquid formulations include those that: which exhibits desired characteristics after storage at temperatures including 25 ℃ and 40 ℃ for periods including 1 month, 3 months, 6 months. Typical acceptable criteria for stability are as follows: the pharmaceutical antibody formulation was colorless, or clear to slightly milky, by visual analysis. The concentration, pH and osmolality of the formulation have a variation of no more than + -10%. Typically no more than about 10%, preferably no more than about 5% truncation is observed. Usually no more than about 10%, preferably no more than about 5% of aggregates are formed.
An antibody "retains its physical stability" in a pharmaceutical formulation if it does not exhibit a significant increase in aggregation, precipitation and/or denaturation after visual inspection of color and/or clarity, or as measured by UV light scattering, size Exclusion Chromatography (SEC) and Dynamic Light Scattering (DLS). The change in protein conformation can be assessed by fluorescence spectroscopy (which determines the tertiary structure of the protein) and by FTIR spectroscopy (which determines the secondary structure of the protein).
An antibody "retains its chemical stability" in a pharmaceutical formulation if it does not exhibit a significant chemical change. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often alter the chemical structure of proteins include hydrolysis or truncation (assessed by methods such as size exclusion chromatography and SDS-PAGE), oxidation (assessed by methods such as peptide spectroscopy in combination with mass spectrometry or MALDI/TOF/MS), deamidation (assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide spectroscopy, isoaspartic acid measurement, etc.), and isomerization (assessed by measuring isoaspartic acid content, peptide spectroscopy, etc.).
An antibody "retains its biological activity" in a pharmaceutical formulation if the biological activity of the antibody at a given time is within a predetermined range of biological activities exhibited when the pharmaceutical formulation is prepared. The biological activity of an antibody may be determined, for example, by an antigen binding assay.
The three-letter and one-letter codes for amino acids used in the present invention are described in J.biol. Chem,243, p3558 (1968).
The term "antibody" as used herein refers to an immunoglobulin that is a tetrapeptide chain structure formed by two identical heavy chains and two identical light chains joined by interchain disulfide bonds. The immunoglobulin heavy chain constant region differs in amino acid composition and sequence, and thus, in antigenicity. Accordingly, immunoglobulins can be classified into five classes, or isotypes of immunoglobulins, i.e., igM, igD, igG, igA and IgE, with their respective heavy chains being the μ, δ, γ, α and ε chains, respectively. The same class of Ig can be further divided into different subclasses, e.g., igG can be divided into IgG1, igG2, igG3 and IgG4, depending on the amino acid composition of the hinge region and the number and position of the heavy chain disulfide bonds. Light chains are classified by the difference in constant regions as either kappa chains or lambda chains. Each class Ig of the five classes of Igs may have either a kappa chain or a lambda chain.
In the present invention, the antibody light chain of the present invention may further comprise a light chain constant region comprising a kappa, lambda chain of human or murine origin or variants thereof.
In the present invention, the antibody heavy chain of the present invention may further comprise a heavy chain constant region comprising IgG1, igG2, igG3, igG4 or variants thereof of human or murine origin.
The sequences of the heavy and light chains of the antibody near the N-terminus vary widely, being the variable region (V region); the remaining amino acid sequence near the C-terminus is relatively stable and is a constant region (C-region). The variable region includes 3 hypervariable regions (HVRs) and 4 Framework Regions (FR) that are relatively conserved in sequence. The 3 hypervariable regions determine the specificity of the antibody, also known as Complementarity Determining Regions (CDRs). Each light chain variable region (VL or LCVR) and heavy chain variable region (VH or HCVR) consists of 3 CDR regions and 4 FR regions, arranged in order from amino-terminus to carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The 3 CDR regions of the light chain refer to LCDR1, LCDR2 and LCDR3; the 3 CDR regions of the heavy chain are referred to as HCDR1, HCDR2 and HCDR3.
The term "recombinant human antibody" includes human antibodies prepared, expressed, created, or isolated by recombinant methods, the techniques and methods involved being well known in the art, such as (1) antibodies isolated from transgenes of human immunoglobulin genes, transchromosomal animals (e.g., mice), or hybridomas prepared therefrom; (2) An antibody isolated from a host cell transformed to express the antibody, such as a transfectoma; (3) an antibody isolated from a recombinant combinatorial human antibody library; and (4) antibodies prepared, expressed, created or isolated by splicing human immunoglobulin gene sequences to other DNA sequences, and the like. Such recombinant human antibodies comprise variable and constant regions that utilize specific human germline immunoglobulin sequences encoded by germline genes, but also include rearrangements and mutations that occur later, such as during antibody maturation.
The term "murine antibody" is herein a monoclonal antibody to human GITR made according to the knowledge and skill in the art. The preparation is performed by injecting the test subject with the GITR antigen and then isolating hybridomas expressing antibodies having the desired sequence or functional properties. In a preferred embodiment of the present invention, the murine anti-GITR antibody or antigen binding fragment thereof may further comprise a light chain constant region of murine kappa, lambda chain or variant thereof, or further comprise a heavy chain constant region of murine IgG1, igG2, igG3 or IgG4 or variant thereof.
The term "humanized antibody (humanized antibody)", also referred to as CDR-grafted antibody (CDR-grafted antibody), refers to an antibody produced by grafting a mouse CDR sequence into the variable region framework of a human antibody. The strong immune response induced by chimeric antibodies due to the large number of mouse protein components can be overcome. To avoid a decrease in activity while reducing immunogenicity, the human antibody variable region may be subjected to minimal reverse mutation (back mutation, i.e., mutation of amino acid residues in the FR region of human antibody to amino acid residues at positions corresponding to the original source antibody) to maintain activity.
The term "chimeric antibody (chimeric antibody)" refers to an antibody in which a variable region of a murine antibody is fused to a constant region of a human antibody, and which can reduce an immune response induced by the murine antibody. The method comprises the steps of establishing chimeric antibody, selecting hybridoma secreting murine specific monoclonal antibody, cloning variable region genes from mouse hybridoma cells, cloning constant region genes of human antibody according to requirements, connecting the mouse variable region genes and the human constant region genes into chimeric genes, inserting the chimeric genes into a human vector, and finally expressing chimeric antibody molecules in a eukaryotic industrial system or a prokaryotic industrial system. The constant region of a human antibody may be selected from the heavy chain constant region of a human IgG1, igG2, igG3 or IgG4 or variant thereof, preferably comprising the heavy chain constant region of a human IgG2 or IgG4, or IgG1 which is not toxic by ADCC (antibody-dependent cell-dependent cellular cytotoxicity) after amino acid mutation.
"antigen-binding fragments" as used herein, refer to Fab fragments, fab 'fragments, F (ab') 2 fragments, and Fv fragments sFv fragments that bind to human GITR; comprising one or more CDR regions in an antibody of the invention. Fv fragments contain the antibody heavy and light chain variable regions, but no constant regions, and have the smallest antibody fragment with the entire antigen binding site. Generally, fv antibodies also comprise a polypeptide linker between the VH and VL domains, and are capable of forming the structures required for antigen binding. The two antibody variable regions may also be joined by different linkers into one polypeptide chain, known as a single chain antibody (single chain antibody) or single chain Fv (sFv).
The term "binds to" GITR in the present invention refers to being capable of interacting with human GITR. The term "antigen binding site" according to the invention refers to a three-dimensional spatial site that is not contiguous on an antigen, and that is recognized by an antibody or antigen binding fragment of the invention. The term "anti-GITR antibody" or "GITR antibody" refers to an antibody that binds to GITR.
The term "epitope" refers to a site on an antigen that specifically binds to an immunoglobulin or antibody. Epitopes can be formed by contiguous amino acids, or non-contiguous amino acids juxtaposed by tertiary folding of the protein. Epitopes formed by adjacent amino acids are typically maintained after exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost after treatment with denaturing solvents. Epitopes typically comprise at least 3-15 amino acids in a unique spatial conformation. Methods for determining what epitopes are bound by a given antibody are well known in the art and include immunoblotting and immunoprecipitation detection assays, among others. Methods for determining the spatial conformation of an epitope include techniques in the art and those described herein, such as X-ray crystallography, two-dimensional nuclear magnetic resonance, and the like.
The terms "specifically bind", "selectively bind" and "selectively bind" as used herein refer to the binding of an antibody to an epitope on a predetermined antigen. Typically, when recombinant human GITR is used as the analyte and antibodies are used As ligand, antibodies were found to be approximately below 10 as determined by Surface Plasmon Resonance (SPR) techniques in the instrument -7 M or even smaller equilibrium dissociation constant (K D ) Binds to the predetermined antigen and has an affinity to bind to the predetermined antigen that is at least twice as great as its affinity to bind to non-specific antigens other than the predetermined antigen or closely related antigens (e.g., BSA, etc.). The term "antibody that recognizes an antigen" may be used interchangeably herein with the term "antibody that specifically binds".
The term "competitive binding" refers to an antibody that recognizes the same epitope (also referred to as an epitope) or a portion of the same epitope on the extracellular region of human GITR as the monoclonal antibody of the present invention and binds to the antigen. An antibody that binds to the same epitope as the monoclonal antibody of the present invention refers to an antibody that recognizes and binds to the amino acid sequence of human GITR recognized by the monoclonal antibody of the present invention.
The term "nucleic acid molecule" refers to both DNA molecules and RNA molecules. The nucleic acid molecule may be single-stranded or double-stranded, but is preferably double-stranded DNA. A nucleic acid is "operably linked" when it is placed into 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.
The term "cross-reactive" refers to the ability of an antibody of the invention to bind to GITR from a different species. For example, an antibody of the invention that binds human GITR may also bind GITR of another species. Cross-reactivity is measured by detecting specific reactivity with purified antigen, or binding or functional interaction with cells physiologically expressing GITR, in binding assays (e.g., SPR and ELISA). Methods of determining cross-reactivity include standard binding assays as described herein, such as Surface Plasmon Resonance (SPR) analysis, or flow cytometry.
The terms "inhibit" or "block" are used interchangeably and encompass both partial and complete inhibition/blocking. Inhibition/blocking of GITR preferably reduces or alters the normal level or type of activity that occurs when GITR binding occurs without inhibition or blocking. Inhibition and blocking is also intended to include any measurable decrease in GITR binding affinity when contacted with an anti-GITR antibody as compared to GITR not contacted with an anti-GITR antibody.
The term "inhibit growth" (e.g., involving a cell) is intended to include any measurable decrease in cell growth.
The terms "inducing an immune response" and "enhancing an immune response" are used interchangeably and refer to stimulation (i.e., passive or adaptive) of an immune response to a particular antigen. The term "induce" with respect to inducing CDC or ADCC refers to stimulating a specific direct cell killing mechanism.
The term "ADCC", namely, antibody-dependent cell-mediated cytotoxicity, as used herein, refers to antibody-dependent cell-mediated cytotoxicity, which means that cells expressing Fc receptors directly kill target cells coated with antibodies by recognizing the Fc segment of the antibodies. ADCC effector function of antibodies may be reduced or eliminated by modification of the Fc fragment on IgG. The modification refers to mutation in the heavy chain constant region of the antibody, such as N297A, L234A, L235A selected from IgG 1; igG2/4chimera, F235E of IgG4, or L234A/E235A mutation.
The fusion protein is a protein product obtained by DNA recombination and co-expressed by two genes. Recombinant GITR extracellular region Fc fusion protein a fusion protein that coexpresses the GITR extracellular region and the human antibody Fc fragment by DNA recombination. The extracellular region of GITR refers to the portion of GITR protein expressed outside the cell membrane.
Methods for producing and purifying antibodies and antigen binding fragments are well known and can be found in the art, e.g., in the guidelines for antibody experimentation in Cold spring harbor, chapters 5-8 and 15. For example, mice can be immunized with human GITR or fragments thereof, the resulting antibodies can be renatured, purified, and amino acid sequenced using conventional procedures. Antigen binding fragments can likewise be prepared by conventional methods. The antibodies or antigen binding fragments of the invention are engineered to incorporate one or more human FR regions in the CDR regions of non-human origin. Human FR germline sequences can be obtained from the website http:// imgt. Cines. FR of ImMunoGeneTics (IMGT), or from the journal of immunoglobulins, (2001) ISBN: 012441351. Specifically, the light chain FR germline used by the antibodies or antigen binding fragments of the invention includes Vk3-11 and Vk4-1. Specific heavy chain FR germline for use with the antibodies or antigen binding fragments of the invention include VH3-48 and VH1-2.
The engineered antibodies or antigen binding fragments of the invention can be prepared and purified by conventional methods. Exemplary GITR antibodies or antigen binding fragments and their preparation are disclosed in PCT application PCT/CN2018/093572, which is incorporated herein in its entirety.
In one non-limiting example, cDNA sequences encoding the heavy and light chains of a GITR antibody or antigen-binding fragment, can be cloned and recombined into a GS expression vector. Recombinant immunoglobulin expression vectors can stably transfect CHO cells. As a more recommended prior art, mammalian expression systems can lead to glycosylation of the antibody, particularly at the highly conserved N-terminus of the FC region. Stable clones were obtained by expressing antibodies that specifically bound to human antigens. Positive clones were expanded in serum-free medium of the bioreactor to produce antibodies. The antibody-secreting culture may be purified and collected using conventional techniques. The antibodies can be concentrated by filtration using conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves, ion exchange. The resulting product is either immediately frozen, e.g., -70 ℃, or lyophilized.
The antibody of the present invention refers to a monoclonal antibody. The monoclonal antibodies (mabs) of the present invention refer to antibodies derived from a single clonal cell line, which is not limited to eukaryotic, prokaryotic, or phage clonal cell lines. Monoclonal antibodies or antigen binding fragments may be obtained by recombinant techniques such as hybridoma techniques, recombinant techniques, phage display techniques, synthetic techniques (e.g., CDR-grafting), or other prior art techniques.
"administration" and "treatment" when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid refers to the contact of an exogenous drug, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. "administration" and "treatment" may refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of a cell includes contacting a reagent with the cell, and contacting the reagent with a fluid, wherein the fluid is in contact with the cell. "administration" and "treatment" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, diagnosis, binding composition, or by another cell. "treatment" when applied to a human, veterinary or research subject refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.
"treatment" means administration of an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the invention, to a patient having one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered to the subject patient or population in an amount effective to alleviate one or more symptoms of the disease, whether by inducing regression of such symptoms or inhibiting the development of such symptoms to any clinically undetectable extent. The amount of therapeutic agent (also referred to as a "therapeutically effective amount") effective to alleviate any particular disease symptom can vary depending on a variety of factors, such as the disease state, age, and weight of the patient, and the ability of the drug to produce a desired therapeutic effect in the patient. Whether a disease symptom has been reduced can be assessed by any clinical test method that a physician or other healthcare professional typically uses to assess the severity or progression of the symptom. While embodiments of the present invention (e.g., methods or articles of manufacture) may be ineffective in alleviating the symptoms of the target disease in each patient, it should be determined according to any statistical test method known in the art, such as Student t test, chi-square test, U test according to Mann and Whitney, kruskal-Wallis test (H test), jonckheere-Terpstra test, and Wilcoxon test, that the symptoms of the target disease should be alleviated in a statistically significant number of patients.
The term "consisting essentially of … …" or variations thereof as used throughout the specification and claims is meant to include all such elements or groups of elements, and optionally other elements of similar or different nature to those described, which do not significantly alter the basic or novel nature of a given dosing regimen, method or composition. As a non-limiting example, a binding compound consisting essentially of the mentioned amino acid sequences may also include one or more amino acids that do not significantly affect the properties of the binding compound.
The term "naturally occurring" as applied to an object in the present invention refers to the fact that the object may be found in nature. For example, polypeptide sequences or polynucleotide sequences that are present in organisms (including viruses) that can be isolated from natural sources and that have not been intentionally modified by man in the laboratory are naturally occurring.
An "effective amount" comprises an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the route of administration and the dosage and severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.
"exogenous" refers to a substance that is to be produced by background outside an organism, cell or human. "endogenous" refers to substances produced in cells, organisms or humans according to background.
"homology" refers to sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in both comparison sequences is occupied by the same base or amino acid monomer subunit, for example if each position of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent homology between two sequences is a function of the number of matched or homologous positions shared by the two sequences divided by the number of positions compared x 100%. For example, in the optimal alignment of sequences, if there are 6 matches or homologies at 10 positions in the two sequences, then the two sequences are 60% homologous. In general, a comparison is made when two sequences are aligned to give the greatest percent homology.
The expressions "cell", "cell line" and "cell culture" are used interchangeably herein and all such designations include their progeny. Thus, the words "transformant" and "transformed cell" include primary test cells and cultures derived therefrom, regardless of the number of transfers. It should also be understood that all offspring may not be exactly identical in terms of DNA content due to deliberate or unintentional mutations. Including mutant progeny having the same function or biological activity as screened in the original transformed cell. Where different names are meant, they are clearly visible from the context.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "optionally comprising 1-3 antibody heavy chain variable regions" means that the antibody heavy chain variable regions of a particular sequence may be, but need not be, present.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
Detailed Description
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention. The experimental method without specific conditions being noted in the embodiment of the invention is generally according to conventional conditions, such as an antibody technical laboratory manual and a molecular cloning manual of cold spring harbor; or according to the conditions recommended by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
Example 1: immune antigen, sequence of screening antigen and preparation
The sequences were synthesized after gene optimization of the sequences encoding mFc-tagged human GITR (huGITR-mFc), the sequences encoding hFc-tagged human GITR (huGITR-hFc) and his×6-tagged human GITRL (huGITRL-His 6), each of which GITR recombinant proteins was designed by the inventors of the present application as a template sequence, and cloned into pcdna3.1 vector (available from Invitrogen), respectively.
huGITR-mFc sequence
MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCIDCASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSPPAEPKLENLYFQGPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK SEQ ID NO:1
huGITR-hFc sequences
MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCCRVHTTRCCRDYPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCIDCASGTFSGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSPPAEPKLENLYFQGTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:2
huGITRL-His6 sequence
MGVLLTQRTLLSLVLALLFPSMASMQLETAKEPCMAKFGPLPSKWQMASSEPPCVNKVSDWKLEILQNGLYLIYGQVAPNANYNDVAPFEVRLYKNKDMIQTLTNKSKIQNVGGTYELHVGDTIDLIFNSEHQVLKNNTYWGIILLANPQFISHHHHHH SEQ ID NO:3, respectively transfecting the constructed recombinant plasmid into 293F cells for 7 days, centrifuging the 293 cell expression supernatant sample at a high speed, filtering with a 0.45 mu m filter membrane to remove impurities, balancing a Protein A column with PBS solution, and flushing the column by 2-5 times of column volume. The supernatant samples were loaded onto a column. The column was rinsed with PBS solution until the a280 reading dropped to baseline. The target protein was eluted with 0.1M Citric (pH 3.2) solution and the collected elution peak was neutralized with 1M Tris-HCl (pH 9.0). And replacing the neutralized eluent to PBS solution, and subpackaging the obtained protein for standby after electrophoresis identification. To obtain huGITR with mFc and hFc tag.
After the constructed recombinant plasmid was transfected into 293F cells for 7 days, the 293 cell expression supernatant samples were centrifuged at high speed and filtered through a 0.45 μm filter to remove impurities, and imidazole was added to a final concentration of 5mM. The nickel column was equilibrated with PBS containing 5mM imidazole and washed 2-5 column volumes. The supernatant samples were loaded onto a column. The column was rinsed with PBS solution containing 5mM imidazole until the a280 reading dropped to baseline. The column was washed with PBS+10mM imidazole, nonspecifically bound heteroproteins were removed, and the effluent was collected. The target protein was eluted with a PBS solution containing 500mM imidazole, and the elution peaks were collected. The collected eluent is replaced to PBS solution, and the obtained protein is split into separate packages for standby after electrophoresis identification. Thus, his-tagged huGITRL was obtained.
Example 2: anti-human GITR monoclonal antibody production
Anti-human GITR monoclonal antibodies were generated by immunizing mice. BALB/c white mice for experiments, females, 6 weeks old (animal production license number: 44007200025291, guangdong medical laboratory animal center). Feeding environment: SPF stage. After the mice are purchased, the mice are fed in a laboratory environment for 1 week, the light/dark period is regulated for 12/12 hours, and the temperature is 20-25 ℃; humidity 40-60%,5 groups. The immune antigen is a human GITR recombinant protein with an mFc tag (GITR-mFc). Emulsification with Freund's adjuvant (sigma Lot Num: F5881/F5506): first Freund's complete adjuvant (CFA) was used, and the remainder was used to boost Freund's incomplete adjuvant (IFA). The antigen to adjuvant volume ratio was 1:1, 250 μl/50 μg/dose (priming), 250 μl/50 μg/dose (boosting). The antigen was emulsified and inoculated for days 0, 14, 28, 42. Day 0 subcutaneous (sc) multiple injections of 50-point injection of emulsified post-antigen alone. Back or intraperitoneal injections of antigen were selected on days 14, 28, 42, based on back caking and abdominal swelling. Immunization was boosted 3 days before spleen cell fusion was performed.
Blood tests were performed on days 24, 38 and 52, and the mouse serum was tested by ELISA method of test example 1 to determine the antibody titer in the mouse serum. Selecting a mouse with high antibody titer in serum for spleen cell fusion, and adopting an optimized PEG-mediated fusion step to ensure that spleen lymphocytes and myeloma cells Sp2/0 cells are [ (split-split) in the serum CRL-1581 TM ) And (5) fusing to obtain the hybridoma cells. And tested by ELISA method of example 3, binding assay of example 4 blocking GITRL and cross-binding activity of example 5 with mouse GITR (mouse-GITR), cynomolgus monkey GITR (cyno-GITR), the results are shown in Table 1.
TABLE 1 in vitro Activity of murine antibodies against different germline GITRs
Note that: N/A indicates that it is Not applicable (Not applicable)
Selecting a monoclonal hybridoma cell strain with good in vitro activity, collecting hybridoma cells in logarithmic growth phase, extracting RNA with RNAprep culture cell/bacteria total RNA extraction kit (Tiangen, cat# DP 430) (according to kit specification steps), and reverse transcription (PrimeScript) TM Reverse Transcriptase, takara, cat# 2680A). The cDNA obtained by reverse transcription is subjected to PCR amplification by using a mouse Ig-Primer Set (Novagen, TB326 Rev.B 0503), then is sent to a sequencing company for sequencing, and the repeated or highly similar sequences with the same CDR are removed, so that the mouse monoclonal antibody sequences 8A11, 18F10, 7D9 and 16G9 are obtained.
The heavy and light chain variable region sequences of murine mab 8a11 were as follows:
8A11 HCVR
EVKLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQTPEKRLEWVAYISSGGSTYYPDSVKGRFTISRENARNILYLQMSSLRSEDTAMYYCAREGYGTYGDYWGQGTTLTVSS SEQ ID NO:4
8A11 LCVR
DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYLRTFGGGTKLEIK SEQ ID NO:5
the heavy and light chain variable region sequences of murine mab 18F10 were as follows:
18F10 HCVR
QVQLQQSGAELVRPGVSVKISCKCSGYTFTGYDLHWVKQSHAKSLDWIGVISTYYGDANYNQKFKGKATMTVDKSSSTAYMELARLTSEDSAIYYCTRLAESYFFDYWGQGTTLTVSS SEQ ID NO:6
18F10 LCVR
QILLTQSPAIMSASPGEKVTMTCRASSSVSYIHWYQQKPGSSPKPWIYDTSDLASGFPARFSGTGSGTSYSLIISSMEAEDAATYYCHQRSSYPFTFGSGTKLEIK
SEQ ID NO:7
the heavy and light chain variable region sequences of murine mab 7D9 were as follows:
7D9 HCVR
DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWLGYISYSGSTYYNPSLKSRISLTRDTSKNQFFLQLNSVTSEDTATYYCARWDYRYDGRGFDYWGQGTTLTVSS SEQ ID NO:8
7D9 LCVR
DIQMTQSPSSLSASLGERVSLTCRASQDIGSGLNWLQQEPDGTIKRLIYATSSLDSGVPKRFSGSRSGSDYSLTISSLESEDFVDYNCLQYTSTPWTFGGGTKLEIK
SEQ ID NO:9
the heavy and light chain variable region sequences of murine mab 16G9 were as follows:
16G9 HCVR
QVQLQQSGAELAKPGASVKMSCKASGYTFTTYWIHWIKQRPGQGLEWIGYINPSTGYTDYNQNFKDKATLTADQYSSTAYMQLSSLTFEDSAVYYCANYYGSTPYYWGRGTTLTVSS SEQ ID NO:10
16G9 LCVR
QIVLTQSPAIMSASPGEKVTMTCSASSSVTYVHWYQQKSGASPERWIFDASKLASGVPARFSGSGSGTSYSLTISSMETEDAATYYCQQWSSNPLTFGAGTKLELK
SEQ ID NO:11
Example 3: ELISA binding assay
GITR antibodies block GITR from binding to GITR-related receptors on the cell membrane by binding to GITR, thereby blocking the signaling pathway downstream of GITR. ELISA experiments were used to detect binding characteristics of GITR antibodies. The huGITR-mFc was coated onto an elisa plate and the intensity of the signal after antibody addition was used to determine the binding activity of the antibody to GITR.
huGITR-mFc was diluted to a concentration of 1 μg/ml with CBS buffer ph9.5 and added to 96-well elisa plates at a volume of 50 μl/well and incubated overnight at 4 ℃. After discarding the liquid, 300. Mu.l/well of 1% BSA blocking solution diluted with PBS was added and incubated in an incubator at 37℃for 2.5 hours for blocking. After blocking, the blocking solution was discarded, and after 3 plate washes with PBST buffer (pH 7.4PBS containing 0.05% tween-20), 50. Mu.l/well of the different concentrations of antibody to be tested diluted with the sample dilution was added and incubated in an incubator at 37℃for 30 minutes. After incubation, plates were washed 3 times with PBST, 50. Mu.l/well of HRP-labeled goat anti-human secondary antibody (Jackson Immuno Research, 115-035-088) diluted with sample dilution was added and incubated at 37℃for 30 minutes. After washing the plate 3 times with PBST, 50. Mu.l/well TMB chromogenic substrate was added, incubated at room temperature for 5min, 50. Mu.l/well 1M H was added 2 SO 4 The reaction was terminated, the absorbance was read at 450nm using an MD plus384 microplate reader,analysis of the data with SoftMax pro6.2.1 gave the binding EC50 values of GITR antibodies for GITR, see table 1.
Example 4: anti-GITR antibodies block GITR and GITRL binding assays
GITR can bind to co-receptors of cell surface signaling pathways to inhibit pathway activity. In this example, the screened anti-human GITR antibody was tested for blocking human GITR and human GITRL binding by an in vitro blocking assay. The specific method is that after the huGITR-hFc is coated on a 96-well enzyme label plate, an antibody against GITR protein is added for pre-incubation, and GITRL-his protein is added for co-incubation for 30 minutes. After plate washing, binding signals of GITRL to GITR were detected and data were analyzed for EC50 values of GITR antibodies for GITR active site blocking using SoftMax pro 6.2.1.
huGITR-mFc was diluted to 2 μg/ml with CBS buffer ph9.5 and added to 96-well elisa plates at a volume of 50 μl per well and incubated overnight at 4 ℃. After discarding the liquid, 300. Mu.l/well of 1% BSA blocking solution diluted with PBS was added and incubated in an incubator at 37℃for 2.5 hours for blocking. After blocking was completed, blocking solution was discarded, and after washing the plate 3 times with PBST buffer (PH7.4PBS containing 0.05% tween-20), 50. Mu.l of anti-GITR antibody diluted with sample dilution (PBS pH 7.4) was added for pre-incubation, and then human GITRL-his protein at a concentration of 0.15. Mu.g/ml was added at a volume of 50. Mu.l/well, and after mixing, incubated in an incubator at 37℃for 30 minutes. After the incubation, the reaction solution in the ELISA plate was discarded, and after washing the plate 3 times with PBST, 50. Mu.l/well of HRP-labeled murine anti-his secondary antibody diluted with sample dilution at a concentration of 1:4000 was added and incubated at 37℃for 30 minutes. After washing the plate 3 times with PBST, 50. Mu.l/well TMB chromogenic substrate was added, incubated at room temperature for 5min, 50. Mu.l/well 2M H was added 2 SO 4 The reaction was stopped, the absorbance was read at 450nm by MD plus 384 microplate reader, and the data was analyzed by SoftMax Pro6.2.1 to obtain the EC50 values of the GITR antibody for blocking GITR binding to GITRL, as shown in Table 1.
Example 5: cross-binding experiments of anti-GITR antibodies with different species of GITR
To test the ability of the screened anti-GITR antibodies to bind to GITR of different species sources in vitro, mouse GITR and cynomolgus GITR were used for in vitro binding assays.
The different species of GITR proteins (mouse/cynomolgus GITR) were diluted to 1 μg/ml with PBS buffer at ph9.5, added to 96-well elisa plates at a volume of 50 μl/well and left at 4 ℃ overnight (16-18 hours). The plate was discarded, and 300. Mu.l/well of 1% BSA blocking solution diluted with PBS was added thereto, and the plate was incubated at 37℃for 2.5 hours for blocking. After blocking was completed, blocking solution was discarded, and after washing the plate 3 times with PBST buffer (pH 7.4 PBS containing 0.05% tween-20), 50. Mu.l of GITR test antibodies diluted to different concentrations with sample dilution (pH 7.4 PBS) were added, and incubated in an incubator at 37℃for 30 minutes. After the incubation, the reaction solution in the ELISA plate was discarded, and after washing the plate 3 times with PBST, 50. Mu.l/well of HRP-labeled goat anti-mouse secondary antibody (Jackson ImmunoResearch, 109-035-088) diluted with the sample dilution was added, and incubated at 37℃for 1 hour. After washing the plate 6 times with PBST, 50. Mu.l/well TMB chromogenic substrate (NEOGEN, 308177) was added, incubated at room temperature for 5min, 50. Mu.l/well 2M H was added 2 SO 4 The reaction was stopped and absorbance was read at 450nm using an MD plus 384 microplate reader to calculate the binding EC50 value of the GITR antibody to GITR, as shown in Table 1.
Example 6: in vitro binding affinity and kinetic experiments
The humanized anti-GITR antibodies to be tested and human GITR affinity were measured using a Biacore, GE instrument.
The reaction signal was detected in real time using a Biacore instrument (Biacore T200, GE) using a bio-sensor chip Protein a (cat.# 29-1275-56, GE) of the Biacore instrument (Biacore T200, GE) to affinity capture a certain amount of antibodies to be tested, and then passing GITR antigen (human H-GITR-his antigen selected from the group consisting of sino biological company (cat.# 13643-H08H)) under a series of concentration gradients over the chip surface to obtain binding and dissociation curves. After completion of dissociation in each cycle, the biochip was washed and regenerated with 10mM glycine, pH 1.5. The buffer was PBST, pH7.4. The experimentally obtained data were fitted with Biacore T200 Evaluation 2.0, GE software in the (1:1) Langmuir model to give affinity values, see Table 2.
Example 7: anti-GITR antibody cell Activity assay
This example evaluates GI based on stimulated IL-2 secretion levels by measuring cellular activityIn vitro cellular activity of TR antibodies. Preparing anti-CD 3 (2.0 mug/mL), coating at 50 mug/hole, and coating at 4 ℃ overnight; the next day, anti-GITR antibody was diluted with pre-chilled PBS 300 μl/well once, diluted with PBS at experimental design concentrations, and coated in 96-well plates (50 μl PBS was added to anti-CD 3 reference wells) at 37 ℃,5% co 2 3h (300. Mu.L PBS was added to the periphery of 96 well plates); washing with 300. Mu.L/well pre-chilled PBS once (anti-CD 28 wells without washing), freshly isolating or resuscitating cells (PBMC) in 10% RPMI 1640Medium (resuscitated cells need to be incubated at 37℃for 2-3 h), adding 200. Mu.L of cell suspension at a density of 6X 10 to 96 well cell culture plates 5 cells/mL, 10% RPMI 1640Medium (wells co-stimulated with anti-CD 28 with 2.0. Mu.g/mL of anti-CD 28 antibody: wells coated with anti-CD 3 but not with anti-GITR antibody) were incubated in an incubator for 48 hours (37 ℃,5% CO) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the The cell supernatant was collected by centrifugation at 110. Mu.L/well, and the IL-2 content was measured using an IL-2ELISA kit. The results of the in vitro cell activity assay for each murine antibody are shown in FIG. 1, where 8A11, 18F10 and 20H11 are functionally active and superior to the reference antibody BMAB (Merck MK-4166 antibody).
Example 8: mouse antibody humanization experiments
In this example, two strains (8A 11 and 18F 10) having the strongest functional activities among the obtained murine antibodies were humanized. Based on the obtained typical structure of the VH/VLCDR of the murine antibody, the heavy and light chain variable region sequences are compared with an antibody Germline database to obtain the human Germline template with high homology. Wherein the human germline light chain framework region is derived from a human kappa light chain gene, the antibodies of the invention are preferably human germline light chain templates IGKV4-1 x 01 (8 a 11) and IGKV3-11 x 01 (18F 10). Human germline heavy chain framework regions are derived from human heavy chains, and antibodies of the invention are preferably human germline heavy chain templates IGHV3-48 x 03 (8 a 11) and IGHV1-2 x 02 (18F 10).
Human germline heavy chain template IGHV3-48 x 03 (SEQ ID NO: 12):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYEMNWVRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR
human germline light chain template IGKV4-1 x 01 (SEQ ID NO: 13):
DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTP
human germline heavy chain template IGHV1-2 x 02 (SEQ ID NO: 14):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCAR
human germline light chain template IGKV3-11 x 01 (SEQ ID NO: 15):
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWP
the CDR regions of the murine antibodies were grafted onto selected humanized templates, substituted for humanized variable regions, and recombined with IgG constant regions. Then, based on the three-dimensional structure of the murine antibody, the embedded residues, the residues with direct interaction with the CDR region, and the residues with important influence on the conformation of VL and VH are subjected to back mutation, and the amino acid residues in the CDR region are adjusted and optimized to obtain a series of humanized molecules. The heavy chain variable region and the light chain variable region are shown in SEQ ID NO. 16-27.
hu8A11-VH-a(SEQ ID NO:16):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQTPGKRLEWVAYISSGGSTYYPDSVKGRFTISRENAKNILYLQMNSLRAEDTAVYYCAREGYGTYGDYWGQGTTLTVSS
hu8A11-VH-b(SEQ ID NO:17):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVAYISSGGSTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYGTYGDYWGQGTTLTVSS
hu8A11-VH-c(SEQ ID NO:18):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSYISSGGSTYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYGTYGDYWGQGTTLTVSS
hu8A11-VL-a(SEQ ID NO:19):
DIVMTQSPSSLAVSVGERVTMSCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDLAVYYCQQYYSYLRTFGGGTKLEIK
hu8A11-VL-b(SEQ ID NO:20):
DIVMTQSPSSLAVSVGERVTISCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYLRTFGGGTKLEIK
hu8A11-VL-c(SEQ ID NO:21):
DIVMTQSPSSLAVSVGERVTISCKSSQSLLYSTNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYLRTFGGGTKLEIK
hu18F10-VH-a(SEQ ID NO:22):
QVQLVQSGAEVVKPGASVKISCKASGYTFTGYDLHWVKQAHGQGLDWIGVISTYYGDATYNQKFQGRATMTVDTSSSTAYMELSRLTSEDTAVYYCTRLAESYFFDYWGQGTTLTVSS
hu18F10-VH-b(SEQ ID NO:23):
QVQLVQSGAEVVKPGASVKVSCKASGYTFTGYDLHWVRQAPGQGLEWIGVISTYYGDANYNQKFQGRVTMTVDTSSSTAYMELSRLRSEDTAVYYCTRLAESYFFDYWGQGTTLTVSS
hu18F10-VH-c(SEQ ID NO:24):
QVQLVQSGAEVVKPGASVKVSCKASGYTFTGYDLHWVRQAPGQGLEWIGVISTYYGDANYNQKFQGRVTMTVDTSISTAYMELSRLRSEDTAVYYCTRLAESYFFDYWGQGTTLTVSS
hu18F10-VL-a(SEQ ID NO:25):
QIVLTQSPATLSASPGERVTMTCRASSSVSYIHWYQQKPGQAPKPWIYDTSNLASGFPARFSGDGSGTDYSLIISSMEAEDAATYYCHQRSSYPFTFGSGTKLEIK
hu18F10-VL-b(SEQ ID NO:26):
EIVLTQSPATLSASPGERVTLTCRASSSVSYLHWYQQKPGQAPKPWIYDTSDLASGFPARFSGDGSGTDYTLTISSLEAEDAAVYYCHQRSSYPFTFGSGTKLEIK
hu18F10-VL-c(SEQ ID NO:27):
EIVLTQSPATLSASPGERVTLTCRASSSVSYLHWYQQKPGQAPKPLIYDTSDLASGIPARFSGDGSGTDYTLTISSLEAEDAAVYYCHQRSSYPFTFGSGTKLEIK
The final humanized hu8A11 (using VH-b heavy and VL-b light chains) and hu18F10 antibody molecules (using VH-b heavy and VL-b light chains) were comprehensively evaluated and selected via the antibody miniexpression test and back mutation number comparison of each light and heavy chain combination above, with their respective complete light and heavy chain sequences as shown in SEQ ID NOS 28-31.
hu8A11 HC
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVAYISSGGSTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYGTYGDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQID NO:28
hu8A11 LC
DIVMTQSPSSLAVSVGERVTISCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSYLRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO:29
hu18F10 HC
QVQLVQSGAEVVKPGASVKVSCKASGYTFTGYDLHWVRQAPGQGLEWIGVISTYYGDANYNQKFQGRVTMTVDTSSSTAYMELSRLRSEDTAVYYCTRLAESYFFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQID NO:30
hu18F10 LC
EIVLTQSPATLSASPGERVTLTCRASSSVSYLHWYQQKPGQAPKPWIYDTSDLASGFPARFSGDGSGTDYTLTISSLEAEDAAVYYCHQRSSYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Seq id NO:31 example 9: humanized antibody Activity test data
And combining the constructed humanized recombinant heavy chain and light chain plasmids (molar ratio 1:1), respectively transfecting HEK293F cells for 7 days, centrifuging the 293 cell expression supernatant sample at a high speed, filtering with a 0.45 mu m filter membrane to remove impurities, balancing a Protein A column with PBS solution, and flushing 2-5 times of column volume. The supernatant samples were loaded onto a column. The column was rinsed with PBS solution until the a280 reading dropped to baseline. The target protein was eluted with 0.1M Citric (pH 3.2) solution and the collected elution peak was neutralized with 1M Tris-HCl (pH 9.0). The neutralized eluent is replaced to PBS solution, and the obtained protein is split and reserved after being identified by SEC-HPLC.
The final humanized versions of antibody molecules hu8a11 and hu18F10 were tested by the in vitro binding affinity and kinetic experiments of example 6 and the cell activity experiments of example 7 and compared to the Merck reference antibody BMAB, the results are shown in table 2 and figure 2, respectively.
TABLE 2 in vitro affinity kinetic data for humanized antibodies
The above results show that the humanized anti-human GITR antibodies of the present invention retain the binding activity prior to humanization, possess comparable BMAB reference, and have strong in vitro binding affinity.
Example 10: inhibition of tumor cell growth by anti-GITR antibody hu8a11
Peripheral blood of normal human was collected and PBMCs of healthy human were isolated by density gradient centrifugation. Monocytes were sorted using the cd14+ microblads kit and mixed with a375 melanoma cells (cell bank from Shanghai department, cultured in DMEM medium with 10% fetal bovine serum) and inoculated subcutaneously into each NCG mouse (university of south-Beijing-biomedical institute, adaptive feeding for 5 days). The experimental animals are all fed in independent ventilating boxes with constant temperature and humidity, the temperature of the feeding room is 18.0-26.0 ℃, the humidity is 40-70%, ventilation is performed for 10-20 times per hour, and the day and night light and shade alternation time is 12h/12h.
The experiments were divided into a control group of human IgG1 antibodies, three constant dose hu8a11 groups (250 μg,500 μg,1000 μg) and a reference antibody BMAB group (1000 μg). 8 mice per group were given subcutaneously. Throughout the experiment, tumor length and width were measured 2 times per week with vernier calipers.
Tumor volume (mm) 3 ) =0.5× (tumor long diameter×tumor short diameter 2 )
Relative tumor inhibition rate TGI (%): TGI% = (1-T/C) ×100%
T/C% is the relative tumor proliferation rate, i.e., the percentage value of the treated and control groups relative to the tumor volume or tumor weight at a certain time point. T and C are Tumor Volume (TV) or Tumor Weight (TW) at a particular time point in the treatment group and IgG1 control group, respectively.
The results are shown in table 3, fig. 3 and fig. 4, where humanized anti-GITR antibody hu8a11 had a significant tumor-inhibiting effect relative to IgG1 control, and the tumor-inhibiting effect was significantly greater than that of the same dose of reference antibody BMAB.
TABLE 3 NCG mice bearing tumor growth (mm) of A375 melanoma co-transplanted with human PBMC 3 )
Example 11: screening of anti-GITR antibody preparation buffer System
An anti-GITR antibody (hu 8a11, the same applies as follows) formulation was formulated at an antibody concentration of 50mg/ml with the following buffers:
1) 10mM acetic acid-sodium acetate, pH 5.0
2) 10mM acetic acid-sodium acetate, pH 5.5
3) 10mM sodium succinate, pH 5.0
4) 10mM sodium succinate, pH 5.5
5) 10mM sodium succinate, pH 6.0
6) 10mM citric acid-sodium citrate, pH 5.0
7) 10mM citric acid-sodium citrate, pH 5.5
8) 10mM citric acid-sodium citrate, pH 6.0
9) 10mM citric acid-sodium citrate, pH 6.5
10 10mM histidine-HCl, pH 6.0
11 10mM histidine-HCl, pH 6.5.
The samples were subjected to high temperature (40 ℃) stability studies using Size Exclusion Chromatography (SEC), non-reduced protein capillary electrophoresis (NR-CE) and whole column Imaging Capillary Electrophoresis (ICE) as evaluation criteria, and the test results are shown in Table 4, wherein the anti-GITR antibody preferably had a buffer system of 10mM acetic acid-sodium acetate and 10mM histidine-hydrochloric acid, and a pH range of 5.5 to 6.5. The anti-GITR antibody stability buffer system may be selected from histidine buffer or acetate buffer, e.g., histidine-acetate buffer, acetate-sodium acetate buffer, histidine-hydrochloric acid buffer, in combination with the pH range.
TABLE 4 pH screening results for anti-GITR antibodies
Note that: m represents a month, for example M1 represents 1 month; d represents a day.
Example 12: screening of stabilizers in anti-GITR antibody formulations
anti-GITR antibody formulations were prepared at antibody concentrations of 50mg/ml with different sugars and buffers:
1) 10mM acetic acid-sodium acetate pH 5.5, 80mg/ml sucrose;
2) 10mM acetic acid-sodium acetate pH 5.5, 80mg/ml alpha, alpha-trehalose dihydrate;
the prepared preparation samples are respectively subjected to high-temperature (40 ℃) and low-temperature illumination (5+/-3 ℃,4500 lx) stability study, the results are shown in Table 5, and the results show that sucrose and trehalose have stabilizing effects on anti-GITR antibodies and can be used as stabilizers of the anti-GITR antibodies. Wherein the osmotic pressure is about 300mosm/kg at a sucrose concentration of 80mg/ml, which is approximately isotonic, and thus an alternative sucrose concentration of 80mg/ml.
TABLE 5 results of stabilizer screening experiments
Note that: d represents day, e.g. D10 represents day 10; m represents a month, for example M1 represents 1 month.
Example 13: screening of surfactants in anti-GITR antibody formulations
An anti-GITR antibody preparation having a sucrose concentration of 80mg/ml and an antibody concentration of 50mg/ml was prepared using the following different types and concentrations of surfactants:
1) 10mM acetic acid-sodium acetate pH 5.5;
2) 10mM acetic acid-sodium acetate pH 5.5,0.2mg/ml polysorbate 80;
3) 10mM acetic acid-sodium acetate pH 5.5,0.4mg/ml polysorbate 80;
4) 10mM acetic acid-sodium acetate pH 5.5,0.6mg/ml polysorbate 80;
5) 10mM acetic acid-sodium acetate pH 5.5,0.4mg/ml polysorbate 20.
The 1-5 groups of anti-GITR antibody preparation samples prepared according to the above method were diluted to 0.9% sodium chloride injection, respectively, the protein concentration was diluted to 0.5mg/ml, and insoluble microparticles after dilution were observed for each group of samples. The results of the experiment are shown in Table 6, which shows that polysorbate 80 has good stability against the GITR antibody, so that polysorbate 80 is selected as the surfactant of the anti-GITR antibody, and the concentration can be between 0.2 and 0.6 mg/ml.
TABLE 6 Polysorbate screening-dilution results for anti-GITR antibodies
Example 14: buffer ionic strength screening in anti-GITR antibody formulations
anti-GITR antibody formulations with sucrose concentration of 80mg/ml and antibody concentration of 50mg/ml were prepared using the following histidine-acetic acid buffers of different ionic strengths and pH 6.0:
1) 10mM histidine-acetic acid pH 6.0;
2) 20mM histidine-acetic acid pH 6.0;
3) 30mM histidine-acetic acid pH 6.0;
the pH values of the samples before and after the replacement are measured by adopting 6 times of volume replacement of the membrane package, so that the sample buffer solution is the buffer solution with the 3 ionic strengths, the results are shown in Table 7, and the results show that the pH values of the samples after the replacement of the buffer solutions with different ionic strengths are basically consistent, which shows that the buffer capacity of the 10 mM-30 mM ionic strength buffer solution is enough, so that the 10mM ionic strength can be selected.
TABLE 7 results of anti-GITR antibody buffer ion intensity screening
Sequence number | pH after substitution |
1 | 6.12 |
2 | 6.11 |
3 | 6.09 |
Example 15: comprehensive screening of formulation ingredients
In order to further optimize the protein concentration, polysorbate 80 concentration, and pH, the DOE experimental design was performed using JMP software, and a series of prescriptions were obtained using RSM model, and 10mM histidine-acetic acid system was prepared in buffers containing the following different polysorbate 80 concentrations, different pH, at 80mg/ml sucrose, as anti-GITR antibody formulations at different concentrations:
1) 10mM histidine-acetic acid pH 6.0, 50mg/ml GITR antibody, 0.5mg/ml polysorbate 80;
2) 10mM histidine-acetic acid pH 6.5, 40mg/ml GITR antibody, 0.8mg/ml polysorbate 80;
3) 10mM histidine-acetic acid pH 6.0, 50mg/ml GITR antibody, 0.2mg/ml polysorbate 80;
4) 10mM histidine-acetic acid pH 5.5, 60mg/ml GITR antibody, 0.8mg/ml polysorbate 80;
5) 10mM histidine-acetic acid pH 6.5, 40mg/ml GITR antibody, 0.2mg/ml polysorbate 80;
6) 10mM histidine-acetic acid pH 6.0, 60mg/ml GITR antibody, 0.5mg/ml polysorbate 80;
7) 10mM histidine-acetic acid pH 5.5, 60mg/ml GITR antibody, 0.2mg/ml polysorbate 80;
8) 10mM histidine-acetic acid pH 6.5, 60mg/ml GITR antibody, 0.2mg/ml polysorbate 80;
9) 10mM histidine-acetic acid pH 6.0, 50mg/ml GITR antibody, 0.8mg/ml polysorbate 80;
10 10mM histidine-acetate pH 5.5, 50mg/ml GITR antibody, 0.5mg/ml polysorbate 80;
11 10mM histidine-acetic acid pH 6.0, 40mg/ml GITR antibody, 0.5mg/ml polysorbate 80;
12 10mM histidine-acetate pH 5.5, 40mg/ml GITR antibody, 0.8mg/ml polysorbate 80;
13 10mM histidine-acetate pH 5.5, 40mg/ml GITR antibody, 0.2mg/ml polysorbate 80;
14 10mM histidine-acetate pH 6.5, 50mg/ml GITR antibody, 0.5mg/ml polysorbate 80;
15 10mM histidine-acetic acid pH 6.5, 60mg/ml GITR antibody, 0.8mg/ml polysorbate 80.
The 1-15 groups of anti-GITR antibody preparation samples prepared according to the method are stored at 40 ℃ for stability analysis, the difference value of neutral peaks and the difference value of acidic peaks of appearance, SEC and ICE are taken as evaluation indexes, the results are subjected to statistical analysis by a least square method, the test results are shown in Table 8, and the results show that a 10mM pH 6.0 histidine-acetic acid system containing 0.4mg/ml polysorbate 80 is more beneficial to the stability of the anti-GITR antibody, the protein concentration is more stable between 40 mg/ml and 60mg/ml, and 50mg/ml of the median value is taken as the final protein concentration of the anti-GITR antibody.
TABLE 8 results of high temperature storage stability experiments for GITR antibodies
Note that: m represents a month, for example M1 represents 1 month; d represents a day.
Example 16: lyophilization of anti-GITR antibody formulations
anti-GITR antibody formulations were prepared at concentrations of 50mg/ml with 10mM histidine-acetic acid buffer, pH 6.0 or pH5.8, containing 80mg/ml sucrose, 0.4mg/ml polysorbate 80. The antibody was filled into 6mL penicillin bottles at 2.15 mL/bottle, filled into lyophilization boxes, and lyophilized. The lyophilization procedure is prefreezing, primary drying and secondary drying. After the lyophilization procedure was completed, vacuum stoppered. The reconstituted samples were subjected to lyophilization before and after comparison. The results show that the reconstituted solution can maintain good performance of the liquid formulation.
Table 9 lyophilization step of the formulations
Note that: N/A indicates that it is Not applicable (Not applicable)
Example 17: other alternative formulation formulations
In addition, the invention provides anti-GITR antibody pharmaceutical formulations of other formulation formulations, including but not limited to:
(1) 100mg/ml anti-GITR antibody, 150mg/ml sucrose, 0.7mg/ml polysorbate 80, and 40mM histidine-acetate buffer at pH 6.0;
(2) 1mg/ml GITR antibody, 70mg/ml sucrose, 0.3mg/ml polysorbate 80, and 5mM histidine-acetate buffer at pH 5.6;
(3) 50mg/ml GITR antibody, 90mg/ml sucrose, 0.6mg/ml polysorbate 80, and 10mM histidine-acetate buffer at pH 6.5;
(4) 100mg/ml GITR antibody, 110mg/ml trehalose, 0.6mg/ml polysorbate 80, and 10mM acetic acid-sodium acetate buffer at pH 5.5;
(5) 60mg/ml GITR antibody, 120mg/ml sucrose, 0.4mg/ml polysorbate 80, and 20mM acetic acid-sodium acetate buffer at pH 5.7;
(6) 90mg/ml of GITR antibody, 90mg/ml trehalose, 0.6mg/ml polysorbate 80, and 10mM acetic acid-sodium acetate buffer at pH 5.6;
(7) 40mg/ml GITR antibody, 70mg/ml sucrose, 0.2mg/ml polysorbate 80, and 10mM acetic acid-sodium acetate buffer at pH 5.8;
(8) 70mg/ml GITR antibody, 75mg/ml sucrose, 0.8mg/ml polysorbate 80, and 30mM acetic acid-sodium acetate buffer at pH 6.0;
(9) 50mg/ml GITR antibody, 90mg/ml sucrose, 0.5mg/ml polysorbate 80, and 30mM acetic acid-sodium acetate buffer at pH 5.5;
(10) 30mg/ml GITR antibody, 90mg/ml trehalose, 0.5mg/ml polysorbate 80, and 20mM acetic acid-sodium acetate buffer at pH 6.0;
(11) 80mg/ml GITR antibody, 80mg/ml sucrose, 0.6mg/ml polysorbate 80, and 10mM histidine-hcl buffer at pH 5.5;
(12) 60mg/ml GITR antibody, 85mg/ml sucrose, 0.6mg/ml polysorbate 80, and 10mM histidine-hcl buffer at pH 5.6;
(13) 40mg/ml GITR antibody, 120mg/ml sucrose, 0.4mg/ml polysorbate 80, and 20mM histidine-HCl buffer at pH 5.8;
(14) 50mg/ml GITR antibody, 100mg/ml trehalose, 0.7mg/ml polysorbate 80, and 10mM histidine-HCl buffer at pH 5.9;
(15) 10mg/ml GITR antibody, 80mg/ml trehalose, 0.6mg/ml polysorbate 80, and 10mM histidine-hcl buffer at pH 6.0;
(16) 100mg/ml GITR antibody, 150mg/ml trehalose, 0.6mg/ml polysorbate 80, and 10mM histidine-hcl buffer at pH 6.1;
(17) 70mg/ml GITR antibody, 130mg/ml trehalose, 0.5mg/ml polysorbate 80, and 20mM histidine-hcl buffer at pH 6.2;
(18) 85mg/ml GITR antibody, 140mg/ml trehalose, 0.5mg/ml polysorbate 80, and 30mM histidine-hcl buffer at pH 6.5;
(19) 0.5mg/ml GITR antibody, 80mg/ml trehalose, 0.6mg/ml polysorbate 80, and 30mM histidine-HCl buffer at pH 6.0.
Sequence listing
<110> Jiangsu Hengrui medical Co., ltd., shanghai Hengrui medical Co., ltd
<120> an anti-GITR antibody pharmaceutical composition and use thereof
<130> 390273CG-380336
<150> 201811653884.5
<151> 2018-12-29
<160> 31
<170> SIPOSequenceListing 1.0
<210> 1
<211> 403
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> huGITR-mFc sequence
<400> 1
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu Pro Lys Leu Glu Asn Leu Tyr Phe Gln Gly Pro Arg Gly Pro Thr
165 170 175
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
180 185 190
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
195 200 205
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu
210 215 220
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
225 230 235 240
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu
245 250 255
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
260 265 270
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
275 280 285
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
290 295 300
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
305 310 315 320
Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
325 330 335
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
340 345 350
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
355 360 365
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
370 375 380
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
385 390 395 400
Pro Gly Lys
<210> 2
<211> 396
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> huGITR-hFc sequence
<400> 2
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu Pro Lys Leu Glu Asn Leu Tyr Phe Gln Gly Thr His Thr Cys Pro
165 170 175
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
180 185 190
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
195 200 205
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
210 215 220
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
225 230 235 240
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
245 250 255
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
260 265 270
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
275 280 285
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
290 295 300
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
305 310 315 320
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
325 330 335
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
340 345 350
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
355 360 365
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
370 375 380
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
385 390 395
<210> 3
<211> 159
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> huGITRL-His6 sequence
<400> 3
Met Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser Leu Val Leu Ala
1 5 10 15
Leu Leu Phe Pro Ser Met Ala Ser Met Gln Leu Glu Thr Ala Lys Glu
20 25 30
Pro Cys Met Ala Lys Phe Gly Pro Leu Pro Ser Lys Trp Gln Met Ala
35 40 45
Ser Ser Glu Pro Pro Cys Val Asn Lys Val Ser Asp Trp Lys Leu Glu
50 55 60
Ile Leu Gln Asn Gly Leu Tyr Leu Ile Tyr Gly Gln Val Ala Pro Asn
65 70 75 80
Ala Asn Tyr Asn Asp Val Ala Pro Phe Glu Val Arg Leu Tyr Lys Asn
85 90 95
Lys Asp Met Ile Gln Thr Leu Thr Asn Lys Ser Lys Ile Gln Asn Val
100 105 110
Gly Gly Thr Tyr Glu Leu His Val Gly Asp Thr Ile Asp Leu Ile Phe
115 120 125
Asn Ser Glu His Gln Val Leu Lys Asn Asn Thr Tyr Trp Gly Ile Ile
130 135 140
Leu Leu Ala Asn Pro Gln Phe Ile Ser His His His His His His
145 150 155
<210> 4
<211> 117
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> 8A11 HCVR sequence
<400> 4
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Tyr Gly Thr Tyr Gly Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 5
<211> 113
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> 8A11 LCVR sequence
<400> 5
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Thr Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 6
<211> 118
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> 18F10 HCVR sequence
<400> 6
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Cys Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Asp Leu His Trp Val Lys Gln Ser His Ala Lys Ser Leu Asp Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ala Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Thr Arg Leu Ala Glu Ser Tyr Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 7
<211> 106
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> 18F10 LCVR sequence
<400> 7
Gln Ile Leu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Asp Thr Ser Asp Leu Ala Ser Gly Phe Pro Ala Arg Phe Ser Gly Thr
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Ile Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Ser Ser Tyr Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 8
<211> 121
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> 7D9 HCVR sequence
<400> 8
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Leu Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Leu Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Tyr Arg Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 9
<211> 107
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> 7D9 LCVR sequence
<400> 9
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ser Gly
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Asn Cys Leu Gln Tyr Thr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 10
<211> 117
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> 16G9 HCVR sequence
<400> 10
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Trp Ile His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Thr Gly Tyr Thr Asp Tyr Asn Gln Asn Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Gln Tyr Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Phe Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Tyr Tyr Gly Ser Thr Pro Tyr Tyr Trp Gly Arg Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 11
<211> 106
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> 16G9 LCVR sequence
<400> 11
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Val
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Glu Arg Trp Ile Phe
35 40 45
Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Thr Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 12
<211> 98
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> human germline heavy chain template IGHV3-48 x 03 sequences
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg
<210> 13
<211> 101
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> human germline light chain template IGKV4-1 x 01 sequence
<400> 13
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Thr Pro
100
<210> 14
<211> 98
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> human germline heavy chain template IGHV1-2 x 02 sequences
<400> 14
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg
<210> 15
<211> 95
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> human germline light chain template IGKV3-11 x 01 sequence
<400> 15
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro
85 90 95
<210> 16
<211> 117
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu8A11-VH-a sequence
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Tyr Gly Thr Tyr Gly Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 17
<211> 117
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu8A11-VH-b sequence
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Tyr Gly Thr Tyr Gly Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 18
<211> 117
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu8A11-VH-c sequence
<400> 18
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Tyr Gly Thr Tyr Gly Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 19
<211> 113
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu8A11-VL-a sequence
<400> 19
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Thr Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 20
<211> 113
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu8A11-VL-b sequence
<400> 20
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Thr Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 21
<211> 113
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu8A11-VL-c sequence
<400> 21
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Thr Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 22
<211> 118
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu18F10-VH-a sequence
<400> 22
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Asp Leu His Trp Val Lys Gln Ala His Gly Gln Gly Leu Asp Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ala Thr Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Leu Ala Glu Ser Tyr Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 23
<211> 118
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu18F10-VH-b sequence
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Asp Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ala Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Leu Ala Glu Ser Tyr Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 24
<211> 118
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu18F10-VH-c sequence
<400> 24
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Asp Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ala Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Leu Ala Glu Ser Tyr Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 25
<211> 106
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu18F10-VL-a sequence
<400> 25
Gln Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Pro Trp Ile Tyr
35 40 45
Asp Thr Ser Asn Leu Ala Ser Gly Phe Pro Ala Arg Phe Ser Gly Asp
50 55 60
Gly Ser Gly Thr Asp Tyr Ser Leu Ile Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Ser Ser Tyr Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 26
<211> 106
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu18F10-VL-b sequence
<400> 26
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Leu
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Pro Trp Ile Tyr
35 40 45
Asp Thr Ser Asp Leu Ala Ser Gly Phe Pro Ala Arg Phe Ser Gly Asp
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Ala Glu
65 70 75 80
Asp Ala Ala Val Tyr Tyr Cys His Gln Arg Ser Ser Tyr Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 27
<211> 106
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu18F10-VL-c sequence
<400> 27
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Leu
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Pro Leu Ile Tyr
35 40 45
Asp Thr Ser Asp Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Asp
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Ala Glu
65 70 75 80
Asp Ala Ala Val Tyr Tyr Cys His Gln Arg Ser Ser Tyr Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 28
<211> 447
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu8A11 HC sequence
<400> 28
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Tyr Gly Thr Tyr Gly Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 29
<211> 220
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu8A11 LC sequence
<400> 29
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Thr Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 30
<211> 448
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu18F10 HC sequence
<400> 30
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Asp Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ala Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Leu Ala Glu Ser Tyr Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 31
<211> 213
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> DOMAIN
<223> hu18F10 LC sequence
<400> 31
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Leu
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Pro Trp Ile Tyr
35 40 45
Asp Thr Ser Asp Leu Ala Ser Gly Phe Pro Ala Arg Phe Ser Gly Asp
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Ala Glu
65 70 75 80
Asp Ala Ala Val Tyr Tyr Cys His Gln Arg Ser Ser Tyr Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
Claims (30)
1. A pharmaceutical composition comprising an anti-GITR antibody or antigen-binding fragment thereof, and a buffer selected from a histidine buffer or an acetate buffer;
the histidine buffer is histidine-acetic acid buffer or histidine-hydrochloric acid buffer with the pH of 5.5 to 6.5, or the acetate buffer is acetic acid-sodium acetate buffer with the pH of 5.0 to 5.5;
the anti-GITR antibody or antigen-binding fragment thereof comprises: the sequence is shown in SEQ ID NO:17, and a heavy chain variable region having the sequence set forth in SEQ ID NO:20, and a light chain variable region shown in seq id no;
the concentration of the anti-GITR antibody or antigen-binding fragment thereof is 40mg/ml to 60mg/ml.
2. The pharmaceutical composition of claim 1, wherein the pH of the acetic acid-sodium acetate buffer is 5.5.
3. The pharmaceutical composition of claim 1, wherein the histidine-acetic buffer has a pH of 5.5 to 6.5.
4. The pharmaceutical composition of claim 3, wherein the histidine-acetate buffer has a pH of 5.8 to 6.2.
5. The pharmaceutical composition of claim 1, wherein the buffer concentration is 5mM to 40mM.
6. The pharmaceutical composition of claim 5, wherein the buffer concentration is 10mM to 30mM.
7. The pharmaceutical composition of claim 5, wherein the buffer concentration is 10mM.
8. The pharmaceutical composition of claim 1, wherein the anti-GITR antibody or antigen-binding fragment thereof is at a concentration of 50mg/ml.
9. The pharmaceutical composition of claim 1, further comprising a sugar.
10. The pharmaceutical composition of claim 9, wherein the sugar is trehalose or sucrose.
11. The pharmaceutical composition of claim 9, wherein the sugar is sucrose.
12. The pharmaceutical composition of claim 9, wherein the sugar concentration is 70mg/ml to 150mg/ml.
13. The pharmaceutical composition of claim 12, wherein the sugar concentration is 70mg/ml to 90mg/ml.
14. The pharmaceutical composition of claim 12, wherein the sugar concentration is 80mg/ml.
15. The pharmaceutical composition of claim 1, further comprising a surfactant that is polysorbate 80.
16. The pharmaceutical composition of claim 15, wherein the concentration of polysorbate 80 is 0.2mg/ml to 0.8mg/ml.
17. The pharmaceutical composition of claim 16, wherein the concentration of polysorbate 80 is 0.2mg/ml to 0.6mg/ml.
18. The pharmaceutical composition of claim 16, wherein the concentration of polysorbate 80 is 0.4mg/ml.
19. The pharmaceutical composition according to claim 1, comprising:
a) 40mg/ml to 60mg/ml of an anti-GITR antibody or an antigen-binding fragment thereof,
b) 5mM to 40mM histidine-acetic acid buffer or histidine-hydrochloric acid buffer at pH 5.5 to 6.5 or acetic acid-sodium acetate buffer at pH 5.0 to 5.5,
c) 70mg/ml to 150mg/ml of sucrose, and
d) 0.2mg/ml to 0.8mg/ml polysorbate 80.
20. The pharmaceutical composition according to claim 19, comprising:
a) 40mg/ml to 60mg/ml of an anti-GITR antibody or an antigen-binding fragment thereof,
b) 10mM to 30mM histidine-acetate buffer at pH 5.5 to 6.5,
c) 70mg/ml to 90mg/ml sucrose, and
d) 0.2mg/ml to 0.6mg/ml polysorbate 80.
21. A pharmaceutical composition comprising: 10mM histidine-acetic buffer pH 5.8 to 6.2, 50mg/ml anti-GITR antibody, 80mg/ml sucrose, and 0.4mg/ml polysorbate 80;
the anti-GITR antibody comprises: the sequence is shown in SEQ ID NO:17, and a heavy chain variable region having the sequence set forth in SEQ ID NO:20, and a light chain variable region shown in seq id no.
22. The pharmaceutical composition of claim 1, wherein the anti-GITR antibody or antigen-binding fragment thereof further comprises a constant region.
23. The pharmaceutical composition of claim 22, wherein the antibody heavy chain constant region is derived from a human IgG1, igG2, igG3 or IgG4 and the light chain constant region is derived from a human kappa, lambda chain.
24. The pharmaceutical composition of claim 1, wherein the anti-GITR antibody or antigen-binding fragment thereof comprises: the sequence is shown in SEQ ID NO:28, and the sequence set forth in SEQ ID NO:29, and a full-length sequence of the light chain shown in seq id no.
25. A method of preparing the pharmaceutical composition of any one of claims 1-24, comprising the step of mixing an anti-GITR antibody or antigen-binding fragment thereof with a pharmaceutically acceptable excipient.
26. A lyophilized formulation comprising an anti-GITR antibody or antigen-binding fragment thereof, obtained by lyophilizing the pharmaceutical composition of any one of claims 1-24.
27. A reconstituted solution comprising an anti-GITR antibody or antigen-binding fragment thereof, the reconstituted solution being obtained by reconstitution of the lyophilized formulation of claim 26.
28. A lyophilized formulation comprising an anti-GITR antibody or antigen-binding fragment thereof, which is reconstituted to form the pharmaceutical composition of any one of claims 1-24.
29. An article of manufacture comprising a container containing a pharmaceutical composition according to any one of claims 1 to 24, or a lyophilized formulation according to claim 26 or 28, or a reconstituted solution according to claim 27.
30. Use of a pharmaceutical composition according to any one of claims 1 to 24, or a lyophilized formulation according to claim 26 or 28, or a reconstituted solution according to claim 27, or an article according to claim 29, in the manufacture of a medicament for the treatment of cancer;
Wherein the cancer is selected from the group consisting of melanoma, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, renal cancer, lung cancer, liver cancer, stomach cancer, colorectal cancer, bladder cancer, esophageal cancer, cervical cancer, gall bladder cancer, and glioblastoma.
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CN105829343A (en) * | 2013-08-30 | 2016-08-03 | 美国安进公司 | Gitr antigen binding proteins |
WO2017096276A1 (en) * | 2015-12-02 | 2017-06-08 | Agenus Inc. | Anti-gitr antibodies and methods of use thereof |
CA3042727A1 (en) * | 2016-11-19 | 2018-05-24 | Potenza Therapeutics, Inc. | Anti-gitr antigen-binding proteins and methods of use thereof |
CN108883173A (en) * | 2015-12-02 | 2018-11-23 | 阿吉纳斯公司 | Antibody and its application method |
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CN105829343A (en) * | 2013-08-30 | 2016-08-03 | 美国安进公司 | Gitr antigen binding proteins |
WO2017096276A1 (en) * | 2015-12-02 | 2017-06-08 | Agenus Inc. | Anti-gitr antibodies and methods of use thereof |
CN108883173A (en) * | 2015-12-02 | 2018-11-23 | 阿吉纳斯公司 | Antibody and its application method |
CA3042727A1 (en) * | 2016-11-19 | 2018-05-24 | Potenza Therapeutics, Inc. | Anti-gitr antigen-binding proteins and methods of use thereof |
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