Antibody-polymer-conjugates

Abstract

To provide antibody-polymer conjugates which have high drug carrying capacity and which can realize active targeting thanks to the antibody existing thereon.SOLUTION: An antibody-polymer conjugate in the form of a random copolymer of formula 1 is provided, wherein A is a monoclonal antibody, D is a therapeutic agent, L1 is a cleavable linker, and L2 is a cleavable or non-cleavable linker.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to antibody-polymer conjugates that have high drug carrying capacity and can achieve active targeting by the antibody present thereon. [Background technology]

[0002] The conjugation of humanized or non-humanized monoclonal antibodies to cytotoxic small molecule drugs through chemical bonds represents a significant change in the design of cancer chemotherapy. (Chari et al,2014; Perez et al,2014;Bouchard et al,2014;Jain et al,2015;McCombs and Owen,2015;Chudasama et al.,2016;Diamantis and Banerji,2016).

[0003] The most important advantages offered by antibody-drug conjugates are the possibility of target-specific therapy, low cytotoxicity to non-target healthy cells, and low immunogenicity.

[0004] In preparing antibody-drug conjugates, cleavable bonds such as hydrazones and disulfides can be used, as well as non-cleavable bonds such as amides.

[0005] Antibody-drug conjugates are commercially available. One example is brentuximab vedotin (Adcetris®). Adcetris consists of the monoclonal antibody brentuximab (Mab) and the drug monomethylauristatin. The monoclonal antibody and drug molecule are linked to each other via a Val-Cit linker that can be cleaved in vivo by the enzyme cathepsin B. In such conjugates, there are an average of four drug molecules per antibody, which are linked to each other via a linker that can be cleaved in vivo. Once the conjugate reaches the target tumor cells with the help of the monoclonal antibody, the bond present in the conjugate is cleaved by the enzyme cathepsin B, releasing the cytotoxin monomethylauristatin at the tumor site. This allows the monomethylauristatin molecule, which was previously inaccessible due to its high toxicity, to be used for treatment.

[0006] Another antibody-drug conjugate, trastuzumab-emtansine, is commercially available and known as Kadcyla®. This product uses trastuzumab as the antibody and the cytotoxic drug emtansine, abbreviated as DM1. While trastuzumab alone binds to the HER2 receptor and inhibits cancer cell growth, the trastuzumab-emtansine conjugate is transported into the cell by the receptor and degraded in lysosomes, resulting in the release of emtansine. The released emtansine then binds to tubulin, arresting the mitotic cycle and killing the cancer cell. Trastuzumab is specific for the HER2 receptor, which is typically expressed in higher amounts only in cancer cells, allowing the trastuzumab-emtansine conjugate to specifically target tumor cells.

[0007] In this conjugate, the drug is attached to the antibody via succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate (SMCC). The thiol group present in emtansine reacts with the maleimide, and the succinimide group present in SMCC reacts with the lysine present in trastuzumab to form an amide bond. There are approximately 3.5 drug molecules for each trastuzumab.

[0008] Kopecek et al., 2018 (Eur. J. Pharm. Sci., 2017 103, 36-46) developed epirubicin copolymerized with HPMA conjugated with rituximab to improve therapeutic efficacy and patient tolerance in patients with B-cell lymphoma. However, the HPMA monomer used to obtain this conjugate has a disadvantage due to its limited water solubility.

[0009] Antibody-drug conjugates, which are well known in the art, are obtained by attaching a drug to an antibody via a cleavable or non-cleavable bond, as in the above-mentioned examples of Adcetris® and Kadcyla®. In such conjugates, the drug-antibody ratio typically averages about 4. In other words, there are 0 to 8 drug molecules on the antibody, with an average of 4 drug molecules. For therapeutic efficiency, more drug molecules on the antibody is desirable, but modifying the antibody to increase the number of drug molecules reduces the activity of the monoclonal antibody, i.e., reduces the binding ability.

[0010] Furthermore, because such antibody-drug conjugates carry small amounts of drugs, the drugs used are usually toxic and cannot be administered alone. If even a small amount of such drugs is shed from the antibody-drug conjugate before reaching the tumor, it can cause serious side effects. Another problem with known antibody-drug conjugates arises during chemical modification of antibodies to attach linkers and drugs. To create suitable reactive regions on the antibody, disulfide bonds present in the antibody structure are cleaved using chemicals such as DTT or TCEP, resulting in thiol-reactive groups. This process leads to changes in the three-dimensional structure of the antibody, resulting in a loss of its ability to bind to the relevant receptor.

[0011] The present inventors prepared the subject antibody-polymer conjugates in order to develop antibody-polymer conjugates that have higher solubility compared to antibody-polymer conjugates existing in the prior art while increasing the amount of drug per antibody. Summary of the Invention

[0012] Brief description of the invention The present inventors have prepared a drug-loading system (antibody-polymer conjugate) formed by a polymer carrying a therapeutic agent conjugated to a monoclonal antibody via a cleavable or non-cleavable bond. The polymer is characterized by containing a (meth)acrylate backbone and poly(ethylene glycol) in the side chain, and the therapeutic agent is connected to the polymer backbone by a cleavable linker.

[0013] The antibody-polymer conjugate allows for the desired amount of drug per polymer. Furthermore, because the polymer in the antibody-polymer conjugate has multiple drug molecules per chain, the drug:antibody ratio increases when the polymer is conjugated to an antibody. Therefore, drugs with less cytotoxicity can be delivered directly to tumor tissues by the conjugate. Furthermore, the poly(ethylene glycol) chains present in the side chains of the polymer structure make the antibody-polymer conjugate highly water-soluble, resulting in high bioavailability. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description of the Invention In a preferred embodiment of the invention, the antibody-polymer conjugate is represented by Formula 1: [ka] where R1, R2, and R3 are independently selected from —H or —CH3. x is a natural number between 1 and 140 y is a natural number between 1 and 40 z is a natural number between 1 and 15 L1 is a cleavable linker L2 is a linker D is a therapeutic agent A is a monoclonal antibody.

[0015] The term "antibody-polymer conjugate" as used within the scope of the present invention describes a polymer structure covalently linked to an antibody. The polymer structure referred to within the scope of the present invention is a polymer having a (meth)acrylate backbone and comprising a therapeutic agent and poly(ethylene glycol) covalently attached to the polymer backbone at the side chains.

[0016] As used within the scope of the present invention, the terms "antibody-polymer conjugate," "Formula 1," and "antibody-polymer conjugate shown in Formula 1" are equivalent to each other and can be used interchangeably.

[0017] The term "(meth)acrylate" as used within the scope of the present invention denotes the terms "acrylate" and "methacrylate". Thus, "(meth)acrylate" can be used instead of "acrylate" and "methacrylate" and includes all of the above-mentioned characteristics of these terms.

[0018] The term "cleavable linker" as used within the scope of the present invention describes a bond that connects the polymer backbone and the therapeutic agent to each other and that can be cleaved in the presence of a specific stimulus, where the stimulus can be any item that can provide for cleavage of said bond, such as light, a chemical agent, a biological agent, any substance that can be present in the mammalian body, heat, etc.

[0019] The term "linker" as used within the scope of the present invention describes the bond connecting the polymer backbone and the antibody to each other, wherein the linker can be cleavable or non-cleavable.

[0020] The term "therapeutic agent" as used within the scope of the present invention describes any agent used to eliminate, slow down, prevent, reduce symptoms, or provide elimination of symptoms of any physiological condition, or to detect the presence of a physiological condition. The agent may be a small molecule, a macromolecule, or have a biologically based structure or a structure that mimics a biologically based molecule.

[0021] The term "monoclonal antibody" as used within the scope of the present invention describes an antibody that reacts with only one epitope and is based on only one B-lymphocyte. The terms "monoclonal antibody" and "antibody" as used within the scope of the present invention are equivalent and can be used interchangeably.

[0022] The numerical value represented by z provided within the scope of the present invention represents the number of polymer chains attached to the antibody. In a preferred embodiment of the present invention, z represents a number of 1.05 to 14, preferably a number of 1.5 to 13. In other embodiments of the present invention, z can be a number of 2.0 to 12, or 2.5 to 11, or 3 to 10. For example, z can be a number such as 1.05, 1.1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, or 11.0.

[0023] The drug:antibody ratio present in a subject antibody-polymer conjugate, i.e., the amount of drug molecules per antibody, can be from 1:1 to 100:1. In other words, from 1 to 100 molecules of drug per antibody can be provided in a subject antibody-polymer conjugate. In preferred embodiments of the invention, the drug-antibody ratio can be from 4:1 to 90:1, and in particularly preferred embodiments, can be from 6:1 to 80:1.

[0024] The term "poly(ethylene glycol)" as used within the scope of the present invention refers to a polyether compound having the structure H-(O-CH2-CH2)n-OR3, where n is a natural number from 1 to 200, and R3 is selected from H or -CH3. PEG is defined as an oligomer or polymer of ethylene oxide. The terms "PEG," "polyethylene glycol," "polyethylene oxide," "PEO," "polyoxyethylene," and "POE" refer to the same structure and can be used interchangeably in this specification.

[0025] The polymers having poly(ethylene glycol) and a therapeutic agent in the subject side chains can be random copolymers or block copolymers in structure. The term "random copolymer" describes a copolymer in which the monomers forming the copolymer do not follow any particular order. The term "block copolymer" describes a copolymer in which all of the monomers of one type are grouped together and all of the monomers of another type are grouped together. In a preferred embodiment of the present invention, the polymers having poly(ethylene glycol) and a therapeutic agent are random copolymers in structure.

[0026] In preferred embodiments of the present invention, in the subject antibody-polymer conjugates, the therapeutic agent can be selected from the group including anti-tumor agents (anti-neoplastic agents), immune system modulating agents, agents that exhibit anti-angiogenic properties on malignant cells, agents that inhibit cell proliferation on malignant cells, or agents that increase immune cell proliferation.

[0027] As used herein, the term "malignant cells" refers to cells that undergo a rapid cell cycle, and / or cells with altered cell structure, and / or cells with uncontrolled proliferation, and / or cells with increased motility, and / or cells with altered cell surface structure, and / or cells with altered secretion of lytic factors, and / or cells with invasive proliferation, and / or cells with chemotactic properties, and / or cells with abnormal shape and / or size, and / or cells with reduced cytoplasm, and / or cells with large nuclei, and / or cells with increased intranuclear pores.

[0028] The term "immune cells" as used herein refers to all cells present in the mammalian body, preferably cells present in the human body. Said cells may be active in different ways in the immune system. Immune cells described within the scope of the present invention may be B cells, dendritic cells, granulocytes, naive lymphocytes, megakaryocytes, monocytes, macrophages, myeloid suppressor cells, platelets, erythrocytes, T cells and thymocytes.

[0029] Antitumor agents (antineoplastic agents) may be selected from subgroups including, but not limited to, nucleoside analogues, antifolates, other metabolites, topoisomerase I inhibitors, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, antihormones, radiopharmaceuticals, tyrosine kinase inhibitors, mammalian target of rapamycin protein complex (mTOR) inhibitors, retinoids, immune system modulators, histone deacetylase inhibitors, and other agents.

[0030] The nucleoside analogue may be selected from the group including, but not limited to, azacitidine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, fluorouracil (5-FU), gemcitabine, mercaptopurine, nelarabine, pentostatin, thioguanine, trifluridine, and tipiracil.

[0031] The antifolate may be selected from the group including, but not limited to, methotrexate, pemetrexed, pralatrexed and raltitrexed.

[0032] Other metabolites may be selected from the group including, but not limited to, hydroxy-carbamide.

[0033] The topoisomerase I inhibitor may be selected from the group including, but not limited to, irinotecan and topotecan.

[0034] The anthracycline may be selected from the group including, but not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone and barbicin.

[0035] The podophyllotoxin can be selected from the group including, but not limited to, etoposide and teniposide.

[0036] The taxane may be selected from the group including, but not limited to, cabazitaxel, docetaxel, and paclitaxel.

[0037] The vinca alkaloid may be selected from the group including, but not limited to, vinblastine, vincristine, vindesine, vinflunine and vinorelbine.

[0038] The alkylating agent may be selected from the group including, but not limited to, bendamustine, chlorambucil, dacarbazine, melphalan, streptozotocin and trabestedin.

[0039] The antihormonal compound may be selected from the group including, but not limited to, abiraterone, bicalutamide, cyproterone, degarelix, exemestane, fulvestrant, goserelin, histrelin, leuprolide, mifepristone and triptorelin.

[0040] The tyrosine kinase inhibitor may be selected from the group including, but not limited to, afatinib, axitinib, bosutinib, cobimetinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, pazopanib, ruxolitinib, sunitinib and vandetanib.

[0041] The mammalian target of rapamycin protein complex (mTOR) inhibitor may be selected from the group including, but not limited to, everolimus and temsirolimus.

[0042] The retinoid may be selected from the group including, but not limited to, alitretinoin, bexarotene, isotretinoin, tamibarotene and tretinoin.

[0043] The immune system modulator may be selected from the group including, but not limited to, lenalidomide, pomalidomide and thalidomide.

[0044] The histone deacetylase inhibitor may be selected from the group including, but not limited to, belinostat, panobinostat, valproate and vorinostat.

[0045] The other agent may be selected from the group including, but not limited to, anagrelide, ceritinib, dabrafenib, idelalisib, ibrutinib, palbociclib, vemurafenib, bleomycin, bortezomib, dactinomycin, eribulin, estramustine, ixabepilone, mitomycin, procarbazine, alectinib, fluximesterone, iobenguane, imigimod, interferon, ixazomib, lanreotide, lentinan, octreotide, omacetaxine, tegafur, gimeradil, oteracil, uracil, combretastatin, emtansine, and chloroquine.

[0046] In a preferred embodiment of the present invention, the therapeutic agent may be selected from an anti-tumor agent (antineoplastic agent), preferably a taxane, an antifolate, a tyrosine kinase inhibitor, an anthracycline, a nucleoside analogue or other agent.

[0047] In the most preferred embodiment, the therapeutic agent is selected from the group comprising docetaxel, pemetrexed, hydroxychloroquine, combretastatin, gemcitabine, doxorubicin, 5-fluorouracil (5-FU), 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib.

[0048] In an embodiment of the present invention, the therapeutic agent is docetaxel. In an embodiment of the present invention, the therapeutic agent is hydroxychloroquine. In an embodiment of the present invention, the therapeutic agent is combretastatin. In an embodiment of the present invention, the therapeutic agent is gemcitabine. In an embodiment of the present invention, the therapeutic agent is doxorubicin. In an embodiment of the present invention, the therapeutic agent is 5-FU. In an embodiment of the present invention, the therapeutic agent is 5'-deoxy-5-fluorocytidine (5'-DFCR). In an embodiment of the present invention, the therapeutic agent is lapatinib. In an embodiment of the present invention, the therapeutic agent is emtansine.

[0049] In an embodiment of the invention, the therapeutic agent is a combination of two or more therapeutic agents selected from the group including docetaxel, pemetrexed, chloroquine, combrestatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine, and lapatinib.

[0050] The therapeutic agent can be present in an amount of 1% to 40%, preferably 2% to 35%, and particularly preferably 3% to 30% by weight of the polymer provided on the antibody-polymer conjugate. The therapeutic agent can be present in an amount of 4% to 25%, or 5% to 24%, or 6% to 23%, or 7% to 22%, or 8% to 20% by weight of the polymer present on the antibody-polymer conjugate.

[0051] Any monoclonal antibody can be used as the antibody in the antibody-polymer conjugates prepared within the scope of the present invention. In a preferred embodiment of the present invention, the monoclonal antibody is selected from the group consisting of 3F8, 8H9, abagovomab, abciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, atidortoxumab, aducanumab, afacevicumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, anrukinzumab (IMA), and 3F8, 8H9, abagovomab, abciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, atidortoxumab, aducanumab, afacevicumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, and 3F8, 8H9, and 3F8, 8H9, and 3F8, 8H9, and 3F8, and 3F9 ... -638), apolizumab, apruzumab ixadotin, arcitumomab, asclinbacumab, acelizumab, atezolizumab, atinumab, atorolimumab, avelumab, azintuxizumab vedotin, bapineuzumab, basiliximab, bavituximab, bCD-100, bectumomab, begelomab, belantamab mafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bermekimab, bersanlimab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciclovir , bimagrumab, bimekizumab, viltamimab, bivatuzumab mertansine, bleselumab, blinatumomab, brontuzumab, brosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontixumab, bromocizumab, bromocizumab, cabilalizumab, camidanlumab tesirin, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, carotuximab, katsu Maxomab, CBR96-doxorubicin immunoconjugate, cedelizumab, cemiplimab, sergituzumab-amnaleukin, certolizumab-pegol, cetrelimab, cetuximab, civisatamab, cirmtuzumab, sitatuzumab-bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab-tetraxetan, codrituzumab, cofetuzumab-peridotin, coltuximab-ravtansine, conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, cloteduumab,CR6261, cusatuzumab, daketuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrecumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, dellotuximab biotin, detumomab, dezamizumab, dinutuximab, zilidabumab, domagrozumab, dorlimomab alitoxin, dostarlimab, drozitumab, DS-8201, durigotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecloneximab, eculizumab , edovacomab, edrecolomab, efalizumab, efungumab, eldelumab, elezanumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblitzumab, enokizumab, enoticumab, ensituximab, epitumomab situxetan, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etigilimab, etorizumab , evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fivatuzumab, ficlatuzumab, figitumumab, filibumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, flobocimab, furnevetomab, furanumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, Gatipotuzumab, gavilimomab, gezivumab, gemtuzumab ozogamicin, gevokizumab, gilvetomab, gimsilumab, girentuximab, glenbatumumab vedotin, golimumab, gomiliximab, goslanemab, guselkumab, ianalumab, ibalizumab, IBI308, ibritumomab tiuxetan, icrucumab, idarucizumab, ifavotuzumab, igovomab, iradatuzumab vedotin, IMAB362, imalumab, imaprelimab, imciromab, imgatuzumab, inlacumab, indatuximab ravtansine,Indusatumab vedotin, Inebilizumab, Infliximab, Intetumumab, Inolimomab, Inotuzumab ozogamicin, Ipilimumab, Iomab-B, Iratumumab, Isatuximab, Iscalimab, Istiratumab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lacnotuzumab, Radilatuzumab vedotin, Lampalizumab, Lanadelumab, Landgrozumab, Laprituximab emtansine, Ralcabiximab, Lebrikizumab, Remaresomab, Lendarizumab, Lembervimab, Lenzilumab, Lerdelimumab , leronlimab, lesofabumab, letolizumab, lexatumumab, ribivirumab, rifastuzumab vedotin, ligelizumab, loncastuximab tesirin, rosatuximab vedotin, rilotumab satetraxistan, lintuzumab, lirilumab, roderucizumab, loxivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, rumiliximab, lumletuzumab, rupartumumab amadotin, rutikizumab, mapatumumab, margetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab Mab, metelimuab, milatuzumab, minletumomab, mirikizumab, mirvetuximab soravtansine, mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab tafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narunatumab, natalizumab, navicixizumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab Nesvacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentan, obilutoxaximab, ocralatuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, oleculumab, orendalizumab, olokizumab, omalizumab, omburtamab, OMS721, onartuzumab, ontuxizumab, ombatilimab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otilimab, otlertuzumab, oxelumab, ozanezumab,Ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pascolizumab, pasotuximab, pateclizumab, patritumab, PDR001, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placurumab, prosalizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabiximab, prasinezumab, prezalizumab, priliximab, pritoxaximab, pritumumab, PRO 140, Kirizumab, Racotumomab, Ladolezumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranevetomab, Ranibizumab, Raxibacumab, Rabagalimab, Ravtolimab, Refanezumab, Regavirumab, Relatolimab, Lemtolumab, Reslizumab, Rilotumumab, Linucumab, Risankizumab, Rituximab, Ribazumab pegol, Lobatumumab, Rmab, Loredumab, Romilkimab, Romosozumab, lontalizumab, rosmantuzumab, rovalpituzumab-tesirin, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab-govitecan, samalizumab, samlotamab-vedotin, sarilumab, satralizumab, satumomab-pendetide, secukinumab, selicrelumab, seribantumab, cetoxaximab, setrusumab, sevirumab, sibrotuzumab, SGN-CD 19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, siltratumab vedotin, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, subratoxumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talacotuzumab Mab, talizumab, tamtubetomab, tanezumab, taplitumomab paptox, talexuzumab, tabolimab, tefibazumab, terimomab alitox, telisotuzumab vedotin, tenatumomab, teneliximab, teplizumab, tepositamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tiburizumab, tildrakizumab, tigatuzumab, timigituzumab, timolumab,Chiragotumab, tislelizumab, tisotumab vedotin, TNX‐650, tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, trastuzumab, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab, ublituximab, urocupulumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab talilline, banalimab, bunduzumab vedotin, bunduzumab The compound may be selected from the group including ctuzumab, vanucizumab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab, veltuzumab, bepalimomab, besencumab, visilizumab, bovalilizumab, volociximab, bonlerolizumab, bopratelimab, borsetuzumab mafodotin, votumumab, bunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, xenoctuzumab, diralimumab, zolbetuximab (=IMAB362, claudiximab), and zolimomab alitoxin. In a preferred embodiment of the present invention, an antibody selected from the group comprising nivolumab, pembrolizumab, trastuzumab, and cetuximab is used. In a particularly preferred embodiment of the present invention, trastuzumab is used.

[0052] The linker (L2) used in the subject antibody-polymer conjugates can be a cleavable linker (L1) or a non-cleavable linker, as mentioned in the definition above. The non-cleavable linker refers to a bond that preserves its conformation and does not fragment or fragments in a negligible amount under physiological conditions in the body. A non-cleavable linker is a bond that is a C1-C 10The linker (L2) may be formed by a hydrocarbon chain, and optionally, one or more carbon atoms present in the hydrocarbon chain may be substituted with -O, -NH, -N, -S, -C(O), or a combination thereof, and the carbon atoms may be adjacent to or separated from one another. In a preferred embodiment of the present invention, the subject linker may contain, in addition to the -O, -NH, -N, -S, or -C(O) substituent, one or more substituents such as -COOH, -OH, -NH, or -SH, independent of the -O, -NH, -N, -S, or -C(O) substituent. In a particularly preferred embodiment of the present invention, -C(O)CHCHC(CH)(CN)- is used as the linker (L2), and the carbonyl group represented by -C(O) reacts with -NH on any amino acid present in the monoclonal antibody structure to link the amino acid to the amino acid through an amide bond.

[0053] The cleavable linker (L1) used in the subject antibody-polymer conjugates can be any substance, such as poly(ethylene glycol), an amino acid, a poly(amino acid) (e.g., a peptide or oligopeptide), or a poly(peptide). In preferred embodiments of the invention, the cleavable linker can be selected from short peptides having specific peptide sequences, such as Gly-Phe-Leu-Gly, which can be written as GFLG, or Val-Cit, or Phe-Lys, or Val-Ala, or Ala-Leu-Ala-Leu, which can be cleaved by cathepsin B.

[0054] The cleavable linkers (L1) used in the subject antibody-polymer conjugates include C1-C1C substituted with at least one acetal, ester, imine, amide, disulfide, carbamate, or binary or ternary combinations thereof. 10 It may be a hydrocarbon.

[0055] In another embodiment of the present invention, the cleavable linker (L1) comprises a peptide chain selected from the group comprising Phe-Lys or Val-Ala or Ala-Leu-Ala-Leu or Val-Cit, GFLG, and a substituted C1-C1 linker containing at least one functional group selected from the group comprising acetal, ester, imine, amide, disulfide, carbonate, carbamate, hydrazone. 10 It may be a combination of hydrocarbons.

[0056] In preferred embodiments of the invention, the subject antibody-polymer conjugates may comprise one or more of the following: -GFLG as the cleavable linker (L1) and -COCH2CH2C(CH3)(CN)- as the linker (L2), a drug selected from the group consisting of docetaxel, pemetrexed, hydroxychloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy-5-fluorocytidine, emtansine (5'-DFCR) and lapatinib as the therapeutic agent, and trastuzumab as the antibody.

[0057] - Val-Cit as the cleavable linker (L1), -COCH2CH2C(CH3)(CN)- as the linker (L2), a drug selected from the group consisting of docetaxel, pemetrexed, hydroxychloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib as the therapeutic agent, and trastuzumab as the antibody.

[0058] -Phe-Lys as the cleavable linker (L1), -COCH2CH2C(CH3)(CN)- as the linker (L2), a drug selected from the group consisting of docetaxel, pemetrexed, hydroxychloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib as the therapeutic agent, and trastuzumab as the antibody.

[0059] - Val-Ala as the cleavable linker (L1), -COCH2CH2C(CH3)(CN)- as the linker (L2), a drug selected from the group consisting of docetaxel, pemetrexed, hydroxychloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib as the therapeutic agent, and trastuzumab as the antibody.

[0060] -Ala-Leu-Ala-Leu as the cleavable linker (L1), -COCH2CH2C(CH3)(CN)- as the linker (L2), a drug selected from the group consisting of docetaxel, pemetrexed, hydroxychloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib as the therapeutic agent, and trastuzumab as the antibody.

[0061] - Disulfide-substituted C1-C as cleavable linker (L1) 10 a hydrocarbon, -COCH2CH2C(CH3)(CN)- as the linker (L2), a therapeutic agent selected from the group consisting of docetaxel, pemetrexed, hydroxychloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and an antibody, trastuzumab.

[0062] -Hydrazone-substituted C1-C as cleavable linker (L1) 10 a hydrocarbon, -COCH2CH2C(CH3)(CN)- as the linker (L2), a therapeutic agent selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy-5-fluorocytidine (5'-DFCR), emtansine, and lapatinib, and an antibody, trastuzumab.

[0063] - GFLG as cleavable linker (L1) and disulfide-substituted C1-C as linker (L2)10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0064] - Val-Cit as cleavable linker (L1) and disulfide-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0065] - Phe-Lys as cleavable linker (L1) and disulfide-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0066] - Val-Ala as cleavable linker (L1) and disulfide-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0067] - Ala-Leu-Ala-Leu as cleavable linker (L1) and disulfide substituted C1-C as linker (L2) 10hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0068] - Disulfide-substituted C1-C as cleavable linker (L1) 10 Hydrocarbon, disulfide-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0069] -Hydrazone-substituted C1-C as cleavable linker (L1) 10 Hydrocarbon, disulfide-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0070] - GFLG as cleavable linker (L1) and hydrazone-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0071] - Val-Cit as cleavable linker (L1) and hydrazone-substituted C1-C as linker (L2) 10hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0072] - Phe-Lys as cleavable linker (L1) and hydrazone-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0073] - Val-Ala as cleavable linker (L1) and hydrazone-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0074] - Ala-Leu-Ala-Leu as cleavable linker (L1) and hydrazone-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0075] - Disulfide-substituted C1-C as cleavable linker (L1) 10 Hydrocarbon, hydrazone-substituted C1-C as linker (L2) 10hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0076] -Hydrazone-substituted C1-C as cleavable linker (L1) 10 Hydrocarbon, hydrazone-substituted C1-C as linker (L2) 10 hydrocarbons, as therapeutic agents, drugs selected from the group consisting of docetaxel, pemetrexed, chloroquine, combretastatin, gemcitabine, doxorubicin, 5-FU, 5'-deoxy 5-fluorocytidine (5'-DFCR), emtansine and lapatinib, and as antibodies, trastuzumab.

[0077] In another aspect, a preferred embodiment of the present invention relates to a method (Method 1) for preparing an antibody-polymer conjugate of Formula 1, said method comprising the steps of: a. Adding a trithiocarbonate or dithioate molecule (RAFT agent) with a carboxylic acid functional group thereon to the C1-C 10 with 2-(pyridin-2-yldisulfanyl)alcohol to obtain a disulfide-containing RAFT agent; b. reacting the RAFT agent obtained in step a) with a (meth)acrylate monomer represented by formula II [ka] and (meth)acrylate-L1-D monomers of formula III [ka] to obtain a polymer-drug conjugate having a disulfide group at one end thereof; wherein R1, R2, and R3 are independently selected from —H or —CH3; L1 is a cleavable bond; D is a therapeutic agent; and n is a natural number from 1 to 200. c. treating the antibody with Traut's reagent (2-iminothiolane hydrochloride); d. Reacting the polymer-drug conjugate obtained in step b) with the antibody obtained in step c) in aqueous and organic solutions at pH 6.0-7.5 to obtain the subject antibody-polymer conjugate (Formula 1).

[0078] In another aspect, in a preferred embodiment of the present invention, the present invention relates to a method (Method 2) for preparing an antibody-polymer conjugate of Formula 1, said method comprising the steps of: a. reacting a trithiocarbonate or dithioate molecule (RAFT agent) having a carboxylic acid functionality thereon with N-hydroxysuccinimide to obtain a modified RAFT agent; b. The RAFT agent obtained in step a) is reacted with a (meth)acrylate monomer represented by formula II [ka] and (meth)acrylate-L1-D monomers of formula III [ka] to obtain a polymer-drug conjugate having a disulfide group at one end thereof; wherein R1, R2, and R3 are independently selected from —H or —CH3; L1 is a cleavable bond; D is a therapeutic agent; and n is a natural number from 1 to 200. c. Reacting the polymer-drug conjugate obtained in step b) with the antibody obtained in step c) in aqueous and organic solutions at pH 6.0-7.5 to obtain the subject antibody-polymer conjugate (Formula 1).

[0079] In Methods 1 and 2, in step a), a trithiocarbonate or dithioate molecule provided with a carboxylic acid functional group is optionally provided with another functional group such as -CN, -N3, etc. The trithiocarbonate or dithioate molecule provided with a carboxylic acid functional group can have any structure as long as a trithiocarbonate or dithioate group and at least one carboxylic acid group are present.

[0080] In Method 1 and Method 2, a second polymerization initiator existing in a known state can be used in the polymerization achieved in step b). In a preferred embodiment of the present invention, 2,2'-azobis(2-methylpropionitrile) (AIBN) or a derivative such as 4,4'-azobis(4-cyanovaleric acid), 4,4'-azobis(4-cyanovaleric acid), 1,1'-azobis(cyclohexanecarbonitrile), or 2,2'-azobis(2-methylpropionamidine) dihydrochloride can be used as the second polymerization initiator.

[0081] In Method 1 and Method 2, the polymerization described in step b) is achieved at a temperature between 25°C and 100°C, preferably between 60°C and 90°C.

[0082] In methods 1 and 2, the antibody-polymer conjugate is formed at a temperature of 20°C to 45°C, preferably at room temperature, and particularly preferably at 25°C.

[0083] In an embodiment of the present invention, a PEG(meth)acrylate (Formula II) having an average molecular weight of 200 to 2000 g / mol is used. In a preferred embodiment, the PEG(meth)acrylate (Formula II) has an average molecular weight of 250 to 1500 g / mol, and in a more preferred embodiment, the PEG(meth)acrylate (Formula II) has an average molecular weight of 300 to 1100 g / mol. The subject PEG (meth)acrylates (Formula II) can have an average molecular weight of, for example, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000 grams / mole.

[0084] The monoclonal antibody contained in the antibody-polymer conjugate utilizes its affinity for a receptor highly expressed within the cell to internalize the bound therapeutic agent upon reaching the target site. Thus, the type of cell targeted changes depending on the type of mAb used. The subject antibody-polymer conjugates can be used to treat different diseases depending on the properties of the monoclonal antibody forming the conjugate.

[0085] As used herein, the term "treatment" or "treating" describes the removal or reduction of at least one biological marker indicative of the presence of a disease (e.g., a tumor or tumor marker), or the prevention, reduction, alleviation, cure, or blocking of at least one symptom that characterizes a pathological disease, in a subject in whom a diagnosis of the disease has been realized or who has been determined to be likely to have the disease.

[0086] The subject antibody-polymer conjugates can generally be applied in the form of pharmaceutical compositions.

[0087] Accordingly, an embodiment of the present invention is a pharmaceutical composition comprising an antibody-polymer conjugate of Formula I and at least one pharmaceutically acceptable excipient.

[0088] Compositions comprising the subject antibody-polymer conjugates can be in any suitable form based on the preferred method of administering the composition to a patient. Compositions comprising the subject antibody-polymer conjugates can be formulated for oral administration, e.g., in the form of a liquid dispersion or aqueous or oily suspension, or the compositions can be formulated for parenteral administration, e.g., subcutaneous, intravenous, intramuscular, intrasternal, intraperitoneal, intradermal, transdermal, or other injection methods. The subject compositions comprising polymer-drug conjugates can also be formulated for administration via the respiratory route in the form of a spray tube, or as a solution for administration via a respiratory device or nebulizer. The subject antibody-polymer conjugates are preferably administered transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intratumorally, etc. In any event, the most suitable form for administration will depend on the particular therapeutic agent provided in the subject antibody-polymer conjugate, the type of disease, and the physical condition of the subject.

[0089] The subject antibody-polymer conjugates can be applied simultaneously, sequentially, or separately with one or more therapeutic agents, which can be in the form of, for example, cancer preventatives or immune system modulators, antivirals, anti-infectives, antibacterials, or anesthetics, or combinations thereof.

[0090] The second therapeutic agent can be any therapeutic agent, provided that it is different from the agent present in the subject antibody-polymer conjugate.

[0091] Within this specification, the term "comprising" is intended to explain the term "including."

[0092] Where technically suitable, embodiments of the invention may be combined.

[0093] In this specification, embodiments are described as including specific features / elements, and the description also covers other embodiments that include or are formed by those features / elements.

[0094] Patents, applications, scientific publications and similar technical literature are incorporated herein by reference.

[0095] Any embodiment explicitly described herein in a specific manner may, together with one or more other embodiments, form the basis of a disclaimer on its own.

[0096] The present invention will now be described with reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the present invention in any way. [Example]

[0097] Example 1: Method for the synthesis of 2-(pyridin-2-yldisulfanyl)ethyl 4-cyano-4-(((dodecylthio)carbonthioyl)thio)pentanoate (PDS-CDTPA) [ka] 2-(Pyridin-2-ylsulfonyl)ethanol (41.7 mg, 0.223 mmol) was dissolved in 4-cyano-4-(dodecylsulfanylthiocarbonyl)sulfanylpentanoic acid (60 mg, 0.148 mmol) and 4-dimethylaminopyridine (DMAP) (18 mg, 0.147 mmol) in CHCl (2 mL). The reaction mixture was cooled to 0 °C in an ice bath, and N,N-dicyclohexylcarbodiimide (DCC) (36.8 mg, 0.178 mmol) dissolved in CHCl (2 mL) was added dropwise to the reaction mixture. The reaction was stirred at 25 °C. The formed dicyclohexylurea (DCU) was removed by filtration. 1H NMR (CDCl3, δ, ppm) 8.49 (d, 1H, J = 3.8 Hz), 7.67-7.64 (m, 2H), 7.12 (bs, 1H), 4.38 (t, 2H, J = 6.3 Hz), 3.33 (t, 2H, J = 7.4 Hz), 3.05 (t, 2H, J = 6.3 Hz), 2.63 - 2.33 (m, 4H), 1.87 (s, 3H), 1.68 (dd, 2H, J = 14.5, 7.1), 1.39-1.26 (m, 18H), 0.88 (t, 3H, J = 6.4 Hz).

[0098] Example 2: Method for the synthesis of 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid succinimide ester (SCPDB) [ka] 4-Cyano-4-(phenylcarbonothioylthio)pentanoic acid (CPADB) (200 mg, 0.72 mmol) is dissolved in N-hydroxysuccinimide (NHS) (91 mg, 0.79 mmol) and CHCl (1.5 mL). N,N'-Dicyclohexylcarbodiimide (DCC) (163 mg, 0.79 mmol) is dissolved in CHCl (0.5 mL) and added dropwise to the reaction mixture in an ice bath. The reaction is stirred at room temperature for 3 hours. The resulting raw material is precipitated in cold ethyl acetate, and the product is purified by column chromatography. 1 H NMR (400 MHz, CDCl3, δ, ppm) δ 7.93 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 3.03 - 2.95 (m, 2H), 2.86 (s, 4H), 2.79 - 2.69 (m, 1H), 2.61 - 2.52 (m, 1H), 1.96 (s, 3H).

[0099] Example 3: Synthesis of PDS-POEGMEMA-DTX copolymer [ka] Dissolve polyethylene glycol monomethyl methacrylate (PEGMEMA) (100 mg, 0.33 mmol) in DMF (0.3 mL). Dissolve PDS-CDTPA (6.8 mg, 0.01 mmol) in DMF (0.1 mL) and AIBN (0.39 mg, 2.4 x 10 -3 (mmol) is dissolved in DMF (0.1 mL). The prepared solution is added to the PEGMEMA solution under N2 atmosphere. A solution of MA-GFLG-DTX (45 mg, 0.04 mmol) previously prepared by dissolving it in DMF (0.4 mL) is added to the reaction mixture. The reaction mixture is stirred at 80 °C. After the reaction is complete, the DMF is removed. The resulting product is precipitated with ether, and the resulting precipitate is removed by filtration and purified using a dialysis membrane. The molecular weight of the resulting polymer is detected by GPC (10 kDa). 1 The 1H NMR results detected the presence of the drug in the polymer chain at a ratio of 10.6%.

[0100] Example 4: NHS-POEGMEMA-DTX copolymer synthesis method [ka] PEGMEMA (86 mg, 0.29 mmol), MA-GFLG-DTX (120 mg, 0.096 mmol), and SCPDB (3.6 mg, 0.096 mmol) were dissolved in DMF (1.00 mL). AIBN (0.36 mg, 0.0019 mmol) was added to the reaction mixture. After polymerization, the DMF was removed. The resulting material was purified by dialysis. The molecular weight of the resulting polymer was determined by GPC (10 kDa). 1 1H NMR results showed that the drug was present in the polymer chain at a ratio of 12 wt%.

[0101] Example 5: Preparation of trastuzumab thiol (Tmab-SH) 2-Iminothiolane (0.1mg, 3.6x10 -3Dissolve trastuzumab (Tmab) (4.6 mg / mL, 3.1 x 10 mmol) in PBS (3 mL, pH 8.2). -5 (mmol) is added to the reaction mixture. The reaction mixture is stirred at 25°C for 2.5 hours. The number of thiol groups attached to the Tmab is determined by the Ellman procedure (1). This experiment confirms that six thiols are obtained for each Tmab. Dialysis is performed against PBS buffer (pH 6.5). To determine the concentration of the Tmab, a BCA analysis is performed (2). The analysis reveals that the concentration of the Tmab is 3.7 mg / mL.

[0102] Example 6: PDS-POEGMEMA-DTX and Tmab-SH copolymer complex formation Tmab-SH and PDS-POEGMEMA-DTX copolymer are dissolved in DMSO and PBS buffer (pH 6.5). The resulting mixture is stirred at room temperature. The resulting product is purified by conventional methods.

[0103] Example 7: Conjugation of NHS-POEGMEMA-DTX copolymer with Tmab Tmab and NHS-POEGMEMA-DTX copolymer are dissolved in DMSO and PBS buffer (pH 6.5). The resulting mixture is stirred at room temperature. The resulting product is purified by conventional methods.

[0104] References 1 “DTNB(Ellman's Reagent)(5,5‐Dithio‐Bis‐(2‐Nitrobenzoic Acid)‐Thermo Fisher Scientific,”16 July 2019. 2 Associate, A., “User Guide:Pierce BCA Protein Assay Kit(MAN0011430 Rev.A).”16 July 2019.

Claims

1. An antibody-polymer conjugate comprising a polymer-drug conjugate attached to a monoclonal antibody by a cleavable or non-cleavable bond, wherein the polymer carrying the therapeutic agent comprises a (meth)acrylate backbone having poly(ethylene glycol) in its side chains, and the therapeutic agent is connected to the polymer backbone by a cleavable bond.

2. The antibody-polymer conjugate of claim 1 , wherein the conjugate has the structure shown in Formula 1: 【Chemical 1】 where R １ , R ２ , R ３ are each independently —H or —CH ３ is selected from x is a natural number from 1 to 140, y is a natural number from 1 to 40, z is a natural number from 1 to 15, L １ is a cleavable linker, L ２ is the linker, D is a therapeutic agent; A is a monoclonal antibody.

3. The antibody-polymer conjugate of claim 2 , which is a random copolymer or a block copolymer.

4. 4. The antibody-polymer conjugate of claims 1 to 3, wherein the therapeutic agent is selected from the group comprising an anti-tumor agent, an immune system modulating agent, an agent that exhibits anti-angiogenic effect on malignant cells, an agent that inhibits cell proliferation of malignant cells, or an agent that increases proliferation of immune cells.

5. 5. The antibody-polymer conjugate of claim 4, wherein the anti-tumor agent is selected from the group including nucleoside analogs, antifolates, other metabolites, topoisomerase I inhibitors, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, antihormones, radiopharmaceuticals, tyrosine kinase inhibitors, mammalian target of rapamycin protein complex (mTOR) inhibitors, retinoids, immune system modulators, histone deacetylase inhibitors, and other agents.

6. 6. The antibody-polymer conjugate of claim 5, wherein the therapeutic agent is selected from the group comprising docetaxel, pemetrexed, hydroxychloroquine, combretastatin, gemcitabine, doxorubicin, 5-fluorouracil (5-FU), 5'-deoxy 5-fluorocytidine (5'-DFCR), emtransin, and lapatinib.

7. The antibody-polymer conjugate of claims 1 to 6, wherein the therapeutic agent is provided on the antibody-polymer conjugate in an amount of 1% to 40%, preferably in an amount of 2% to 35%, particularly preferably in an amount of 3% to 30% by weight of the polymer.

8. Monoclonal antibodies include 3F8, 8H9, abagovomab, abciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, atidortoxumab, aducanumab, afacevicumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, anrukinzumab (IMA-638), apolizumab, apruzumab ixadotin, andazolizumab. Lucitumomab, asclinbacumab, acelizumab, atezolizumab, atinumab, atorolimu- mab, avelumab, azintuximab vedotin, bapineuzumab, basiliximab, bavituximab, bCD-100, bectumomab, begelomab, belantamab mafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bermekimab, bersanlimab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, vilutamimab, bivatuzumab mertansine, breselma blinatumomab, brontuzumab, brosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontuximab, burosumab, cabilalizumab, camidanlumab tesirin, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, carotuximab, catumaxomab, CBR96-doxorubicin immunoconjugate, cedelizumab, cemiplimab, sergituzumab amnaleukin, Certolizumab pegol, cetrelimab, cetuximab, civisatamab, cirumtuzumab, sitatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab peridotine, coltuximab ravtansine, conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, clotedumab, CR6261, cusatuzumab, daketuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrecumab, demcizumab,Denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, dellotuximab biotin, detumomab, dezamizumab, dinutuximab, zilidabumab, domagrozumab, dorlimomab alitox, dostarlimab, drozitumab, DS-8201, durigotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efungumab, eldelumab, elezanumab, elgemtumab, elotuzumab, ersilimomab, emma Ctuzumab, emapalumab, emibetuzumab, emicizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblitzumab, enokizumab, enoticumab, ensituximab, epitumomab situxetan, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etigilimab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, Erbizumab, Fezakinumab, Fivatuzumab, Ficlatuzumab, Figitumumab, Filibumab, Framvotumab, Fretikumab, Flotetuzumab, Fontolizumab, Foralumab, Foravirumab, Fremanezumab, Fresolimumab, Flobocimab, Furnevetomab, Furlanumab, Futuximab, Galcanezumab, Galiximab, Gancotamab, Ganitumab, Gantenerumab, Gatipotuzumab, Gavirimomab, Gedivumab, Gemtuzumab ozogamicin, Gevokizumab, Gilvetumab, Gimsilumab, Girentuximab, Glenbatumumab Vedotin, golimumab, gomiliximab, goslanemab, guselkumab, ianalumab, ibalizumab, IBI308, ibritumomab tiuxetan, icrucumab, idarucizumab, ifavotuzumab, igovomab, iradatuzumab vedotin, IMAB362, imalumab, imaprelimab, imciromab, imgatuzumab, inlacumab, indatuximab ravtansine, indusatumab vedotin, inebilizumab, infliximab, intetumumab, inolimomab, inotuzumab ozogamicin, ipilimumab, iomab-B,Iratumumab, isatuximab, iscalimab, istiratumab, itolizumab, ixekizumab, keliximab, labetuzumab, lacunotuzumab, radiratuzumab vedotin, lampalizumab, lanadelumab, landgrozumab, laprituximab emtansine, ralcabiximab, lebrikizumab, remaresomab, lendalizumab, lembervimab, lenzilumab, lerdelimumab, leronlimab, lesofabumab, letolizumab, lexatumumab, ribivirumab, rifastuzumab vedotin, ligelizumab, loncastuximab tesirine, Rosatuximab vedotin, rilotomab satetraxistan, lintuzumab, lirilumab, roderucizumab, lokivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, rumiliximab, lumletuzumab, rupartumumab amadotin, rutikizumab, mapatumumab, margetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minletumomab, mirikizumab, mirvetuximab soravtansine, mitumomab, modutuximab, mogamulizumab, monalis Mab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab tafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narutumab, natalizumab, nabicixizumab, nabivumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesbacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentan, obinutuzumab, ocaratuzumab, oviltoxaximab Clerizumab, odulimomab, ofatumumab, olaratumab, oleculumab, orendalizumab, olokizumab, omalizumab, omburtamab, OMS721, onartuzumab, ontuxizumab, onvatilimab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otilimab, otlertuzumab, oxelumab, ozonezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pascolizumab, pasotuxizumab,Pateclizumab, Patritumab, PDR001, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab, Placlumab, Prozalizumab, Pogalizumab, Polatuzumab vedotin, Ponezumab, Polgabiximab, Prasinezumab, Prezalizumab, Priliximab, Pritoxaximab, Pritumumab, PRO 140, Kirizumab, Racotumomab, Ladolezumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranevetomab, Ranibizumab, Raxibacumab, Rabagalimab, Ravulizumab, Refanezumab, Regavirumab, Relatolimab, Lemtolumab, Reslizumab, Rilotumumab, Linucumab, Risankizumab, Rituximab, Ribazumab pegol, Lobatumumab, Rmab, Loredumab, Rosman Tuzumab, rovalpituzumab tesirin, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samalizumab, samlotamab vedotin, sarilumab, satralizumab, satumomab pendetide, secukinumab, selicrelumab, seribantumab, cetoxaximab, setrusumab, sevirumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab , siltratumab vedotin, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, subratoxumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talaxuzumab, talizumab, tamtubetomab, tanezumab, tapritumomab paptox, talexuzumab, tabolitumomab, tavolimab, tefibazumab, Terimomab alitox, telisotuzumab vedotin, tenatumomab, teneliximab, teplizumab, tepositamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tiburizumab, tildrakizumab, tigatuzumab, timigituzumab, timolumab, tiragotumab, tislelizumab, tisotuzumab vedotin, TNX-650, tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab,Tralokinumab, trastuzumab, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab, ublituximab, urocupulumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab talilline, banalimab, bundletuzumab vedotin, vanticutuzumab, vanucizumab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab 8. The antibody-polymer conjugate of claims 1 to 7, selected from the group comprising veltuzumab, beparimomab, besencumab, visilizumab, bovalilizumab, volociximab, bonlerolizumab, bopratelimab, borsetuzumab mafodotin, votumumab, bunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, xenoctuzumab, diralimumab, zolbetuximab (=IMAB362, claudiximab), zolimomab alitox.

9. 9. The conjugate of claim 8, wherein the monoclonal antibody is selected from the group comprising nivolumab, pembrolizumab, trastuzumab, cetuximab.

10. The conjugate according to claim 9, wherein trastuzumab is used as the monoclonal antibody.

11. Linker (L ２ ) is a linker (L １ 11. The conjugate according to claim 1, wherein the linker is a non-cleavable linker.

12. The non-cleavable linker is C １ -C １０ The complex of claim 11 comprising a hydrocarbon chain.

13. C １ -C １０ 13. The conjugate of claim 12, wherein one or more carbons in the hydrocarbon chain are independently substituted with -O, -NH, -N, -S, -C(O), or combinations thereof.

14. C １ -C １０ The hydrocarbon chain is -COOH, -OH, -NH ２ 14. The conjugate of claims 12 and 13, which may contain one or more substituents such as -SH.

15. Cleavable linker (L １ ) is selected from the group consisting of acetal, ester, imine, amide, disulfite, carbonate, carbamate, hydrazone, or a peptide chain selected from the group consisting of GFLG, Val-Cit, Phe-Lys, Val-Ala, Ala-Leu-Ala-Leu. １ -C １０ The complex according to any one of claims 1 to 11, which is a hydrocarbon.

16. 16. The composite according to claims 1 to 15, wherein z is a number between 1.05 and 14, particularly preferably between 1.5 and 13.

17. 17. The complex of claim 16, wherein z is a number from 2.0 to 12, for example from 2.5 to 11 or from 3 to 10.

18. A method (Method 1) for use in preparing an antibody-polymer conjugate according to claims 1 to 17, said method comprising the steps of: a. Add a trithiocarbonate or dithioate molecule (RAFT agent) having a carboxylic acid functional group thereon to C １ -C １０ with 2-(pyridin-2-yldisulfanyl) alcohol to obtain a disulfide-containing RAFT agent; b. The RAFT agent obtained in step a) and a (meth)acrylate monomer represented by formula II 【Chemistry 2】 and (meth)acrylate-L represented by formula III １ -D monomer 【Chemistry 3】 to obtain a drug-containing polymer having a disulfide group at one end thereof; Here, R １ , R ２ , R ３ are independently —H or —CH ３ is selected from L １ is a cleavable bond, D is a therapeutic agent, and n is a natural number from 1 to 200; a. Treating the antibody with Traut's reagent (2-iminothiolane hydrochloride); b. Reacting the polymer-drug conjugate obtained in step b) and the antibody obtained in step c) in aqueous solution with an organic solution at pH 6.0-7.5 to obtain the subject antibody-polymer conjugate (Formula 1).

19. A method (Method 2) for use in preparing an antibody-polymer conjugate according to claims 1 to 17, said method comprising the steps of: a. reacting a trithiocarbonate or dithioate molecule (RAFT agent) bearing a carboxylic acid functional group with N-hydroxysuccinimide to obtain a modified RAFT agent; b. The RAFT agent obtained in a) and a (meth)acrylate monomer represented by formula II 【Chemistry 4】 and (meth)acrylate-L represented by formula III １ -D monomer 【Chemistry 5】 to obtain a drug-containing polymer having a disulfide group at one end thereof; Here, R １ , R ２ , R ３ are independently —H or —CH ３ is selected from L １ is a cleavable bond, D is a therapeutic agent, and n is a natural number from 1 to 200; c. Reacting the polymer-drug conjugate obtained in step b) and the antibody obtained in step c) in aqueous solution with an organic solution at pH 6.0-7.5 to obtain the subject antibody-polymer conjugate (Formula 1).

20. 20. The process according to claims 18 and 19, wherein in the polymerization achieved in step b) a second initiator is used selected from 2,2'-azobis(2-methylpropionitrile) (AIBN) or its derivatives, such as; 4,4'-azobis(4-cyanovaleric acid), 4,4'-azobis(4-cyanovaleric acid), 1,1'-azobis(cyclohexanecarbonitrile), 2,2'-azobis(2-methylpropionamidine) dihydrochloride.

21. The process according to claims 18 to 20, wherein the polymerization according to step b) is achieved at a temperature of from 25 to 100°C, preferably from 60 to 90°C.

22. The method according to claims 18 to 21, wherein the antibody-polymer conjugate according to step d) is achieved at a temperature between 20°C and 45°C, preferably at room temperature, particularly preferably at a temperature of 25°C.

23. A pharmaceutical composition comprising as an active substance the antibody-polymer conjugate of claims 1 to 17.

24. 24. The pharmaceutical composition of claim 23, comprising at least one pharmaceutically acceptable excipient.

25. The pharmaceutical composition according to claims 23 to 24, which can be formulated in a manner that the preparation can be applied orally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, transdermally, or intranasally.

26. 24. The pharmaceutical composition of claim 23, wherein the composition comprises a second therapeutic agent.

27. 27. The pharmaceutical composition of claim 26, wherein the second therapeutic agent is selected from the group consisting of an anti-tumor agent, an anti-viral agent, an anti-infective agent, an anti-bacterial agent, or an anesthetic agent, provided that the second therapeutic agent is different from the therapeutic agent provided on the antibody-polymer conjugate.

28. 28. The pharmaceutical composition of claim 27, wherein a second therapeutic agent is administered together with the subject antibody-polymer conjugate, e.g., simultaneously, sequentially, or separately.

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