Adsorbent and methods of manufacturing and using the same

Abstract

The disclosure provides a method of purifying a biological product. The method comprises contacting an adsorbent with an impure solution comprising the biological product. The adsorbent has formula (I). The impure solution comprises one or more impurities. Contacting the impure solution with the adsorbent separates the biological product partially or wholly from the one or more impurities to thereby purify the biological product due to the one or more impurities being partially or wholly adsorbed by the adsorbent and less than 50% of the biological product being adsorbed by the adsorbent. The disclosure also provides an adsorbent having formula (I), intermediate compounds of formulae (II) and (III) which may be used to produce the adsorbent and a method of producing the adsorbent.

Description

[0001]Adsorbent and Methods of Manufacturing and Using the Same The present invention relates to an adsorbent for the capture and removal of impurities from a biological product. The invention also encompasses compounds which may be used to produce the adsorbent, methods of producing the adsorbent, uses of the adsorbent and methods of using the adsorbent to capture and remove target impurities. Removal of endogenous and process-related impurities is a particular challenge in the manufacture of a wide array of biotherapeutic targets including but not limited to recombinant proteins, viral vectors, extracellular vesicles and nucleic acids. In cGMP biotherapeutic manufacturing, removal of host cell proteins (HCPs), endotoxin, host cell DNA and product and process related impurities is necessary due to strict regulation of the allowable limits of these impurities to ensure product efficacy and safety. In particular, host cell proteins can be especially difficult to remove even when using a purification process involving a highly selective affinity capture step. A significant category of biotherapeutic products are monoclonal antibodies (mAbs). At present, over 100 mAb biopharmaceutical products have been approved by the FDA and collectively are forecast to have a market value of over $150 billion by 2025 [1]. These mAb biologics have been released for a number of indications including cancer treatment, rheumatology, hematology and infectious diseases, and a strong pipeline of new mAb products are currently in development [2]. The dominant method of production of recombinant mAbs is by expression from mammalian cell systems, most notably Chinese hamster ovary (CHO) cells. After cell harvest, most downstream processes for mAb purification utilize Protein A, an affinity chromatography step which involves a ligand with specific affinity to the fragment crystallizable (Fc) region of the antibody protein. The eluate from the protein A column is further purified in polishing steps which often include multiple ion exchange and hydrophobic interaction chromatography stages. A particular challenge in the manufacture of mAbs is the purification of the target antibody from upstream impurities including HCPs, host cell DNA, Protein A leachates, endotoxin, high molecular weight aggregates and antibody fragments. HCPs represent a broad array of peptide or protein biomolecules, potentially made up of thousands of individual species. HCPs are intrinsically present in the manufacture of cell-derived products. For example, in the production of mAbs, HCP concentration in the post Protein A eluate typically range from 200 to 3000 ppm, but levels as high as 70,000 ppm have been reported [6]. The profile of HCP impurities can vary significantly depending on the expression system and upstream process parameters. This makes consistent removal of HCPs to the levels required by regulatory authorities [5] particularly challenging. The success of a platform purification solution for HCP removal also therefore requires that the chromatography process is ‘tunable’ to accommodate variation in the target recombinant protein, cell expression system and other process parameters. In mAb manufacturing, anion exchange chromatography (AEX) is often used in the process step immediately after the Protein A affinity step to achieve removal of HCP and other impurities as mentioned above. However, AEX presents some challenges. Firstly, this step typically operates in flow through mode in which impurities are bound to the column whilst the target mAb pass through in the non-bound fraction. Due to the disruption of protein binding in the low pH / high conductivity environment typical of Protein A elution, the solution requires dilution or diafiltration before loading onto the AEX column. This poses a significant issue in large-scale manufacture of mAbs as the requirement to dilute or diafilter Protein A eluate before AEX creates a bottle neck. Secondly, AEX polishing does not typically remove high molecular weight aggregates (HMW aggregates) so that additional polishing steps, incorporating hydrophobic interaction chromatography (HIC), are often required to remove HMW aggregates. These HIC steps require the use of high concentration kosmotropic salts such as ammonium sulphate, which pose waste management concerns in manufacturing environments and can also cause precipitation of the target product. Attempts at using highly hydrophobic HIC media with no salt, exploiting critical hydrophobic interactions, have been reported [4] but with limited success in commercial applications. Other types of chromatography adsorbents have also been used for HCP capture and removal including so-called mixed-mode or multi-mode adsorbents comprising ligands possessing combinations of ionic groups and hydrophobic groups. However, such adsorbents have had mixed success and better-performing adsorbents for HCP removal are required. In addition to the production of mAb products, removal of HCPs and process-related impurities present a challenge in the production of many other biological products. For example, recent advances in the application of extracellular vesicles (EVs) including exosomes as delivery vehicles for therapeutic molecules have required the development of effective downstream purification processes. Current methods for exosome purification [7] typically from HEK 293 cell expression systems can have significant drawbacks. Currently, ultracentrifugation (UC), size exclusion chromatography (SEC), ultrafiltration (UF) and tangential flow filtration (TFF) are commonly used for exosome purification. These methods have significant limitations with regards to scalability, process times and their inability to remove surfactants incorporated in the upstream process. In the case biological products produced in insect cell lines (such as Sf9 and Sf21), the removal of host cell protein is particularly critical due to the tendency of these host cells to generate post translational modifications that can cause potent immunogenic responses. Recombinant Adeno Associated Virus (AAV) expressed in HEK 239 expression systems is another rapidly growing example of vector-based gene therapy. The requirement for large scale manufacturing processes for an expanding range of AAV serotypes has brought into focus the need for development of effective downstream purification processes for AAV and other viral vectors [8]. Despite considerable advances in downstream purification for mAbs [3], recombinant proteins, viral vectors and other biological products isolated from various expression systems, there remains a need for effective removal of process and product related impurities that could impact product safety, stability, and efficacy. The present invention arises from the inventors’ work in attempting to overcome the problems associated with the prior art. In accordance with a first aspect of the invention, there is provided an adsorbent, the adsorbent having formula (I): , wherein: R1and R2are each independently a C1-5alkyl or a C3-6cycloalkyl; L is absent or is a linker; and A is a substrate. Advantageously, the adsorbent of the first aspect can be used to selectively remove HCPs and other impurities from a feedstock without detrimentally affecting yield of a target biological product. Additionally, the adsorbent retains functionality at relatively high conductivity load conditions. Furthermore, the adsorbent is stable to a wide range of pH conditions including 0.5 M NaOH typically used for cleaning and sanitization. Furthermore, the adsorbent can be manufactured sustainably with minimized use of organic solvents and raw materials. R1and R2may be the same or different. In some embodiments, R1and R2may be the same. In some embodiments, at least one of R1and R2is a C1-5alkyl. The alkyl may be a straight chain or branched alkyl. Preferably, the alkyl is a branched alkyl. In one embodiment, at least one of R1and R2is a C2-5alkyl or a C3-4alkyl. Preferably, at least one of R1and R2is a C4alkyl. At least one of R1and R2may be isobutyl. In some embodiments, R1and R2are both isobutyl. Accordingly, the adsorbent may have formula (Ia): H H N N N In some embodiments, at least one of R1and R2is a C3-6cycloalkyl. Preferably, at least one of R1and R2is a C4-6cycloalkyl or a C5-6cycloalkyl. Accordingly, at least one of R1and R2may be cyclohexyl. In some embodiments, R1and R2are both cyclohexyl. Accordingly, the adsorbent may have formula (Ib): Suitable substrate be known in the art. For example, L may be or comprise an amino group, an ether group, a thioether group or an optionally substituted alkyl group optionally interrupted by one or more heteroatoms. Accordingly, L may be: *–L1–L2–L3–L4– wherein L1and L3are independently absent or an optionally substituted C1-24alkylene, an optionally substituted C2-24alkenylene or an optionally substituted C2-24alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms; L2and L4are independently absent or NR4, O, S, COO or CONR4; R4is H, an optionally substituted C1-12alkyl, an optionally substituted C1-12alkenyl or an optionally substituted C1-12alkynyl; and an asterisk indicates the point of attachment to A, or a residue thereof. The or each alkylene, alkenylene, alkynylene, alkyl, alkenyl and alkynyl may be straight or branched. The or each alkylene, alkenylene, alkynylene, alkyl, alkenyl and alkynyl may be unsubstituted or substituted with one or more of halogen, OH, SH, COOH, NH2and / or oxo. In a preferred embodiment, each alkylene, alkenylene, alkynylene, alkyl, alkenyl and alkynyl is unsubstituted or substituted with one or more of OH and / or oxo. In embodiments where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms, the or each heteroatom may be selected from the group consisting of NR5, O and S, wherein R5is H, an optionally substituted C1-12alkyl, an optionally substituted C1-12alkenyl or an optionally substituted C1-12alkynyl. In some embodiments, L2is NR4. R4may be H. Alternatively, L2may be O. In some embodiments, L1is an optionally substituted C1-12alkylene, an optionally substituted C2-12alkenylene or an optionally substituted C2-12alkynylene. L1may be an optionally substituted C1-6alkylene, an optionally substituted C2-6alkenylene or an optionally substituted C2-6alkynylene. Preferably, L1is an optionally substituted C1-3alkylene, an optionally substituted C2-3alkenylene or an optionally substituted C2-3alkynylene. The alkylene, alkenylene or alkynylene may be unsubsituted or substituted with OH. Accordingly, L1may , where an asterisk indicates the point of attachment to A. Alternatively, L1may be absent. Accordingly,*–L1–L2– may asterisk indicates the point In some embodiments, L3may be absent. In some embodiments, L4may be absent. Preferably, in embodiments where L3is absent then L4is also absent. Alternatively, L3and / or L4may be present. Preferably, if L3is present then L4is also present. In embodiments where L3is present, L3may be an optionally substituted C1-12alkylene, an optionally substituted C2-12alkenylene or an optionally substituted C2-12alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms. The alkylene, alkenylene or alkynylene may be unsubsituted or substituted with OH or oxo. In embodiments where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms, the or each heteroatom may be selected from the group consisting of NR5or O. R5is preferably H. In one embodiment, L3may be an optionally substituted C2-8alkylene, an optionally substituted C2-8alkenylene or an optionally substituted C2-8alkynylene. Accordingly, L3may . In an may an C4-12alkylene, an optionally substituted C4-12alkenylene or an optionally substituted C4-12alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms. L3may be an optionally substituted C6-12alkylene, an optionally substituted C6-12alkenylene or an optionally substituted C6-12alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is interrupted by one or more heteroatoms. L3may be an optionally substituted C7-10alkylene, an optionally substituted C7-10alkenylene or an optionally substituted C7-10alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is interrupted by one or more heteroatoms. Accordingly, L3may or . In some embodiments, L4is NR4. R4may be H. . or , where an asterisk indicates the point of The substrate may be a solid support. The solid support may be selected from the group consisting of a controlled pore glass, a magnetic controlled pore glass, a silica- containing particle, a polymer, a magnetic polymer and a controlled pore glass grafted with a polymer. The solid support may be or comprise a polymer. The polymer may be or comprise a natural polymer or a synthetic polymer. The polymer may be or comprise a polysaccharide, a polymethacrylate, a polymer of styrene, a copolymer of styrene and divinylbenzene, a copolymer of styrene and divinylbenzene grafted with polyethyleneglycol or a copolymer of dimethylacrylamide and N,N,- bisacryloylethylenediamine. The polysaccharide may be or comprise agarose, cellulose, hemicellulose, dextran, carrageenan or chitin. The substrate may be a fibre, a nanofibre, a fibre mat, a nanofibre mat, a membrane, a solid bead, a porous bead, a monolith or a solid gel. In accordance with a second aspect, there is provided a compound of formula (II) or (III): wherein R1, R2, L3and L4are as defined in relation to the first aspect; R3is a reactive leaving group; and R6is a reactive nucleophile or a reactive electrophile. Advantageously, a compound of formula (II) or (III) may be used to produce the adsorbent of the first aspect. R3may be a halogen. Accordingly, R3may be chlorine, bromine or iodine. In some embodiments, R3is chlorine. In embodiments where R6is a reactive nucleophile, R6may be NR7R8, OR9or SR9, where R7and R8are H, an optionally substituted C1-12alkyl, an optionally substituted C1-12alkenyl or an optionally substituted C1-12alkynyl and R9is H. Preferably, R7is H. Preferably, R8is H. Preferably, R6is NR7R8. The attachment of a compound of formula (II) or formula (III) to a substrate (A), via a linker (L), may be achieved by use of an activating agent to introduce chemically reactive groups onto the surface of the substrate (A). Examples of such activating agents are known in the art and include but are not limited to epichlorohydrin, 1,4- butanedioldiglycidylether, allyl bromide, allylglycidylether, sodium periodate, cyanogen bromide or divinylsulphone. Where an activated substrate comprises a primary amine group or a carboxyl group, attachment to a compound of formula (II) may be facilitated by use of reagents that promote amide bond formation including but not limited to N- hydroxysuccinimide or a carbodiimide. In accordance with a third aspect, there is provided a method of producing an adsorbent, the method comprising either: - contacting a first activated substrate and cyanuric chloride to provide a dichlorotriazine activated substrate; and - contacting the dichlorotriazine activated substrate and a compound of formula (IV): NH2R1(IV) , wherein R1is as defined in relation to the first aspect; to thereby provide the adsorbent; or - contacting a first activated substrate and provided a compound of formula (II) or (III): H H R1N N N R2, and aspects to The method may provide the adsorbent of the first aspect. The dichlorotriazine activated substrate may be understood to be a compound of (V): wherein A and L are as defined in to first aspect. The first activated substrate may be understood to be a substrate which comprises a reactive group. Accordingly, the first activated substrate may have formula (VI): A–L1–L2–L3–R10(VI) , wherein R10is NHR4, OH or SH; and L1, L2, L3, R4and A are as defined in relation to the first aspect. The first activated substrate and cyanuric chloride or the compound of formula (II) or (III) may be contacted at a molar ratio of between 10:1 and 20:1, between 5:1 and 1:10, between 3:1 and 1:5, between 2:1 and 1:3, between 1:1 and 1:2, between 1:1.2 and 1:1.75 or between 1:1.3 and 1:1.5. The molar ratio may be understood to be a ratio of the moles of a reactive group (e.g. R6) on the substrate to moles of cyanuric chloride. The first activated substrate and cyanuric chloride or the compound of formula (II) or (III) may be contacted at a temperature between -100 and 100°C, between -75 and 75°C, between -50 and 50°C, between -30 and 30°C, between -20 and 20°C, between - 10 and 10°C, between -5 and 7.5°C or between 0 and 4°C. The first activated substrate and cyanuric chloride or the compound of formula (II) or (III) may be contacted for at least 1 minute, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes or at least 50 minutes. The first activated substrate and cyanuric chloride may be contacted for between 1 minute and 72 hours, between 5 minutes and 24 hours, between 10 minutes and 12 hours, between 20 minutes and 6 hours, between 30 minutes and 2 hours, between 40 and 90 minutes or between 50 and 70 minutes. The first activated substrate and cyanuric chloride or the compound of formula (II) or (III) may be contacted in the presence of a first solvent. The first solvent may be or comprise water and / or an organic solvent. The organic solvent may be or comprise acetone, tetrahydrofuran, dioxane or combinations thereof. In some embodiments, the first solvent may comprise a combination of water and the organic solvent. The first solvent may comprise water and the organic solvent at a volumetric ratio of between 1:10 and 10:1, between 1:5 and 5:1, between 1:3 and 3:1, between 1:2 and 2:1 or between 1:1.5 and 1.5:1. The first activated substrate and cyanuric chloride or the compound of formula (II) or (III) may be contacted in the presence of a pH buffer. The pH buffer may be a phosphate, preferably potassium phosphate. The pH buffer may be present at a concentration of between 0.01 and 10 M, between 0.02 and 5 M, between 0.04 and 2 M, between 0.06 and 1 M, between 0.08 and 0.75 M, between 0.1 and 0.5 M or between 0.2 and 0.3 M. The dichlorotriazine activated substrate and compound of formula (IV) may be contacted at a temperature between 0 and 200°C, between 10 and 150°C, between 20 and 125°C, between 20 and 100°C, between 30 and 90°C, between 40 and 80°C, between 50 and 70°C or between 55 and 65°C. The dichlorotriazine activated substrate and compound of formula (IV) may be contacted for at least 1 minute, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours or at least 6 hours. The first activated substrate and cyanuric chloride may be contacted for between 1 minute and 4 weeks, between 30 minutes and a week, between 1 and 72 hours, between 2 and 48 hours, between 3 and 24 hours, between 4 and 12 hours, between 5 and 8 hours or between 6 and 7 hours. The dichlorotriazine activated substrate and compound of formula (IV) may be contacted in a second solvent. The second solvent may be or comprise water and / or an organic solvent. The organic solvent may be or comprise an alcohol or acetone. The alcohol may be or comprise ethanol or isopropyl alcohol (IPA). The dichlorotriazine activated substrate and the compound of formula (IV) may be contacted in a weight ratio of between 5,000:1 and 1:1, between 2,000:1 and 5:1, between 1,000:1 and 10:1, between 1,000:2 and 100:5, between 1,000:4 and 100:2 or between 1,000:6 and 100:1. The dichlorotriazine activated substrate and the compound of formula (IV) may be contacted in a molar ratio of between 3:1 and 1:50, between 2:1 and 1:20, between 1:1 and 1:15, between 1:2 and 1:10, between 1:3 and 1:8 or between 1:4 and 1:6. The molar ratio may be understood to be the ratio of the number of moles of the dichlorotriazine groups on the substrate to the number of moles of the compound of formula (IV). Prior to contacting the first activated substrate and cyanuric chloride or the compound of formula (II) or (III), the method may comprise contacting a pre-activated substrate and ammonia or a diamine to provide the first activated substrate. The pre-activated substrate may be an epoxy-activated substrate, an allyl activated substrate or an oxidised substrate. An epoxy-activated substrate may be understood to be a substrate which comprises an epoxy group. An allyl activated substrate may be understood to be a substrate which comprises an allyl group. A oxidised substrate may be understood to be a substrate which has been oxidised. The diamine may be a compound of formula (VII): R11R12N-L5-NR13R14(VII) wherein L5is an optionally substituted C1-24alkylene, an optionally substituted C2-24alkenylene or an optionally substituted C2-24alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms; and R11, R12, R13and R14are independently H, an optionally substituted C1-12alkyl, an optionally substituted C1-12alkenyl or an optionally substituted C1-12alkynyl. Preferably, L5is an optionally substituted C3-12alkylene, an optionally substituted C3-12alkenylene or an optionally substituted C3-12alkynylene. More preferably, L5is an optionally substituted C4-8alkylene, an optionally substituted C4-8alkenylene or an optionally substituted C4-8alkynylene. R11, R12, R13and R14may independently be H, an optionally substituted C1-6alkyl, an optionally substituted C1-6alkenyl or an optionally substituted C1-6alkynyl. R11, R12, R13and R14may independently be H, an optionally substituted C1-3alkyl, an optionally substituted C1-3alkenyl or an optionally substituted C1-3alkynyl. In some embodiment, R11, R12, R13and R14may each be H. Accordingly, the diamine may be 1,6-diaminohexane. The method may comprise contacting the pre-activated substrate with ammonia or the diamine in the presence of a third solvent. The third solvent may be or comprise water. The volumetric ratio of the third solvent to the ammonia may be between 1:10 and 50:1, between 1:5 and 30:1, between 1:2 and 20:1, between 1:1 and 10:1, between 2:1 and 7.5:1, between 3:1 and 5:1 or between 3.5:1 and 4.5:1. The epoxy-activated substrate and ammonia may be contacted at a temperature between -10 and 100°C, between 0 and 90°C, between 10 and 80°C, between 20 and 60°C, between 30 and 50°C or between 35 and 45°C. The epoxy-activated substrate and ammonia may be contacted for at least 1 minute, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 12 hours or at least 18 hours. The first activated substrate and cyanuric chloride may be contacted for between 1 minute and 4 weeks, between 1 hour and 1 week, between 2 and 72 hours, between 4 and 48 hours, between 6 and 36 hours, between 12 and 24 hours or between 16 and 20 hours. In embodiments where the pre-activated substrate is an epoxy-activated substrate, prior to contacting the pre-activated substrate and ammonia or the diamine, the method may comprise contacting a substrate and a compound of formula (VIII): (VIII) wherein L6is an optionally substituted C1-24alkylene, an optionally substituted C2-24alkenylene or an optionally substituted C2-24alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms; and O R15is a reactive leaving group ; to provide the epoxy-activated In embodiments where R15is a leaving group, R15may be a halogen. Accordingly, R15may be chlorine, or iodine. In some embodiments, R15is chlorine. In embodiments where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms, the or each heteroatom may be selected from the group consisting of NR5, O and S, wherein R5is H or an optionally substituted C1-12alkyl, an optionally substituted C1-12alkenyl or an optionally substituted C1-12alkynyl. L6may be an optionally substituted C1-12alkylene, an optionally substituted C2-12alkenylene or an optionally substituted C2-12alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms. Preferably, L6is an optionally substituted C1-6alkylene, an optionally substituted C2-6alkenylene or an optionally substituted C2-6alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms. In one embodiment, L6is an optionally substituted C1-3alkylene, an optionally substituted C2-3alkenylene or an optionally substituted C2-3alkynylene. In one embodiment, L6is –CH2–. In an alternative embodiment, the backbone of the alkylene, alkenylene or alkynlene is interrupted by one or more heteroatoms, preferably 2 heteroatoms. The or each heteroatom may be O. Accordingly, L6may be –CH2-O-(CH2)4-O-CH2–. Accordingly, the compound of formula (VIII) may be epichlorohydrin or 1,4-butanediol diglycidyl ether. In embodiments where the pre-activated substrate is an allyl-activated substrate, prior to contacting the pre-activated substrate and ammonia or the diamine, the method may comprise contacting a substrate and a compound of formula (IX): 16 wherein R is a reactive leaving group; to provide the allyl-activated substrate. R16may be a halogen. Accordingly, R16may be chlorine, bromine or iodine. In some embodiments, R16is bromine. Accoridngly, the compound of formula (IX) may be allyl bromide. In embodiments where the pre-activated substrate is an oxidised substrate, prior to contacting the pre-activated substrate and ammonia or the diamine, the method may comprise contacting a substrate and an oxidising agent. The oxidising agent may be a periodate, optionally sodium periodate or potassium periodate. The substrate may be as defined in relation to the first aspect. The substrate and the compound of formula (VIII) or (IX) may be contacted in a weight ratio of between 100:1 and 1:2, between 50:1 and 1:1, between 20:1 and 5:2 or between 10:1 and 5:1. The substrate and compound of formula (VIII) or (IX) may be contacted in the presence of a base. The base may be or comprise a hydroxide, a carbonate or an amine. Accordingly, the base may be or comprise sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, diisopropylethylamine, trimethylamine or n- methyl morpholine. The method may comprise contacting the substrate and the compound of formula (VIII) or (IX) in the presence of a fourth solvent. The fourth solvent may be or comprise water. The hydroxide may be present at a concentration of between 0.001 and 50 M, between 0.01 and 20 M, between 0.05 and 10 M, between 0.1 and 5 M, between 0.3 and 3 M, between 0.5 and 2 M, between 0.7 and 1.5 M, between 0.9 and 1.3 M, between 1 and 1.2 M or between 1.05 and 1.15 M. In accordance with a fourth aspect, there is provided use of the adsorbent of the first aspect to purify a biological product. In accordance with a fifth aspect, there is provided a method of purifying a biological product, the method comprising contacting an adsorbent with an impure solution comprising the biological product, wherein the adsorbent is as defined in the first aspect, the impure solution comprises one or more impurities and contacting the impure solution with the adsorbent separates the biological product partially or wholly from the one or more impurities to thereby purify the biological product. It may be appreciated that the use of the fourth aspect may be in adsorption chromatography. Similarly, the method of the fifth aspect is preferably a method of conducting adsorption chromatography. The method may comprise contacting the adsorbent with the impure solution in a batch process. Accordingly, the method may comprise disposing the adsorbent and the impure solution in a container. The method may comprise disposing the adsorbent and the impure solution in the container for a period of time. The period of time may depend upon a number of factors. Suitable periods of time may be suitably selected by the skilled person. The period of time may be at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes or at least 25 minutes. Suitable periods of time may be between 1 minute and 1 week, between 5 minutes and 48 hours, between 10 minutes and 24 hours, between 15 minutes and 12 hours, between 20 minutes and 6 hours, between 25 minutes and 2 hours or between 30 minutes and 1 hour. The method may subsequently comprise separating the adsorbent and the impure solution. Alternatively, the method may comprise contacting the adsorbent with the impure solution in a continuous process. Accordingly, the method may comprise disposing the adsorbent in a container and flowing the impure solution through the container. In some embodiments, the container may be a column or a filter housing. In embodiments where the container is a column, disposing the adsorbent in the column may comprise: - packing the column with the adsorbent; - equilibrating the column; and - feeding the impure solution through the column. Packing the column with the adsorbent may comprise disposing the adsorbent in the column and causing a packing solution to flow therethrough. Equilibrating the column may comprise causing an equilibration buffer to flow through the column. Suitable packing solutions and equilibration buffers will be known in the art. The biological product may be selected from the group consisting of an amino acid, a peptide, an affimer, a protein, an enzyme, a glycoprotein, a lipopolysaccharide, an antibody or an antigen-binding fragment thereof, an antigen, a nucleic acid, an organic polymer, a virus, a virus related structure, a viral vector, a bacterium, a bacterium related structure, a cell, a cell-related structure, an exosome, an extracellular vesicle and combinations thereof. The biological product may have a molecular weight of at least 1 kDa, at least 10 kDa, at least 25 kDa, at least 50 kDa, at least 75 Da, at least 100 kDa, at least 120 kDa or at least 140 kDa. The biological product may have a molecular weight of between 1 and 10,000 kDa, between 10 and 1,000 kDa, between 25 and 750 kDa, between 50 and 500 kDa, between 75 and 250 kDa, between 100 and 200 kDa, between 120 and 180 kDa or between 140 and 160 kDa. The impure solution may comprise the biological product at a concentration of between 0.001 and 500 mg / mL. In one embodiment, the impure solution may comprise the biological product at a concentration of between 0.01 and 250 mg / mL, between 0.1 and 100 mg / mL, between 0.5 and 75 mg / mL, between 1 and 50 mg / mL, between 2 and 20 mg / mL, between 3 and 10 mg / mL, between 4 and 8 mg / mL, between 5 and 6 mg / ml or between 5.25 and 5.75 mg / mL. In an alternative embodiment, the impure solution may comprise the biological product at a concentration of between 0.001 and 10 mg / mL, between 0.005 and 7.5 mg / ml or between 0.01 and 5 mg / mL. Alternatively, or additionally, the impure solution may comprise the biological product at a concentration of between 1 x 106and 1 x 1020particles per ml, between 1 x 107and 1 x 1015particles per ml, between 1 x 108and 1 x 1014particles per ml or between 1 x 1010and 1 x 1013particles per ml. In some embodiments, the biological product is an antibody or antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof may be a polyclonal or monoclonal antibody or antigen-binding fragment thereof. Preferably, the antibody or antigen- binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof may be IgA, IgD, IgE, IgG, and IgM. Preferably, the antibody or antigen-binding fragment thereof is IgG. The antibody or antigen-binding fragment thereof may be monovalent, divalent or polyvalent. Monovalent antibodies are dimers (HL) comprising a heavy (H) chain associated by a disulphide bridge with a light chain (L). The antibody fragment may include an individual heavy or light chain, or a fragment thereof, such as VL, VH and Fd; a monovalent fragment, such as Fv, Fab, and Fab'; a bivalent fragment, such as F(ab')2; a single chain Fv (scFv); or a Fc fragment. The antigen-binding fragment of the antibody may be a single domain antibody (sdAb) (also referred to as a nanobody). The skilled person would understand that an sdAb is an antibody fragment consisting of a single monomeric variable antibody domain (referred to as a VHH). Alternatively, in another embodiment, the antigen-binding fragment of the antibody may be a single-chain antibody, an intrabody, a peptide (e.g. a bicyclic peptide), or any other type of fragment. The antibody or antigen-binding fragment thereof may have a molecular weight of at least 1 kDa, at least 10 kDa, at least 25 kDa, at least 50 kDa, at least 75 Da, at least 100 kDa, at least 120 kDa or at least 140 kDa. The antibody or antigen-binding fragment thereof may have a molecular weight of between 1 and 10,000 kDa, between 10 and 1,000 kDa, between 25 and 750 kDa, between 50 and 500 kDa, between 75 and 250 kDa, between 100 and 200 kDa, between 120 and 180 kDa or between 140 and 160 kDa. The impure solution may comprise the antibody or antigen-binding fragment thereof at a concentration of between 0.001 and 500 mg / mL, between 0.01 and 250 mg / mL, between 0.1 and 100 mg / mL, between 0.5 and 75 mg / mL, between 1 and 50 mg / mL, between 2 and 20 mg / mL, between 3 and 10 mg / mL, between 4 and 8 mg / mL, between 5 and 6 mg / ml or between 5.25 and 5.75 mg / mL. In some embodiments, the biological product is a virus or a viral vector. The virus or viral vector may be or comprise an adenovirus, a retrovirus, a poxvirus, a baculovirus, a herpes simplex virus, an adeno-associated virus, a lentivirus, or an Espirito Santo virus (ESV). The virus or viral vector may be an engineered virus or viral vector. Accordingly, the adenovirus may be an engineered adenovirus, the adeno-associated virus may be an engineered adeno-associated virus and the lentivirus may be an engineered lentivirus. The adeno-associated virus may be or comprise an AAV1 – AAV9 serotype. The impure solution may comprise the virus or viral vector at a concentration of between 1 x 106and 1 x 1020particles per ml, between 1 x 107and 1 x 1015particles per ml, between 1 x 108and 1 x 1014particles per ml or between 1 x 1010and 1 x 1013particles per ml. In some embodiments, the biological product is a nucleic acid. The nucleic acid may be or comprise DNA, plasmid DNA, doggy-bone DNA, RNA, micro RNA, small interfering RNA, messenger RNA, transfer RNA or antisense RNA. The impure solution may comprise the nucleic acid at a concentration of between 0.001 and 10 mg / mL, between 0.005 and 7.5 mg / ml or between 0.01 and 5 mg / mL. In some embodiments, the biological product is a microvesicle, an exosome or an extracellular vesicle. The microvesicle, exosome or extracellular vesicle may be isolated from a eukaryotic cell. The eukaryotic cell may be a HEK293 cell, a stem cell, a dendritic cell, a human amniotic epithelial cell or a chimeric antigen receptor (CAR)-T cell. The stem cell may be a mesenchymal stem cell. The impure solution may have a desired pH. The desired pH may be between 0 and 14 at 20°C, between 2 and 13 at 20°C, between 4 and 12 at 20°C, between 5 and 11 at 20°C, between 6 and 10 at 20°C, between 7 and 9 at 20°C, between 7.5 and 8.5 at 20°C or between 7.75 and 8.25 at 20°C. The method may comprise adjusting the pH of the impure solution comprising the biological product to the desired pH. The impure solution may have a desired osmolality. The osmolality may be between 1 and 50 mS / cm, between 2 and 25 mS / cm, between 3 and 20 mS / cm, between 4 and 17.5 mS / cm or between 5 and 15 mS / cm. The method may comprise separating the biological product, or a solution comprising the biological product, from the adsorbent. The one or more impurities are preferably partially or wholly captured and removed by an adsorbent of the invention. Preferably, the one or more impurities are partially or wholly adsorbed by the adsorbent. An impurity may be understood to partially adsorbed by the adsorbent if at least 50% of the impurity is adsorbed, more preferably at least 60%, at least 70% or at least 80% of the impurity is adsorbed, and most preferably at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% of the impurity is adsorbed. An impurity may be understood to be adsorbed by the adsorbent if it is no longer present in a solution after it has contacted the adsorbent. The amount of the impurity which has been adsorbed may be calculated by determining the concentration of the impurity in a solution prior to and after contacting the adsorbent and calculating a percentage reduction. Preferably, the biological product is not adsorbed by the adsorbent. The biological product may be understood to not be adsorbed by the adsorbent if less than 50% of the biological product is adsorbed, more preferably less than 40%, less than 30% or less than 20% of the biological product is adsorbed, and most preferably less than 10%, less than 9%, less than 8%, less than 7%, less than 6% or less than 5% of the biological product is adsorbed. The biological product may be understood to be adsorbed by the adsorbent if it is still present in a solution after it has contacted the adsorbent. The amount of the biological product which has been adsorbed may be calculated by determining the concentration of the biological product in a solution prior to and after contacting the adsorbent and calculating a percentage reduction. Accordingly, the biological product may be understood to flow through the adsorbent, and is thereby purified. It will be appreciated by one skilled in the art that the properties of the impure solution may be adjusted prior to contact with an adsorbent to promote the adsorption of impurities, discourage the adsorption of the biological product and / or maintain the integrity and activity of the biological product. The one or more parameters may include, but are not limited to, pH, ionic strength, osmolality, polarity, temperature, buffer composition, buffer concentration and / or the concentration of the biological product. The method may comprise identifying an optimum state for one or more parameters of the impure solution. For instance the optimum state may be an optimum pH, osmolality, polarity, temperature, buffer composition, buffer concentration and / or concentration of the biological product. Identifying the optimum state of the one or more parameters of the impure solution may comprise providing a plurality of samples of the impure solution wherein a parameter varies between the plurality of samples. The method may comprise contacting the adsorbent with the plurality of samples and measuring a variable. The variable may be the amount of an impurity and / or the amount of the biological product which is adsorbed. The optimum state of the one or more parameters may be understood to be the state of the parameter in the sample which exhibits the most desirable outcome as ascertained by measuring the variable. For instance, the most desirable outcome may be the most amount of the impurity adsorbed and / or the least amount of the biological product adsorbed. The method may comprise adjusting one or more parameters of the impure solution to the determined optimum state. The one or more impurities may be selected from the group consisting of an amino acid, a peptide, an affimer, a protein, an enzyme, a glycoprotein, a lipopolysaccharide, an antibody or a fragment thereof, a nucleic acid, an organic polymer, a virus, a virus- related structure, a viral vector, a bacterium, a bacterium-related structure, a cell, a cell-related structure, an exosome, an extracellular vesicle, an endogenous impurity, a process-related impurity, a product-related impurity, fragments thereof and combinations thereof. In some embodiments, the one or more impurities may comprise one or more contaminant proteins. The one or more contaminant proteins may be selected from the group consisting of an intracellular protein, an extracellular protein, a host cell protein, a cytosolic protein, an enzyme, a hormone, an antibody, a cytokine, a membrane associated protein, a structural protein, a muscle protein, a neuronal protein, a nucleic acid associated protein, a secreted protein, a transport protein, a plasma protein, an intein, a lectin, a virus associated protein, a viral coat protein, a product-related protein, a process- related protein, fragments, modifications or aggregates thereof and combinations thereof. The contaminant protein may be a host cell protein. The host cell may be a bacterial cell, a plant cell, a fungal cell, an insect cell or an animal cell. In some embodiments, the host cell is an animal cell. In some embodiments, the host cell is a mammalian cell, optionally a Chinese hamster ovary (CHO) cell or a human embryonic kidney (HEK) cell. In some embodiments, the host cell is an insect cell, such as a Spodoptera frugiperda cell (e.g. Sf9 or Sf21). In alternative embodiments, the host cell is a bacterial cell, for instance an E. coli cell. In alternative embodiments, the host cell is a fungal cell. The fungal cell may be a yeast cell, for instance a Pichia pastoris cell or a Saccharomyces cerevisiae cell. The contaminant protein may be an enzyme, e.g. an in vitro transcription enzyme. The host cell may be used in a process to produce the biological product. The contaminant protein may have a weight of less than 10,000 kDa, less than 1,000 kDa, less than 500 kDa, less than 200 kDa, less than 100 kDa, less than 75 kDa or less than 60 kDa. The contaminant protein may have a weight of between 0.1 and 10,000 kDa, between 1 and 1,000 kDa, between 10 and 500 kDa, between 10 and 200 kDa, between 20 and 100 kDa, between 30 and 75 kDa or between 40 and 60 kDa. In some embodiments, the one or more impurities may comprise a contaminant antibody and / or a contaminant antibody fragment. The contaminant antibody fragment may be an antigen-binding fragment of an antibody. In some embodiments, the biological product is an antibody and the one or more impurities comprise a contaminant antibody fragment, wherein the contaminant antibody fragment is a fragment of the biological product. The contaminant antibody fragment may have a molecular weight of less than 100 kDa, less than 75 kDa, less than 50 KDa, less than 40 kDa or less than 30 kDa. The contaminant antibody fragment may have a molecular weight of between 0.1 and 100 kDa, between 1 and 75 kDa, between 5 and 50 kDa, between 10 and 40 kDa or between 20 and 30 kDa. In some embodiments, the one or more impurities may comprise one or more contaminant nucleic acids. The one or more contaminant nucleic acids may be or comprise DNA, plasmid DNA, doggy-bone DNA, RNA, micro RNA, small interfering RNA, messenger RNA, transfer RNA, antisense RNA, an oligonucleotide, one or more fragments thereof and / or combinations thereof. For instance, the one or more contaminant nucleic acids may comprise one or more oligonucleotides. The one or more contaminant nucleic acids may comprise one or more double stranded nucleic acid fragments. The impure solution may comprise or be a fermentor broth, a clarified fermentor broth, a filtered fermentor broth, a concentrated fermentor broth, a buffer-exchanged fermentor broth, a cell culture media, a clarified cell culture media, a filtered cell culture media, a concentrated cell culture media, a buffer-exchanged cell culture media, a microbial cell extract, a plant cell or plant tissue extract, a fungal cell or fungal tissue extract, an animal cell or animal tissue extract, or an eluate from a precursor adsorbent such as an affinity chromatography, steric exclusion chromatography (SXC), a thiophilic capture step, a hydrophobic interaction capture step, a multi-mode or mixed- mode capture step and / or an ion exchange capture step. An eluate may be understood to be a solution which comprises the biological product. The eluate may be understood to be obtained from chromatography, wherein the biological product has been adsorbed onto a precursor adsorbent. The eluate may be understood to be a solution which is produced when the biological product is released from the precursor adsorbent. As indicated above, the impure solution may comprise or be the eluate. Accordingly, the method may comprise: - conducting a chromatography or capture step on a feedstock solution comprising the biological product to produce an eluate containing the biological product; and - contacting the adsorbent with the impure solution, wherein the impure solution is or comprises the eluate, and thereby purifying the biological product. The chromatography or capture step may comprise affinity chromatography, steric exclusion chromatography, a thiophilic capture step, a hydrophobic interaction capture step, a mixed-mode or multi-mode capture step or an ion exchange capture step. In some embodiments, the impure solution may comprise or be an eluate from a Protein A column. In one embodiment, the method may comprise: - contacting a Protein A column with a feedstock solution comprising the target biomolecule to produce an eluate comprising the biological product; and - contacting the adsorbent with the eluate, and thereby purifying the biological product. SXC may be used when the biological product is a virus (for instance AAV) and the eluate may comprise one or more impurities (e.g. host cell proteins from a HEK 293 cell line and / or additional recombinant proteins added to the process stream, such as a nuclease, nucleic acids, fragments of host cell DNA, and mixtures thereof). Accordingly, in an alternative embodiment, the method may comprise: - conducting steric exclusion chromatography on a feedstock solution comprising the biological product to produce an eluate containing the biological product; and - contacting the adsorbent with the eluate, and thereby purifying the biological product. Affinity chromatography may be understood to comprise an affinity interaction capture step. In this embodiment, the biological product may be or comprise a nucleic acid, e.g. a single stranded mRNA. The feedstock solution may comprise a buffer. The buffer may be configured to maintain the feedstock solution at a pH between 4 and 11, between 5 and 10 or between 6 and 9 at 20°C. The feedstock solution may have an osmolality between 5- 15 mS / cm. The affinity interaction capture step may comprise a poly adenine affinity interaction. The feedstock solution and / or the eluate may comprise one or more impurities. The one or more impurities may comprise one or more oligonucleotides, one or more proteins (e.g. In Vitro Transcription enzymes), one or more double stranded nucleic acid fragments and / or mixtures thereof. In some embodiments, the feedstock solution may be purified using a thiophilic, hydrophobic, and / or ion exchange capture step. The biological product may be or comprise a nucleic acid. In one embodiment, from the feedstock solution may be purified using a hydrophobic interaction capture step and the biological product may be or comprise a double stranded plasmid DNA. The feedstock solution may comprise a buffer. The buffer may be configured to maintain the feedstock solution at a pH between 4 and 11, between 5 and 10 or between 6 and 9 at 20°C.. The feedstock solution may have an osmolality between 5- 15 mS / cm. The feedstock solution and / or the eluate may comprise one or more impurities. The one or more impurities may comprise one or more (e.g. Host Cell Proteins from E Coli). The method may provide the biological product in a non-bound solution. The non- bound solution may be understood to be the solution obtained from contacting the adsorbent and the impure solution comprising the biological product. Advantageously, the method removes one or more contaminant biomolecules which are present in the impure solution. Accordingly, the non-bound solution may comprise fewer impurities than the impure solution. Subsequent to contacting the adsorbent with the impure solution, the method may comprise cleaning and / or sanitising the adsorbent. Cleaning and / or sanitising the adsorbent may comprise contacting the adsorbent with a suitable cleaning solution. Suitable cleaning solutions may be known in the art. Advantageously, the adsorbent may then be used to purify further biological products. All features described herein (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which:- Figure 1 shows protein staining for SDS-PAGE (non-reduced). Lane 1 – MW marker, Lane 2 – Load (1 in 8 dilution), and Lane 3 – elution from product of Example 1; and Figure 2 shows an experiment layout on a 96 micro column plate. EXAMPLE 1 – Solid-Phase Synthesis of Bis- isobutylamine Triazine Ligand Adsorbent 1.1 Epoxy-Activation of Agarose Beads Water washed beaded agarose, 6% cross-linked, 90 µm (Purabead 6HF), 1 kg, was slurried with 675 mL water and 85 mL of 10 M NaOH. Epichlorohydrin, 127 mL, was added and the mixture stirred for 16 hours at 18 °C. The epoxy-activated agarose was washed 10 times with 1 L of water and allowed to drain under gravity. 1.2 Amination of Agarose Beads The epoxy-activated agarose beads prepared in 1.1 above were slurried in 800 mL water to which 200 mL of ammonia solution (0.88 specific gravity) was added and the mixture stirred for 18 hours at 40° C. Following this, the aminated agarose was washed 10 times with 1 L of water and allowed to drain under gravity. 1.3 Dichlorotriazine (DCT) activation of the aminated base matrix The aminated base matrix resulting from step 1.2 was slurried in an aqueous solution of 1 M potassium phosphate, followed by settling under gravity. The settled gel was re- suspended in 1 M potassium phosphate (250 mL) and water (250 mL) followed by the addition of 500 mL of acetone before cooling under stirring to approximately 2 °C. Approximately 1.4 molar equivalents of cyanuric chloride with respect to the precursor activation density was dissolved in acetone, then added to the slurried aminated base matrix, followed by incubation at 0 - 4 °C for approximately one hour. After this reaction period, the gel was drained, washed with aqueous acetone solutions of decreasing concentration, then a final wash in water, after which the slurry was settled under gravity. The final product of this reaction is the DCT-activated base matrix. 1.4 Amination of DCT activated base matrix with iso-butylamine The DCT activated base matrix prepared in step 1.3 was slurried in approximately 1 L of water with 11 mL of iso-butylamine. The slurry was heated at 60 °C with stirring for at least 6 hours before draining and washing 10 times with 1 L of water. The product from this series of synthesis steps is a chromatographic material containing a ligand which binds host cell proteins, as demonstrated below. EXAMPLE 2 – Use of product of Example 1 for purification of mAb from CHO feedstock. 2.1 Chromatography column packing with product of Example 1 A 10 mm internal diameter column, 1.0mL volume was packed with the product of Example 1 in 0.1 M NaCl at 10 mL / min (780 cm / h) for 10 column volumes (CV). The quality of the pack was checked by measurement of asymmetry and resolution at operational flow rate (1 mL / min, 78 cm / h) in 0.1 M NaCl. The final packed column achieved an asymmetry between 0.8 – 1.6 and a plate count of ≥ 2000 N / m. 2.2 Purification chromatography using product of Example 1 The feedstock used for this example was an IgG enriched CHO lysate initially purified with a capture step using a Protein A affinity column. The eluate from this Protein A column was adjusted to pH 8 to provide a feedstock load solution with an IgG concentration of approximately 5.5 mg / mL. After equilibration in 10 CV of 25 mM sodium citrate, 25 mM Tris base pH 8.0, the column packed in step 2.1 was loaded with 0.8 mL of the IgG enriched feedstock. Following this, a post load wash with 10 CV of equilibration buffer was performed. Both the flow through and post load wash samples were collected and pooled to give a non- bound sample. 2.3 Testing non-bound purified sample for IgG yield and HCP clearance. HCP concentration in the load and non-bound sample was determined using a CHO HCP ELISA kit from Cygnus Technologies. This demonstrated a reduction in HCP concentration from over 1,600 ppm in the load to approximately 100 ppm in the non- bound fraction representing a greater than a 1 log clearance. The concentration of IgG in the load and non-bound fractions was determined by UV- Visible spectrophotometry, measuring the absorbance of the solutions at 280 nm. The concentration of IgG in the non-bound fraction compared to the load concentration was greater than 90% indicating negligible loss due to binding of the target IgG. EXAMPLE 3 – Use of product of example 1 for removal of light chain IgG and host cell impurities from monoclonal antibody CHO feedstock. A 96 well micro column plate containing 0.25 mL per column of the product of Example 1 was equilibrated by flushing the columns with 3 x 1.0 mL aliquots of 50mM sodium phosphate, 75 mM NaCl, pH 7.4. The columns were loaded with CHO monoclonal antibody feed at pH 7.5 (1.0 mL per column). The columns were then treated with a post load wash consisting of 4 x 0.75 mL aliquots of equilibration buffer. The flow through from the load and the first two post load washes were collected and pooled to give a non-bound fraction. Following post load wash, the columns were treated with 50 mM sodium citrate, pH 30 elution buffer and the elution fractions collected. As shown in Figure 1, the elution fraction was tested by SDS-PAGE showing negligible recovery of whole IgG (~150 kDa), but significant recovery of light chain IgG (25 kDa) and a 45 kDa host cell protein impurity band. EXAMPLE 4 - Performance of similar hydrophobic triazine ligand products for HCP removal from CHO IgG Products identical to that of Example 1 were produced with the exception of aminating with alternative hydrophobic amines in place of isobutylamine as described in example step 1.4. These alternative amines independently included n-hexylamine, (3‐ methylphenyl)methanamine, 4‐(aminomethyl)phenol, benzylamine and 4- (aminomethyl)pyridine. All five of these products were tested as described in Example 3. None of these candidates were capable of removing HCPs without simultaneous capture of the target IgG. This demonstrates the unique ability of the adsorbents of the invention for the application of HCP removal from IgG in comparison to other aliphatic and aromatic hydrophobic amines. EXAMPLE 5 - Use of Capto L and Product of example 1 for purification of IgG variable domain kappa (Vκ) from E. coli feedstock. 5.1 Chromatography column packing with Capto L A 10 mm internal diameter column, 4.87 mL volume was packed with Capto L (Cytiva, Cat# 17547801) in 0.1 M NaCl at 20 mL / min (1600 cm / h) for 3 column volumes (CV). The quality of the pack was checked by measurement of asymmetry and resolution at operational flow rate (1.2 mL / min, 96 cm / h) in 0.1 M NaCl. The final packed column achieved an asymmetry between 0.8 – 1.6 and a plate count of ≥ 2000 N / m. 5.2 Purification chromatography using Capto L The feedstock used for this example was generated by purification of a Vk enriched E. Coli periplasmic extract with a capture step using a Capto L affinity column. Buffers for the Capto L run were the following: ^ Equilibration buffer: 20 mM citrate, 800 mM NaCl, pH 5.0 ^ Pre-elution buffer: 20 mM citrate, pH 5.0 ^ Elution buffer: 20 mM citrate pH 2.8 ^ CIP: 15 mM NaOH The Capto L run proceeded as follows: Equilibration: 5 CV, 3 mL / min (229 cm / h), equilibration buffer. Load: 342 mL, 1.2 mL / min (92 cm / h), 4-minute residence time PLW: 4 CV, 1.2 mL / min (92 cm / h), equilibration buffer PEW: 1 CV, 1.2 mL / min (92 cm / h), pre-elution buffer Elution: 4 CV, 1.2 mL / min (92 cm / h), elution buffer CIP: 5 CV, 1.2 mL / min (92 cm / h), 10 CV CIP solution and 5 CV elution buffer Re-equilibration: 5 CV, 3 mL / min (229 cm / h), equilibration buffer The eluate from this protein was adjusted to pH 8 to provide a feedstock load solution with a Vk concentration of 2.42 mg / mL. 5.3 Screening conditions on 96 well micro column plates to optimise removal of E. coli HCP from Vκ E. coli feedstock using product of Example 1. A 96 well micro column plate containing, 0.25 mL per well of the product of Example 1, was equilibrated by flushing the columns with 3 x 1.0 mL aliquots of 50 mM Tris-citrate buffer (10 mM citric acid, 40 mM Tris) adjusted to the following pH and conductivity conditions in separate columns: pH 6, 6 mS / cm pH 6, 18 mS / cm pH 7, 12 mS / cm pH 8, 6 mS / cm pH 8, 18 mS / cm Experiments were performed in replicate with the plate layout shown in Figure 2. The columns were loaded with E. coli Vκ feed (2.5 mg Vκ per column) before treatment with a post load wash consisting of 4 x 0.75 mL aliquots of the respective equilibration buffers. The flow through from the load and the first post load wash were collected and pooled to give a non-bound fraction. Following post load wash, the columns were treated with 50 mM sodium citrate, pH 3.0 elution buffer and the elution fractions collected. As the resin works in flowthrough mode, only the non-bound fractions were analysed. 5.4 Testing non-bound purified sample for Vk yield and HCP clearance. HCP concentration in the load and non-bound sample was determined using a E. coli HCP ELISA kit from Cygnus Technologies. The best binding conditions of those tested were found to be pH 6 at 6 mS / cm conductivity. These conditions demonstrated a reduction in HCP concentration from over 30,000 ppm in the load to approximately 200 ppm in the non-bound fraction. The concentration of Vk in the load and non-bound fractions was determined by UV- Visible spectrophotometry, measuring the absorbance of the solutions at 280 nm. With the optimum conditions described above (pH 6 at 6 mS / cm conductivity), the concentration of Vk in the non-bound fraction compared to the load concentration was greater than 80% indicating little loss due to binding of the target Vk. EXAMPLE 6 - Solid-Phase Synthesis of Bis-cyclohexylamine Triazine Ligand Adsorbent A dichlorotriazine (DCT) activated substrate was prepared as described in Example 1 up to and including Step 1.3. Amination of DCT activated substrate with cyclohexylamine The DCT activated substrate prepared in Example 1 Step 1.3 was slurried in approximately 1 L of water with 25 mL of cyclohexylamine. The slurry was heated at 60 °C with stirring for at least 6 hours before draining and washing 10 times with 1 L of water. The product from this series of synthesis steps is a chromatographic material containing a ligand which binds host cell proteins, as demonstrated in Example 7. EXAMPLE 7 – Use of product of Example 6 for purification of mAb from CHO feedstock. 7.1 Chromatography column packing with product of Example 6 A 5 mm internal diameter column, 1.0 mL volume was packed with the product of Example 6 in 0.1 M NaCl at 2 mL / min (600 cm / h) for 10 column volumes (CV). This yielded a column with 5.0 cm bed height. 7.2 Purification chromatography using product of Example 1 The feedstock used for this example was an IgG enriched CHO lysate initially purified with a capture step using a Protein A affinity column. The eluate from this Protein A column was adjusted to pH 8 to provide a feedstock load solution with an IgG concentration of approximately 5.5 mg / mL. 7.3 After equilibration in 10 CV of 25 mM sodium citrate, 25 mM Tris base pH 8.0, the column packed in step 7.2 was loaded with 10 mL of the IgG enriched feedstock. Following this, a post load wash with 10 CV of equilibration buffer was performed. Both the flow through and post load wash samples were collected and pooled to give a non- bound sample. 7.4 Testing non-bound purified sample for IgG yield and HCP clearance. HCP concentration in the load and non-bound sample was determined using a CHO HCP ELISA kit from Cygnus Technologies. This demonstrated a reduction in HCP concentration from over 880 ppm in the load to approximately 460 ppm in the non- bound fraction. 7.5 The concentration of IgG in the load and non-bound fractions was determined by UV-Visible spectrophotometry, measuring the absorbance of the solutions at 280 nm. The concentration of IgG in the non-bound fraction compared to the load concentration was greater than 95% indicating negligible loss due to binding of the target IgG. Conclusions The application in Examples 2 and 7 demonstrates the capability of the adsorbent to remove HCPs and other impurities from a CHO feed stock without detrimentally effecting yield of the target protein IgG. It will be apparent to those skilled in the art that these products may also be used to remove such impurities from CHO systems expressing other recombinant proteins. It will also be apparent to those skilled in the art that this adsorbent may be used to remove contaminants from other expression systems including but not limited to Escherichia coli, Pichia pastoris, Saccharomyces cerevisiae, Spodoptera frugiperda (Sf9 and Sf21) and HEK293 cells. ADVANTAGES: ^ In the application of IgG purification from a CHO expression system, the product has been demonstrated to selectively bind light chain IgG as well as HCP whilst maintaining high IgG yields. ^ The product retains functionality at relatively high conductivity load conditions compared to IEX polishing steps which would require dilution. This removes potential bottlenecks in manufacturing operations requiring high volume in- process hold tanks [1] for dilution of capture step column elution fractions. ^ Caustic stability – the chemical stability of the triazine ligand attached via a spacer involving an ether moiety has been previously demonstrated. The adsorbent is stable to a wide range of pH conditions including 0.5 M NaOH typically used for cleaning and sanitization. ^ Sustainable manufacturing – due to the reactivity of the triazine activated substrate, reactions are possible under relatively mild conditions allowing reduction of raw material excess and lower energy usage. Process for manufacturing is mainly aqueous reducing the requirement for solvent usage. References: [1] Mullard, A. (2021). FDA approves 100th monoclonal antibody product. Nature Reviews Drug Discovery, 20(7), 491-495. [2] Lu, RM., Hwang, YC., Liu, IJ. et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27, 1 (2020). https: / / doi.org / 10.1186 / s12929-019- 0592-z [3] Shukla AA, Wolfe LS, Mostafa SS, Norman C. Evolving trends in mAb production processes. Bioeng Transl Med.2017 Apr 3;2(1):58-69. doi: 10.1002 / btm2.10061. PMID: 29313024; PMCID: PMC5689530. [4] Ghose S, Tao Y, Conley L, Cecchini D. Purification of monoclonal antibodies by hydrophobic interaction chromatography under no-salt conditions. MAbs.2013 Sep- Oct;5(5):795-800. doi: 10.4161 / mabs.25552. Epub 2013 Jun 26. PMID: 23884181; PMCID: PMC3851231. [5] U.S. Pharmacopeia National Formulary USPNF810G-GC-1132-2017-01 (USP 39 NF 34 General Chapter 1132) [6] Marichal‐Gallardo, P., & Álvarez, M. (2012). State‐of‐the‐art in downstream processing of monoclonal antibodies: Process trends in design and validation. Biotechnology Progress, 28(4), 899-916. [7] Ahn S et al. Manufacturing Therapeutic Exosomes: from Bench to Industry. Mol. Cells.2022 May 31; 45(5): 284-290 [8] Nass S. A., et al. Universal Method for the Purification of Recombinant AAV Vectors of Differing Serotypes, Mol Ter Methods Clin Dev.2018 June 15; 9: 33-46

Claims

Claims 1. A method of purifying a biological product, the method comprising contacting an adsorbent with an impure solution comprising the biological product, wherein the adsorbent has formula (I):, wherein: R1and R2are each independently a C1-5alkyl or a C3-6cycloalkyl; L is absent or is a linker; and A is a substrate, the impure solution comprises one or more impurities; and contacting the impure solution with the adsorbent separates the biological product partially or wholly from the one or more impurities to thereby purify the biological product due to the one or more impurities being partially or wholly adsorbed by the adsorbent and less than 50% of the biological product being adsorbed by the adsorbent.

2. The method according to claim 1, wherein at least one of R1and R2is a C2-5alkyl.

3. The method according to claim 2, wherein the adsorbent has formula (Ia): H H N N N4. The method to or at least one of R1and R2is a C4-6 cycloalkyl.

5. The method according to claim 4, wherein the adsorbent has formula (Ib):

6. The method according to any preceding claim, wherein L is: *–L1–L2–L3–L4– wherein L1and L3are independently absent or an optionally substituted C1-24alkylene, an optionally substituted C2-24alkenylene or an optionally substituted C2-24alkynylene, where the backbone of the alkylene, alkenylene or alkynlene is optionally interrupted by one or more heteroatoms; L2and L4are independently absent or NR4, O, S, COO or CONR4; R4is H, an optionally substituted C1-12alkyl, an optionally substituted C1-12alkenyl or an optionally substituted C1-12alkynyl; and an asterisk indicates the point of attachment to A, or a residue thereof.

7. The method according to claim 6, wherein L , *–NH–,8. The method according to any preceding claim, wherein the substrate is a solid support selected from the group consisting of a controlled pore glass, a magnetic controlled pore glass, a silica-containing particle, a polymer, a magnetic polymer and a controlled pore glass grafted with a polymer.

9. The method according to claim 8, wherein the solid support comprises a polymer, preferably wherein the polymer is a polysaccharide, a polymethacrylate, a polymer of styrene, a copolymer of styrene and divinylbenzene, a copolymer of styrene and divinylbenzene grafted with polyethyleneglycol or a copolymer of dimethylacrylamide and N,N,-bisacryloylethylenediamine.

10. The method according to claim 9, wherein the polymer is a polysaccharide, and the polysaccharide is agarose, cellulose, hemicellulose, dextran, carrageenan or chitin.

11. The method of any one of the preceding claims, wherein the biological product is selected from the group consisting of an amino acid, a peptide, an affimer, a protein, an enzyme, a glycoprotein, a lipopolysaccharide, an antibody or an antigen-binding fragment thereof, an antigen, a nucleic acid, an organic polymer, a virus, a virus related structure, a viral vector, a bacterium, a bacterium related structure, a cell, a cell-related structure, an exosome, an extracellular vesicle and combinations thereof.

12. The method of claim 11, wherein the biological product is an antibody or antigen-binding fragment thereof.

13. The method of claim 12, wherein the antibody or antigen-binding fragment thereof has a molecular weight of between 1 and 10,000 kDa, between 10 and 1,000 kDa, between 25 and 750 kDa, between 50 and 500 kDa, between 75 and 250 kDa, between 100 and 200 kDa, between 120 and 180 kDa or between 140 and 160 kDa.

14. The method of claim 12 or 13, wherein the impure solution comprises the antibody or antigen-binding fragment thereof at a concentration of between 0.001 and 500 mg / mL, between 0.01 and 250 mg / mL, between 0.1 and 100 mg / mL, between 0.5 and 75 mg / mL, between 1 and 50 mg / mL, between 2 and 20 mg / mL, between 3 and 10 mg / mL, between 4 and 8 mg / mL, between 5 and 6 mg / ml or between 5.25 and 5.75 mg / mL.

15. The method of claim 11, wherein the biological product is a virus or a viral vector, optionally wherein the impure solution comprises the virus or viral vector at a concentration of between 1 x 106and 1 x 1020particles per ml, between 1 x 107and 1 x 1015particles per ml, between 1 x 108and 1 x 1014particles per ml or between 1 x 1010and 1 x 1013particles per ml.

16. The method of claim 11, wherein the biological product is a nucleic acid, optionally wherein the impure solution comprises the nucleic acid at a concentration of between 0.001 and 10 mg / mL, between 0.005 and 7.5 mg / ml or between 0.01 and 5 mg / mL.

17. The method of any one of the preceding claims, wherein the impure solution comprising the biological product further comprises one or more impurities, selected from the group consisting of an amino acid, a peptide, an affimer, a protein, an enzyme, a glycoprotein, a lipopolysaccharide, an antibody or a fragment thereof, a nucleic acid, an organic polymer, a virus, a virus-related structure, a viral vector, a bacterium, a bacterium-related structure, a cell, a cell-related structure, an exosome, an extracellular vesicle, an endogenous impurity, a process-related impurity, a product-related impurity, fragments thereof and combinations thereof.

18. The method of claim 17, wherein the one or more impurities comprise one or more contaminant proteins, wherein the one or more contaminant proteins are selected from the group consisting of an intracellular protein, an extracellular protein, a host cell protein, a cytosolic protein, an enzyme, a hormone, an antibody, a cytokine, a membrane associated protein, a structural protein, a muscle protein, a neuronal protein, a nucleic acid associated protein, a secreted protein, a transport protein, a plasma protein, an intein, a lectin, a virus associated protein, a viral coat protein, a product-related protein, a process-related protein, fragments, modifications or aggregates thereof and combinations thereof, preferably wherein the contaminant protein has a weight of less than 10,000 kDa, less than 1,000 kDa, less than 500 kDa, less than 200 kDa, less than 100 kDa, less than 75 kDa or less than 60 kDa.

19. The method of claim 17 or 18, wherein the one or more impurities comprise a contaminant antibody and / or a contaminant antibody fragment, preferably wherein the contaminant antibody and / or a contaminant antibody fragment has a molecular weight of less than 100 kDa, less than 75 kDa, less than 50 KDa, less than 40 kDa or less than 30 kDa.

20. The method of any one of the preceding claims, wherein the impure solution comprises or is an eluate from an affinity chromatography, steric exclusion chromatography (SXC), a thiophilic capture step, a hydrophobic interaction capturestep, a mixed-mode or multi-mode chromatography capture step or an ion exchange capture step.

21. An adsorbent, the adsorbent having formula (I):, wherein: R1and R2are each independently a C1-5alkyl or a C3-6cycloalkyl; L is absent or is a linker; and A is a substrate.

22. A compound of formula (II) or (III):wherein are as any one to R3is a reactive leaving group; and R6is a reactive nucleophile.

23. A method of producing an adsorbent, the method comprising either: - contacting a first activated substrate and cyanuric chloride to provide a dichlorotriazine activated substrate; and - contacting the dichlorotriazine activated substrate and a compound of formula (IV): NH2R1(IV), wherein R1is as defined in any one of claims 1 to 20; to thereby provide the adsorbent; or - contacting a first activated substrate and provided a compound of formula (II) or (III):, wherein R1, R2, R3, R6, L3L4are as to the adsorbent.

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