WO2010059661A1 - Méthodes de détermination de la polydispersité et/ou de la distribution de masse moléculaire d'un échantillon de polyéthylène glycol - Google Patents

Méthodes de détermination de la polydispersité et/ou de la distribution de masse moléculaire d'un échantillon de polyéthylène glycol Download PDF

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WO2010059661A1
WO2010059661A1 PCT/US2009/064896 US2009064896W WO2010059661A1 WO 2010059661 A1 WO2010059661 A1 WO 2010059661A1 US 2009064896 W US2009064896 W US 2009064896W WO 2010059661 A1 WO2010059661 A1 WO 2010059661A1
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Prior art keywords
peg
neutral
emd
sample
singly charged
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PCT/US2009/064896
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English (en)
Inventor
Jasmin Kemptner
Martina Marchetti-Deschmann
Juergen Siekmann
Peter Turecek
Hans-Peter Schwarz
Guenter Allmaier
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Baxter International Inc.
Baxter Healthcare S.A.
Technische Universitaet Wien
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Application filed by Baxter International Inc., Baxter Healthcare S.A., Technische Universitaet Wien filed Critical Baxter International Inc.
Priority to JP2011536612A priority Critical patent/JP2012509469A/ja
Priority to CA2743907A priority patent/CA2743907A1/fr
Priority to EP09760672A priority patent/EP2366105A1/fr
Priority to AU2009316749A priority patent/AU2009316749A1/en
Publication of WO2010059661A1 publication Critical patent/WO2010059661A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G01N27/622—Ion mobility spectrometry
    • G01N27/624—Differential mobility spectrometry [DMS]; Field asymmetric-waveform ion mobility spectrometry [FAIMS]

Definitions

  • Polymers suitable for protein/peptide conjugation have to fulfill a variety of criteria.
  • the polymer should be readily biodegradable to avoid progressive accumulation in the body. Its polydispersity should be as close as possible to one to yield an acceptable homogeneity of the final protein conjugate. Distribution and accumulation in the desired body compartments as well as prolonged action should be given by a sufficient body/compartment-residence time.
  • the polymer conjugation to the peptide/protein should be obtained via a single reactive group to avoid cross-linking which would provide a inhomogeneous product.
  • PEG is one of the most prominent polymers used for polymer-drug conjugation due to its outstanding properties.
  • PEG is non-toxic, non-immunogenic, non- antigenic, high solubility in water as well as other solvents, and is accepted by the FDA and EMEA for human use. Its solubility in water and in numerous organic solvents allows pegylation of proteins and/or peptides under mild physiological conditions.
  • Both PEG's flexible chain and ability to bind 2-3 water molecules per ethylene oxide unit contribute to its ability to reduce immunogenicity and antigenicity and to prevent enzymatic degradation of peptides/proteins due to the increased steric hindrance.
  • Another important property concerning the pharmaceutical usage of PEG is the possibility of low polydispersity (PDI), M w /M n of about 1.01 to about 1.1.
  • PEG protein conjugates can provide therapeutics having decreased immunogenicity and antigenicity, decreased body -residence time, and increased stability towards metabolic enzymes. While some biological activity may be lost with the PEG conjugate compared to the unmodified protein, often an increased half- life can compensate for this loss. Since the introduction of protein PEGylation in the 1970s, a great number of PEG-drug conjugates have been introduced, e.g. ADAGEN®, NEULASTA®, SOMA VERT®, PEGASYS®, PEG-INTRON®, ONCASPAR®, and more PEG-proteins are currently in clinical trial phases. Further pharmaceutical applications of PEG are conjugation to smaller drugs, like antitumor drugs, peptides, or oligonucleotides and their use as drug delivery systems or diagnostic carriers.
  • mPEG monomethoxylated PEG
  • mPEG is synthesized by anionic ring opening polymerization initiated with methoxide ions. Due to the presence of trace amounts of water during polymerization, commercially available mPEG can contain a considerable amount of diol PEG (up to 15 %), leading to undesired cross-linked co-products and varying degree of coupling groups.
  • a PEG batch is commonly composed of molecules built up by different numbers of monomers, thus yielding in ideal cases a Gaussian molecular mass distribution (MMD).
  • MMD Gaussian molecular mass distribution
  • the methods disclosed herein comprise a) providing the PEG sample comprising a plurality of PEG polymers of different molecular weights and each PEG polymer comprising a first terminus and a second terminus, and the first terminus comprises a reactive functional group; b) ionizing the PEG sample to provide a plurality of ions; c) reducing the plurality of ions to provide neutral or singly charged species; d) separating the plurality of neutral or singly charged species by an electrophoretic mobility diameter (EMD) of each species using a differential mobility analyzer (DMA); and e) correlating the EMD of each species to the PDI and/or MMD of the PEG sample.
  • EMD electrophoretic mobility diameter
  • DMA differential mobility analyzer
  • the second terminus of the PEG comprises a methoxymethyl group.
  • the reactive functional group comprises a succinimidyl succinate group.
  • the concentration of the PEG in the sample can be at least about 1 nM or at least about 0.2 mM. In some specific cases, the concentration of the PEG in the sample is about 5 nM to about 100 mM.
  • Ionizing the of the PEG sample can be by exposing the sample to electrospray ionization. Reducing of the ions can be by exposing the ions to a bipolar atmosphere. In specific cases, the bipolar atmosphere can be generated by a polonium source. The characterizing can be by correlating the EMD of each ion to an EMD of a known molecular weight. The EMD of each ion can be at least about 3 nm.
  • the ions can form unimers, dimers, trimers, or quadramers. In some cases, the ions form trimers and dimers, and both the PDI and MMD of the PEG sample are calculated. In specific cases, the precision of the PDI and/or MMD calculation is at least 5%, or at least 2%.
  • Figure 1 shows the structure of a PEG- succinimidyl succinate and the calculated molecular weight with number of monomers for various PEG samples.
  • Figure 2 shows GEMMA spectra of three PEG samples, where two to three peaks can be observed in each GEMMA spectrum, corresponding to aerosol droplets containing unimers, one singly charged polymer chain, di- or trimers.
  • Figure 3 shows GEMMA spectra of various concentrations of mPEG-SS 2OK.
  • Figure 4 shows shows the MALDI-TOF mass spectra of mPEG-SS 2K prepared by the mentioned techniques (DHB, superDHB and super DHB with NaCl) and acquired in the reflectron mode.
  • the inset of the Figure 4 shows a small m/z range of the mass spectra in detail with the observable molecular ions and the corresponding different in mass ( ⁇ m) values.
  • Figure 5 shows MALDI-TOF mass spectra of mPEG-SS 5K, 1OK and 2OK using superDHB containing NaCl.
  • determining the PDI and/or MMD of a PEG sample are assessed prior to conjugation to a protein or peptide to form a protein conjugate therapeutic. Because such therapeutics typically are strictly controlled or monitored by the various drug administration boards (e.g., FDA and EMDA), such determinations are important to verify suitability of a particular PEG sample for conjugation to a protein or peptide.
  • suitable PEG samples have a PDI that is close to 1, e.g., about 1.05 to about 1.2, or about 1.05 to about 1.1.
  • PEG samples typically have a plurality of polymers, i.e., polymers of different molecular weights due to differing numbers of repeating ethylene glycol monomers. Determination of the distribution of the molecular weight of the PEG polymers in the PEG sample provides the MMD of the sample.
  • the PDI of the sample is a measurement of the ratio of the weight average (M w ) to the number average molecular weight (M n ) of a polymer sample.
  • the M w is a weight average of the mass of a polymer, such that, on average, a randomly selected specific polymer of a polymer sample will have a mass of M w .
  • the M n is a number average mass of a polymer, which is an average of all the molecular weights of all the polymers in a polymer sample.
  • the PEG samples being analyzed in the disclosed methods typically have a reactive functional group at one terminus.
  • the PEG can have at one terminus a suitable reactive group that allows for its conjugation to a protein or peptide and at the other terminus a non-reactive functional group.
  • a nonreactive functional group is one which is inert under specific reaction conditions. Under coupling conditions of a PEG to a protein and/or peptide, a non-reactive functional group can be, but is not limited to, a methoxy group.
  • Reactive functional groups are functional groups that under specific reaction conditions are capable of forming a conjugate with a protein, peptide, or other molecule of interest. Non-limiting examples of such reactive functional groups include a succinimidyl succinate, and the like.
  • the PEG samples are analyzed via mass spectrometry using GEMMA.
  • GEMMA a sample is ionized.
  • the ionization can be by electrospray ionization, but other known ionization techniques can be used.
  • the ions formed are then reduced to form singly charged ions or neutral species.
  • the ions can be reduced by exposing the ions to a reducing environment, such as a bipolar atmosphere. In some cases, the bipolar atmosphere is from an ⁇ -particle source, such as a polonium source.
  • the ions are then separated using a differential mobility analyzer, which separates ions according to their mobility in air. Then, the ions are detected using a condensation particle counter.
  • the electrophoretic mobility diameter (EMD) of each ion can be calculated by using the Millikan equation, which can then be correlated to the ions molecular weight. Typically, such a correlation uses a comparison of the EMD of a molecule of known molecular weight.
  • GEMMA analysis is generally discussed in Allmaier, et al., /. Mass. Spec, 36:1038- 1052 (2001).
  • the EMD of the ions are at least 2 nm, or at least 3 nm.
  • the ions can form unimers (one ion), dimers (two ions clustered together), trimers (three ions clustered together), quadramers (four ions clustered together), or higher order structures. Formation of trimers and quadramers typically have larger EMDs and can therefore more easily be detected by the particle counter. Therefore, formation of such structures can allow for more accurate determination of MMD and/or PDI.
  • Concentration of the PEG in the sample can effect the formation of dimers, trimers, quadramers, etc. The higher the concentration, the more dimers, trimers, and/or quadramers are formed.
  • the PEG sample has a PEG concentration of at least 1 nM, at least 2 nM, at least 3 nM, at least 5 nM, at least 10 nM, at least 50 nM, at least 0.1 mM, or at least 0.2 mM.
  • the precision of the measurement can be determined by methods known in the art.
  • the precision of the PDI and/or MMD measurement can be at least about 5%, at least about 4%, at least about 3%, or at least about 2%.
  • mPEG-SS monomethoxy PEG-succinimidyl succinate
  • PDI PDI
  • the EMD of each sample was determined by GEMMA.
  • Multiply charged macromolecular ions were generated via nano electrospray (nES), and charge was reduced by a bipolar atmosphere generated by a polonium source to obtain neutral and singly charged ions.
  • nES nano electrospray
  • ⁇ CPC condensation particle counter
  • the MMD of the four mPEG-SS derivatives was determined.
  • MALDI-TOF MS was applied. Based on the time the accelerated molecule ions need to pass the distance between the ion source and the detector, accurate molecular weight data of the samples was determined.
  • Sample preparation for MALDI-TOF MS For MALDI-TOF MS analysis, the PEGs were dissolved in water, to give a concentration of 1 mg/mL for mPEG-SS 2K and 10 mg/mL for mPEG-SS 5K, 1OK and 2OK.
  • Three matrix systems based on DHB dissolved in water/EtOH (9:1, v/v) were evaluated in terms of best mass spectrometric resolution.
  • Matrix system A consisted of 10 mg DHB dissolved in 1 mL water/EtOH (9:1, v/v). 2 ⁇ L PEG solution and 1 ⁇ L matrix solution were directly mixed on the stainless steel MALDI target.
  • Matrix system B consisted of superDHB, a mixture of DHB and MSA (9:1, w/w) in water/EtOH (9:1, v/v); PEG solution and matrix solution were pre-mixed (1:4, v/v) in an Eppendorf tube and two times 1.5 ⁇ L of this mixture were applied onto the target. The spot was recrystallized with 0.8 ⁇ L EtOH.
  • Matrix system C consisted of superDHB (DHB/MSA (9:1, w/w) dissolved in 1 mL water/EtOH (9:1, v/v)) with addition of 0.1 M NaCl solution in a ratio of 1:1 (v/v) related to the PEG concentration.
  • Sample preparation for GEMMA analysis For GEMMA analysis, all four PEGs were dissolved in ammonium acetate buffer (pH 6.8; 20 mM) to give a concentration of 1 mg/mL.
  • the GEMMA system consists of a nano-electrospray (nES) unit, a nano-differential mobility analyzer (nDMA) and an ultrafine condensation particle counter ( ⁇ CPC) as detector (all parts from TSI Inc, Shoreview, MN, USA). Multiply charged ions are generated by the electrospray process and charge reduced to yield neutral and singly charged molecules. The ions were size separated according to their electrophoretic mobility diameter (EMD) in the nDMA and detected with the ⁇ CPC.
  • EMD electrophoretic mobility diameter
  • EMD for determination of the PEG size and the derived molecular weight, EMD of several well defined globular standard proteins were determined and used as calibrants. Based on the resulting correlation between EMD and molecular mass of the unknown polymers was characterized.
  • the settings of the nES source were 2 kV and 0.3 L/min CO 2 (99.995 %, Air Liquide, Schwechat, Austria)/1 L/min compressed air (99.999 % synthetic air, Air Liquide) were applied to operate the instrument in a stable cone-jet mode for the used ammonium acetate buffer (pH 6.8; 20 mM).
  • the inner diameter of the fused silica capillary was 150 nm and the electrospray process was operated in the positive ion mode. Ten scans were averaged for each final size GEMMA spectrum.
  • Figure 2 shows the obtained GEMMA spectra for three of the four investigated PEGs. Two to three peaks can be observed in each GEMMA spectrum, corresponding to aerosol droplets containing unimers, one singly charged polymer chain, di- or trimers, two or three polymer chains building a cluster carrying one charge. All EM diameter values and corresponding maxima of the MMD are summarized in Table 1. Due to the functional limit of the ⁇ CPC analyzer at a particle diameter of 3 nm, no GEMMA data could be obtained for mPEG-SS 2K. For the same reason, detection of mPEG-SS 5K unimers was not possible.
  • mPEG-SS 5K di- and trimers of mPEG-SS 5K were detectable at EM diameters of 3.72 nm and 4.29 nm.
  • the GEMMA spectrum of mPEG-SS 1OK exhibited unimers (3.85 nm), as well as di- (4.78 nm) and trimers (5.52 nm).
  • mPEG-SS 2OK yielded a unimer with an EM diameter of 4.78 nm, a dimer of 5.94 nm and a trimer of 6.85 nm.
  • the detection of these multimer clusters is desirable, because these clusters contain individual molecules having their own mass distribution, which provide a relative narrowing of the mass distribution.
  • This relative narrowing of the mass distribution obtained by the clustering process can be used to characterize various PEG standards.
  • the maxima of the MMD were determined, yielding 4.77 kDa for mPEG-SS 5K, 9.76 kDa for mPEG-SS 10K, and 18.70 kDa for mPEG-SS 2OK. Precision of the GEMMA analysis increased from mPEG-SS 5K (+ 4.4 %) to mPEG-SS 2OK (+ 1.8 %). All MMD maxima data are summarized in Table 2.
  • Recrystallization may also be accompanied by an appreciated side effect, the removal of salt contaminations.
  • ionization of synthetic polymers occurs mostly via cationization rather than protonation, thus addition of a (inorganic) cationization agent leads to an increase of mass spectrometric sensitivity.
  • Another effect accompanying the use of a cationization agent is the suppression of other salt contaminations present in the polymer sample, matrix or solvents.
  • Figure 4 shows the MALDI-TOF mass spectra of mPEG-SS 2K prepared by the mentioned techniques (DHB, superDHB and super DHB with NaCl) and acquired in the reflectron mode.
  • the inset of the Figure 4 shows a small m/z range of the mass spectra in detail with the observable molecular ions and the corresponding ⁇ m values.
  • the Na-adduct ions are the most prominent species.
  • the positive ion MALDI mass spectrum of mPEG-SS 5K acquired in the reflectron mode shows a Na-adduct ion distribution starting at m/z 4075 and going up to m/z 5703 with a mass difference of 44 Da between adjacent polymer molecular ions. No K-adducts or protonated molecular ions were observed.
  • mass spectrum of mPEG-SS 1OK was acquired in the linear operation mode, resulting in a series of Na-adduct ions with 44 Da difference.
  • the molecular ion distribution of the polymer species ranges from m/z 8950 to m/z 11590.
  • MALDI-TOF mass spectrometric analysis of mPEG-SS 2OK was also performed in the linear operation mode and yielded a resolved signal starting at m/z 17800 and ending at m/z 21450. In this m/z region the achievable mass spectrometric resolution was not sufficient anymore to resolve the individual molecular ions of the polymer species (which are just 44 Da apart).
  • Table 2 summarizes the maxima of the MMD obtained by MALDI-TOF MS. Following MMD maxima were obtained, for mPEG-SS 2K 2191 Da, mPEG-SS 5 K 4870 Da, mPEG-SS 1OK 10150 Da and for mPEG-SS 2OK 19720 Da.
  • mPEG-SS 2K yields a difference of +200 Da, mPEG-SS 5K of -118 Da, mPEG-SS 1OK of +140 Da and mPEG-SS 2OK of -290 Da. Due to decreasing resolution of the TOF mass analyzer, precision of the MALDI-TOF mass spectrometric analysis decreased from mPEG-SS 2K (+ 0.3 %) up to mPEG-SS 2OK (+ 1.7 %).
  • MMD maxima of 4770 Da (GEMMA) and 4870 Da (MALDI-TOF MS) for mPEG-SS 5K also fulfill the company's specifications from 3600 to 4400 Da.
  • maxima of 9760 Da for GEMMA analysis and 10150 Da for MALDI-TOF analysis were achieved, perfectly fitting to MMD from 9000 to 11000 Da.
  • MMD maxima acquired for mPEG-SS 2OK, 18700 Da (GEMMA) and 19700 (MALDI-TOF MS) were lying within the specifications of 18000 to 22000 Da.
  • Second parameter for characterization of the mPEG-SS derivatives was the polydispersity, data are summarized in Table 3.
  • Polydispersity stated by the company is based on MALDI-TOF MS data as well as on GPC data, given specifications are 1.05 - 1.1.
  • Calculation of the polydispersity on basis of MALDI-TOF data was supported by MALDI-MS application software (Shimadzu Biotech Launchpad 2.7, Shimadzu Biotech Kratos Analytical, Manchester, UK), whereas calculation based on GEMMA data was performed by using other equations.
  • polydispersity was only calculated from MALDI data, because no GEMMA data could be achieved due to functional limits of the ⁇ CPC (GEMMA detector).
  • MALDI-TOF MS yielded a polydispersity of 1.02.
  • polydispersity could be calculated from MALDI-TOF as well as from GEMMA data, yielding a polydispersity of 1.01 consistent through both methods and all experiments. All calculated polydispersity values are in agreement with the company data, they even are lower than the stated limits. So all mPEG-SS samples exhibit a very low MMD indicated by the low polydispersity value.

Abstract

La présente invention concerne des méthodes de détermination de la polydispersité (PDI) et de la distribution de masse moléculaire (MMD) d'échantillons de PEG réactif qui reposent sur la spectrométrie de masse. L'invention concerne plus particulièrement une méthode de spectrométrie de masse désignée GEMMA qui est utilisée pour déterminer la PDI et la MMD d'échantillons de PEG et qui offre des mesures plus précises que l'analyse MALDI-TOF classique pour les échantillons de PEG de haut poids moléculaire.
PCT/US2009/064896 2008-11-18 2009-11-18 Méthodes de détermination de la polydispersité et/ou de la distribution de masse moléculaire d'un échantillon de polyéthylène glycol WO2010059661A1 (fr)

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JP2011536612A JP2012509469A (ja) 2008-11-18 2009-11-18 ポリエチレングリコールサンプルの多分散度および／または分子量分布を決定する方法
CA2743907A CA2743907A1 (fr) 2008-11-18 2009-11-18 Methodes de determination de la polydispersite et/ou de la distribution de masse moleculaire d'un echantillon de polyethylene glycol
EP09760672A EP2366105A1 (fr) 2008-11-18 2009-11-18 Méthodes de détermination de la polydispersité et/ou de la distribution de masse moléculaire d'un échantillon de polyéthylène glycol
AU2009316749A AU2009316749A1 (en) 2008-11-18 2009-11-18 Methods of determining polydispersity and/or molecular weight distribution of a polyethylene glycol sample

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EP2366105A1 (fr) 2011-09-21
US20130043383A1 (en) 2013-02-21
JP2012509469A (ja) 2012-04-19
US20100126866A1 (en) 2010-05-27
KR20110115568A (ko) 2011-10-21
AU2009316749A1 (en) 2011-06-30

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