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`aggregation kinetics after storage for 1 year at 30°C is
`shown in Figure 3. A similar trend of reduced aggrega-
`tion was observed as the amount of either sucrose or
`trehalose was increased from 0 to a molar ratio of ap-
`proximately 500:1 excipient:protein. Formulation with
`carbohydrate in excess of this concentration had less of
`an influence on antibody aggregation, as evidenced by
`the reduced slope in the plot of observed rate constant
`versus excipient concentration. Moreover,
`in all the
`formulations, reduced rates of aggregation were ob-
`tained by reduced storage temperature, but a similar
`trend of the effect of carbohydrate on aggregation was
`observed (data not shown).
`
`antibody structure was obtained from the absorbance of
`excipient-free aqueous protein that had not undergone
`lyophilization (Figure 4A). IR bands were assigned to
`protein secondary structure by comparison to previously
`published IgG antibody spectra.”** For example, bands
`that were characteristic of beta-sheet structure occurred at
`frequencies of 1692 and 1640 cm’, and turn structure
`was represented by the well-resolved bands at frequen-
`cies of 1676 and 1662 cm”. The IR band at 1618 cm’
`was indicative of more beta-sheet structure or was from
`the contribution of amino acid side chains.
`
`A comparison of the FT-IR absorbance of excipient-free
`solid-state and aqueous rhuMAb showedthe occurrence
`of protein secondary structural alteration following
`freeze-drying (Figure 4A). In the solid-state formulation,
`modification of beta-sheet structure was observed as a
`decreased intensity in the IR band at 1640 cm” and a
`broadeningand shifting of the band at 1690 cm’to a fre-
`quency of 1694 cm’. Other structural changes included
`the broadening of the bands that represented rhuMAb
`turn structure and the appearance of a broad band in the
`range of 1650 cm’that may indicate protein unfolding to
`unordered structure.”
`
`A more native-like solid-state rhuMAbstructure was ob-
`tained by formulation with sucrose or trehalose (Figure
`4B, 4C). A comparison of solid-state rhuMAbstructure
`in the carbohydrate-containing formulations to that of
`aqueous protein showed similar beta-sheet structure and
`no evidence of unordered structure following freeze-
`drying. Moreover, native-like turn structure was obtained
`depending on the formulation. For example, formulation
`with sucrose or trehalose at a concentration that was
`equal to or greater than a molar ratio of 500:1 excipi-
`ent:protein resulted in improved resolution of the 2 peaks
`that were indicative of turn structure.
`
`The effect of storage on solid-state rhuMAb conforma-
`tion was determined with protein formulated excipient-
`free and with sucrose at a molar ratio of 500:1 excipi-
`ent:protein. FT-IR absorbance showsthat the solid-state
`rhuMAbsecondary structure of both formulations did not
`change following storage at 30°C for 1 year, a condition
`where, in the case of excipient-free formulation, consid-
`erable soluble aggregate occurred (Figure 5).
`
`Figure 1. SEC-LS of excipient-free freeze-dried rhu-
`MAbthat had been stored for
`1 year at 30°C:
`(A)
`MWay; (B) column elution monitored by the absorbance
`at 280 nm.
`
`Solid-State Protein Structure
`
`Reconstituted Protein Structure
`
`Aqueous and solid-state protein secondary structure
`was evaluated using FT-IR spectrometry. In this analy-
`sis IR absorbance in the amide I region was assessed
`qualitatively following deconvolution using the second
`derivative, an analysis technique that has the advantage
`of being nonsubjective.’ A representation of native
`
`The effect of reconstitution on protein conformation was
`determined by both FT-IR absorbance and circular di-
`chroism of rhuMAb formulated excipient-free and with
`sucrose at a molar ratio of 500:1 excipient:protein. The
`FT-IR absorbance of the samples following reconstitution
`is shown in Figure 6. The spectra of both formula-
`
`Samsung Bioepis Exhibit 1005
`Page 5
`
`AAPS PharmSci 2003; 5 (2) Article 10 (http://www.pharmsci.org).
`
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`Excipient:Protein (mol/mol)
`
`Figure 3. Soluble aggregation kinetics of freeze-dried rhuMAb
`formulated excipient-free and with various concentrations of (open
`circles) sucrose and (open squares) trehalose. Pseudofirst-order rate
`constants were determined from samples stored at 30°C for up to 1
`year.
`
`tein structure was well conserved following lyophiliza-
`tion, storage, and reconstitution.
`
`DISCUSSION
`
`Watertitration of dry protein has shownthat at the ini-
`tial stage of hydration a protein surface contains from
`0% to 7% water that is preferentially bound to charged
`sites on the surface.’’ Solid-state excipient-free freeze-
`dried antibody contained residual water in this range,
`and in this environment water-protein interaction
`probably also occurred with surface-accessible charged
`groups (Table 1). Based on Green and Pauling's hy-
`pothesis, these water-binding sites on a protein consist
`of the side chains of polar amino acids, the C terminus,
`and carbohydrate.”*
`By simply using the protein primary structure and car-
`bohydrate composition, one can calculate the number
`of water-binding sites. Moreover, this estimate may be
`refined by taking into account residue side chain sol-
`vent exposure and the number of hydrogen-bonding
`sites. For example, an estimate of the solvent exposure
`of the polar residues in protein structure has been de-
`termined from the application of a theoretical solvent
`probe to the highly resolved x-ray crystallography
`structure of 50 different water-soluble proteins.”” Fur-
`thermore, the polar side chains of Asp, Asn, Glu, Gln,
`
`and His amino acids contain 2 hydrogen-bondingsites,
`whereas the side chains of Thr, Ser, Tyr, Lys, and Arg
`residues contain a single site.° The application of these
`data to rhuMAb primary structure and carbohydrate
`composition resulted in an estimation of approximately
`550 water-binding sites on the surface of the protein. The
`total amount of water required to interact with these sites
`was 6.7%; this result was in agreement with the water
`monolayer (ie,
`tightly bound water) of excipient-free
`rhuMAb measured by sorption isotherms and calculated
`using the Brunauer-Emmett-Teller equation.*’
`A comparison of the estimated water monolayer with the
`measured residual moisture showed that excipient-free
`freeze-dried rhuMAb contained approximately 25%
`fewer water molecules than required to interact with sur-
`face-accessible protein hydrogen-binding sites. As previ-
`ously discussed, the uncovering of charged sites by de-
`hydration was likely responsible for the observed re-
`versible alteration in solid-state protein structure and the
`related instability during storage of this sample.'' Simi-
`lar results were also observed when freeze-dried excipi-
`ent-free tissue type plasminogen activator was prepared
`at a residual moisture level that was below the estimated
`water monolayer.”
`
`Samsung Bioepis Exhibit 1005
`Page 7
`
`

`

`AAPS PharmSci 2003; 5 (2) Article 10 (http://www.pharmsci.org).
`
`
`drate) exceeded the estimated number of rhuMAb sur-
`face-accessible hydrogen-bonding sites, and this corre-
`lated with improved native-like solid-state protein con-
`formation. Therefore, as predicted by the water substitu-
`tion hypothesis, maintaining a critical amount of excipi-
`ent for interaction with surface-accessible charged sites
`was a key factor in the stabilization of solid-state rhu-
`MAbstructure.
`
`Soluble aggregates may be formed by mechanismsthat
`involve either covalent or non-covalent linkage of protein
`monomers. Because denaturation can expose hydropho-
`bic regions that more readily associate following protein-
`protein contact, the formation of non-covalently linked
`aggregate is often the result of protein structural altera-
`tion.’ Conversely, the formation of covalently linked
`aggregates may or may not involve a change in protein
`structure. For instance, a properly folded protein that
`contains a noncoupled thiol may form aggregates by in-
`termolecular thiol exchange.® On the other hand,protein
`structural alteration may result in disulfide bond break-
`age, and the resulting free thiol may participate in the
`disulfide exchange reaction. In the case of freeze-dried
`trhuMAb,
`the aggregates that occurred during storage
`were characterized as native protein molecules that were
`linked by intermolecular disulfides. As discussed above,
`the preparation of excipient-free formulation caused sig-
`nificant structural alteration in the solid state. This struc-
`tural change probably facilitated the association of con-
`formationally altered protein during storage. Although
`reconstitution resulted in the protein reassuming native
`structure,
`the aggregates were likely stabilized during
`rehydration by the intermolecular exchange of disulfides
`that were placed into close proximity in the solid state.
`Formulation with carbohydrate resulted in improved na-
`tive-like