采用战略性、分阶段方法加速抗体及新型生物制剂的高浓度制剂开发

Principal Scientist, Pharmaceutical Development, Integrated Biologics, Lonza Overcoming challenges to formulation development for highly concentrated biologic drug products(≥ 100 mg/mL) requires specialized knowledge and capabilities. The challenge level increases with morecomplex biologics and with a drive to accelerate development timelines to better serve customer needs.Lonza’s team of experts leverages a unique combination ofin silicoandin vitroassessment tools, design of Growing importance of high-concentration Early biologic drugs were mostly developed for IV adminis-tration at launch. Self-administration involves subcutaneous(SC) delivery. IV formulations are often formulated at lowerconcentrations (typically below 50 mg/mL), which helps avoidchallenges like high viscosity and protein aggregation. Incontrast, subcutaneous delivery, especially via autoinjectors Over the last decade, the number of biologic drug productsmarketed at protein concentrations of 100 mg/mL or higherhas increased noticeably [1]. The main driver for this growth isthe greater focus on development of drug products for Self-administration of biologic therapies offers significantadvantages for patients managing autoimmune, neurologi-cal, gastrointestinal, metabolic, and immunologic conditionsrequiring frequent dosing. The availability of auto-injected The growing interest in self-administration has thus driventhe development of high-concentration formulations as partof life-cycle management activities for many biologics. In ad-dition, market pressure and better understanding of biologic Higher viscosity products present additional difficultiesduringdownstream processing and fill/finish of drug products. It ismore difficult to process higher-viscosity liquids via tan-gential flow filtration (TFF) due to higher pressures and lower Furthermore, administering highly viscous formulations canbe a challenge due to limitations with the typical needle sizesand injection forces known to allow for painless and easy in- High-concentration biologic formulationposes numerous challenges Formulating highly concentrated biologics comes with a spe-cific set of additional challenges. With an increasing concen-tration, protein-protein interactions become prevalent in thebehavior of the solution, potentially leading to higher viscos- To address these challenges efficiently, developers of highlyconcentrated formulations typically use screening strategiesevaluating the effects of pH, ionic strength, and excipients on Figure 2 Differences in surface charge distributions for a standard mAb and Fc-fusion protein. Charges calculated withAdaptative Poisson-Boltzmann Solver (APBS, Holst and F. Saied, Multigrid solution of the Poisson-Boltzmann equation.J. Comput. Chem.14, 105–113, 1993) visualized in Pymol Molecular Graphics system (Schrödinger, LLC). Even greater challenges for complex,novel modalities While mAbs continue to account for the majority of biologicsbrought to the clinic, biologic products based on New Molec-ular Formats (NMFs) account for a growing percentage ofrecombinant proteins entering chemistry, manufacturing, diabodies, and scFv-BsAb swaps or fusions. Finally,Fc-fusionsincrease molecular complexity further and can incorporate The behavior of proteins in solution is largely driven by theirstructures. As such, It is expected that high complexity mo- For instance, the surface charge distributions for NMFs cancreate more challenges than those of more standard mAbs.Comparing computed surface charges for a mAb and an NMFs are extremely diverse with significant heterogeneitywithin each format (Figure 1, previous page). For instance,bispecific antibodies incorporate three or four chains wheth- As can be seen in Figure 2, both molecules are highly chargedat the lowest pH (4.0), which is expected at pH values sig-nificantly lower than the isoelectric point (pI of 7.2 for theFc-fusion and 7.1 for the IgG1). At physiological (7.0) or typical-ly encountered pH levels for mAb formulations (6.0), the IgG1mAb has low and evenly distributed surface charges while fusion shows this steep increase. However, these two casesillustrate some of the challenges to developing highly con-centrated NMFs and underscore the importance of under-standingmolecule-specific requirements for formulation In addition, the above examples clearly demonstrate thatrapidly identifying optimal formulations requires a compre- NMFs comprising domains originating from different pro-teins exhibit complex behaviors due to the varying propertiesof each component. For instance, fusion partners often havelower conformational stabilities, different pI values, and high-er aggregation propensities than Fc fragments or even thanoriginator proteins. As a result, such molecules can behave Figure 3 shows differential scanning fluorimetry (nanoDSF)curves for a conventional mAb and an scFv fusion bsAb. Ascan be seen in the figure, the first thermogram (A) shows 2domains of the