Protein crystallization as a mechanism for biosimilar formulation

Apotex的子公司Apobiologix是生物仿制药生产和分销的市场领导者。 生物仿制药是复杂的生物分子，如蛋白质或抗体，与市场上已上市的其他生物产品高度相似。为了将蛋白质推向市场，它需要在称为配方的过程中进行制备和稳定。在有效的制剂中，蛋白质需要处于高浓度，然而这可能导致不期望的粘度增加、异常蛋白质聚集、沉淀、降解或稳定性损失，所有这些都是不期望的。增加蛋白质浓度的另一种方法是通过结晶;蛋白质晶体是半固体（不像盐晶体），因此保持了非常大的蛋白质浓度，而没有简单地向溶液中添加更多蛋白质的缺点。然而，每种分子的结晶需要独特的条件，这些条件必须在稳定晶体用于下游配制工艺之前通过筛选和优化的经验研究来确定。Apobiologix在蛋白质结晶方面没有内部专业知识，因此与约克大学合作，以确定和优化蛋白质结晶的框架，作为生物仿制药制剂的机制。本申请中概述的研究旨在确定重组人生长激素（rhGH）生物仿制药的结晶和稳定框架。研究将侧重于确定rhGH的多种结晶条件，然后根据规模进行优化，同时确保制剂溶液中rhGH晶体的长期稳定性。然后，结晶和稳定的rhGH可以转移到Apobiologix的生物类似药产品管道中，从而将这种蛋白质生物类似药推向市场。在该提案的支持下，我们的目标是（1）在Apobiologix和约克大学之间建立持续的研究伙伴关系，以及（2）促进未来对产品开发生物仿制药结晶的研究。

Apobiologix, a division of Apotex, is a market leader in the production and distribution of biosimilars. Biosimilars are complex biological molecules, such as proteins or antibodies, which are highly similar to other biological products already on the market. In order to bring a protein to market, it needs to be prepared and stabilized in a process known as formulation. In an effective formulation a protein is required to be at a high concentration, however this can lead to undesirable increases in viscosity, abnormal protein aggregation, precipitation, degradation, or loss in stability, all of which are undesirable. An alternate approach to increase a protein's concentration is through crystallization; protein crystals are semi-solid (unlike salt crystals), and therefore maintain a very large protein concentration without the drawbacks of simply adding more protein to the solution. However, crystallization of each molecule requires unique conditions that must be determined through an empirical investigation of screening and optimization prior to stabilization of the crystals for downstream formulation processes. Apobiologix does not have in-house expertise in protein crystallization, and has therefore partnered with York University to identify and optimize a framework for protein crystallization as a mechanism for biosimilar formulation. The research outlined in the current application seeks to determine a crystallization and stabilization framework for a recombinant human growth hormone (rhGH) biosimilar. Research will focus on identifying multiple crystallization conditions for rhGH that will then be optimized to scale, while ensuring the long term stability of the rhGH crystals in formulation solutions. Crystallized and stabilized rhGH can then be moved into the biosimilar product pipeline at Apobiologix, resulting in bringing this protein biosimilar to market. With the support of this proposal, we aim to (1) develop an on-going research partnership between Apobiologix and York University, and (2) foster future research into the crystallization of biosimilars for product development.