ABSTRACT

Many therapeutic monoclonal antibodies (mAbs) were initially developed for intravenous (IV) administration. As a means to improve mAb drug-ability and the patient experience, subcutaneous (SC) administration is an increasingly important delivery route for mAbs. Unlike IV administration, bioavailability limitations for antibodies have been reported following SC injection and can dictate whether a mAb is administered via this parenteral route. The SC bioavailability of antibodies has been difficult to predict, and it can be variable and partial, with values ranging from ~50% to 100%. The mechanisms leading to the incomplete bioavailability of some mAbs relative to others are not well understood. There are some limited data that suggest the physiochemical properties inherent to a mAb can contribute to its SC absorption, bioavailability, and in vivo fate. In this study, we evaluated the integrated influence of multiple mAb physiochemical factors on the SC absorption and bioavailability of six humanized mAbs in both rats and cynomolgus monkeys. We demonstrate the physiochemical properties of mAbs are critical to their rate and extent of SC absorption. The combination of high positive charge and hydrophobic interaction significantly reduced the rate of the evaluated mAb’s SC absorption and bioavailability. Reduction or balancing of both these attributes via re-engineering the mAbs restored desirable properties of the molecules assessed. This included reduced association with SC tissue, improvements in mAb absorption from the SC space and overall SC bioavailability. Our findings point to the importance of evaluating the relative balance between various physiochemical factors, including charge, hydrophobicity, and stability, to improve the SC drug-ability of mAbs for selecting or engineering mAbs with enhanced in vivo absorption and bioavailability following SC administration.

摘要

最初开发出许多治疗性单克隆抗体（mAb）用于静脉内（IV）给药。作为改善mAb药物治疗能力和改善患者体验的一种手段，皮下（SC）给药是mAb日益重要的递送途径。与静脉内给药不同，已经报道了SC注射后抗体的生物利用度限制，并且可以决定是否通过这种肠胃外途径施用mAb。抗体的SC生物利用度很难预测，并且可以是可变的和部分的，其值约为50％至100％。导致某些mAb相对于其他mAb的生物利用度不完全的机制尚不十分清楚。有一些有限的数据表明，mAb固有的理化特性可能有助于其SC吸收，生物利用度和体内命运。在这项研究中，我们评估了多种mAb理化因素对大鼠和食蟹猴中6种人源化mAb的SC吸收和生物利用度的综合影响。我们证明了mAb的理化特性对于其吸收SC的速率和程度至关重要。高正电荷和疏水性相互作用的结合显着降低了评估的mAb的SC吸收率和生物利用度。通过重新设计mAb减少或平衡这两个属性，可以恢复所评估分子的理想特性。这包括减少与SC组织的联系，改善从SC空间吸收mAb以及提高整体SC生物利用度。我们的发现指出了评估各种物理化学因素（包括电荷，SC给药后的体内吸收和生物利用度。