Influence of physiochemical properties on the subcutaneous absorption and bioavailability of monoclonal antibodies.
Influence of physiochemical properties on the subcutaneous absorption and bioavailability of monoclonal antibodies.
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DOI：
10.1080/19420862.2020.1770028
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发表时间：
2020-01-01
期刊：
影响因子：
5.3
通讯作者：
Millican R
中科院分区：
文献类型：
--
作者：
Datta-Mannan A;Estwick S;Zhou C;Choi H;Douglass NE;Witcher DR;Lu J;Beidler C;Millican R
许多治疗性单克隆抗体（mAb）最初被开发用于静脉内（IV）施用。作为改善mAb药物能力和患者体验的手段，皮下（SC）给药是mAb越来越重要的递送途径。与IV给药不同，SC注射后报告了抗体的生物利用度限制，并且可以决定mAb是否通过这种胃肠外途径给药。抗体的SC生物利用度一直难以预测，并且其可以是可变的和部分的，其值范围为约50%至100%。导致某些单克隆抗体相对于其他单克隆抗体的生物利用度不完全的机制尚不清楚。有一些有限的数据表明，mAb固有的理化性质可能有助于其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六种人源化mAb的SC吸收和生物利用度的综合影响。我们证明了mAb的理化性质对其SC吸收的速率和程度至关重要。高正电荷和疏水相互作用的组合显著降低了所评价的mAb的SC吸收速率和生物利用度。通过重新设计mAb来减少或平衡这两种属性，恢复了所评估分子的期望性质。这包括与SC组织的结合减少，SC空间的mAb吸收和总体SC生物利用度改善。我们的研究结果指出了评估各种理化因素（包括电荷、疏水性和稳定性）之间的相对平衡的重要性，以改善mAb的SC药物能力，从而选择或工程化mAb，使其在SC给药后具有增强的体内吸收和生物利用度。
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.
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影响因子：
11.2
作者：
Yeung, Yik Andy;Wu, Xiumin;Lowman, Henry B.
通讯作者：
Lowman, Henry B.
影响因子：
5.3
作者：
Datta-Mannan, Amita;Witcher, Derrick R.;Wroblewski, Victor J.
通讯作者：
Wroblewski, Victor J.
影响因子：
3.7
作者：
Charman, SA;McLennan, DN;Porter, CJH
通讯作者：
Porter, CJH
影响因子：
2.4
作者：
Igawa, T.;Tsunoda, H.;Hattori, K.
通讯作者：
Hattori, K.
影响因子：
4.8
作者：
Chaparro-Riggers, Javier;Liang, Hong;Rajpal, Arvind
通讯作者：
Rajpal, Arvind