Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration

作者：Zheng Yanan; Tesar Devin B; Benincosa Lisa; Birnboeck Herbert; Boswell C Andrew; Bumbaca Daniela; Cowan Kyra J; Danilenko Dimitry M; Daugherty Ann L; Fielder Paul J; Grimm Hans Peter; Joshi Amita; Justies Nicole; Kolaitis Gerry; Lewin Koh Nicholas; Li Jing; McVay Sami; O'Mahony Jennifer; Otteneder Michael; Pantze Michael; Putnam Wendy S; Qiu Zhihua J; Ruppel Jane; Singer Thomas; Stauch Oliver; Theil Frank Peter; Visich Jennifer; Yang Jihong; Ying Yong

来源：mAbs, 2012, 4(2): 243-255.

DOI：10.4161/mabs.4.2.19387

• mAb IgG
• neonatal Fc receptor (FcRn)
• pharmacokinetics
• subcutaneous bioavailability
• animal model
• minipig

Subcutaneous (SC) delivery is a common route of administration for therapeutic monoclonal antibodies (mAbs) with pharmacokinetic (PK)/pharmacodynamic (PD) properties requiring long-term or frequent drug administration. An ideal in vivo preclinical model for predicting human PK following SC administration may be one in which the skin and overall physiological characteristics are similar to that of humans. In this study, the PK properties of a series of therapeutic mAbs following intravenous (IV) and SC administration in Gottingen minipigs were compared with data obtained previously from humans. The present studies demonstrated: (1) minipig is predictive of human linear clearance; (2) the SC bioavailabilities in minipigs are weakly correlated with those in human; (3) minipig mAb SC absorption rates are generally higher than those in human and (4) the SC bioavailability appears to correlate with systemic clearance in minipigs. Given the important role of the neonatal Fc-receptor (FcRn) in the PK of mAbs, the in vitro binding affinities of these IgGs against porcine, human and cynomolgus monkey FcRn were tested. The result showed comparable FcRn binding affinities across species. Further, mAbs with higher isoelectric point tended to have faster systemic clearance and lower SC bioavailability in both minipig and human. Taken together, these data lend increased support for the use of the minipig as an alternative predictive model for human IV and SC PK of mAbs.

• 出版日期2012-4