Pharmacokinetic comparison of a diverse panel of non-targeting human antibodies as matched IgG1 and IgG2 isotypes in rodents and non-human primates

Abstract

In this study we compared the pharmacokinetic profile of four unrelated antibodies, which do not bind to mammalian antigens, in IgG1 and IgG2 frameworks in both rats and non-human primates (NHP). This allowed for extensive cross comparison of the impact of antibody isotype, complementarity determining regions (CDR) and model species on pharmacokinetics without the confounding influence of antigen binding in the hosts. While antibody isotype had no significant impact on the pharmacokinetics, the CDRs do alter the profile, and there is an inverse correlation between the neonatal Fc receptor (FcRn) affinity and pharmacokinetic performance. Faster clearance rates were also associated with higher isoelectric points; however, although this panel of antibodies all possess basic isoelectric points, ranging from 8.44 to 9.18, they also have exceptional in vivo half-lives, averaging 369 hours, and low clearance rates, averaging 0.18 ml/h/kg in NHPs. This pattern of pharmacokinetic characteristics was conserved between rats and NHPs.

The immunomodulatory functions and molecular mechanism of a new bursal heptapeptide (BP7) in immune responses and immature B cells

“…Additionally, BP7 stimulated increases in IL-4 levels and T cell subpopulation numbers in models in immunization experiments. The IgG1 and IgG2α isotypes are both important IgG subclasses during vaccination [26, 27]. It was reported that the IgG2a subclass is a characteristic of the Th1-type immune response, while IgG1 is a representative factor of the Th2-type immune response [28, 29].…”

VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy

“…At lower doses, the shorter t 1/2 can be attributed to internalization of mAb complexes with both sFlt-1 and membrane-bound Flt-1. Interestingly, the serum t 1/2 of both 21B3 (∼35 h) and 27H6 (∼70 h) was unusually short compared with the typical t 1/2 for IgG mAbs in humans (2–3 weeks) 43 and monkeys (6.5 days), 44 even with the higher doses; this could be attributed to extensive binding to membrane Flt-1, as indicated by our studies in cell lines overexpressing Flt-1. Consequently, the presence of a competing target could potentially exhaust the pool of mAbs, leaving enough uninhibited sFlt-1 to act as a VEGF sink.…”

Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer’s Disease in Rat and Dog

“…Relatively consistent clearance among all groups suggested linear pharmacokinetics at selected dose range (Table I). These clearance values are higher than those of a typical non-targeting mAb but lower than a typical sdAb without Fc domain (33)(34)(35). Target of FC5, TMEM30A (Cdc50a) 2 FC5 binding to canine, rat and human endothelial cells.…”