Influence of Molecular size on the clearance of antibody fragments

Abstract

Purpose To establish a continuous relationship between the size of various antibody fragments and their systemic clearance (CL) in mice. Methods Two different orthogonal approaches have been used to establish the relationship. First approach uses CL values estimated by non-compartmental analysis (NCA) to establish a correlation with protein size. The second approach simultaneously characterizes the PK data for all the proteins using a 2-compartment model to establish a relationship between protein size and pharmacokinetic (PK) parameters. Results Simple mathematical functions (e.g. sigmoidal, power law) were able to characterize the CL vs. protein size relationship generated using the investigated proteins. The relationship established in mouse was used to predict rat, rabbit, monkey, and human relationships using allometric scaling. The predicted relationships were found to capture the available spares data from each species reasonably well. Conclusions The CL vs. protein size relationship is important for establishing a robust quantitative structure-PK relationship (QSPKR) for protein therapeutics. The relationship presented here can help in a priori predicting plasma exposure of therapeutic proteins, and together with our previously established relationship between plasma and tissue concentrations of proteins, it can predict the tissue exposure of non-binding proteins simply based on molecular weight/radius and dose.

Effect of Size on Solid Tumor Disposition of Protein Therapeutics

“…The calculated CL values for F(ab) 2 and Fab were 4.2E204 and 4.6E203 l/h, respectively. These values are also close to the calculated values from the collected PK studies of F(ab) 2 and Fab in mice (4.4E204 and 2.7E203 l/h, respectively) in the literature (Li et al, 2017). The smallest molecule, scFv (;27 kDa), had a plasma half-life of less than 1 hour (;0.5 hour) in both tumor models.…”

“…The calculated clearance (CL) of normal IgG was around 1.0E205 l/h, which is close to the average calculated values from the literature-reported PK data of IgGs in mice (1.6E205 l/h). (Li et al, 2017). For FcRn nonbinding IgG (;150 kDa), the plasma half-life was similar in both tumor models (;8 hours).…”

“…The calculated CL value for scFv was 1.5E202 l/h, which was roughly 10fold higher than the calculated value from the literature collected studies (1.6E203 l/h). (Li et al, 2017) Of note, to avoid any confounding effect of labeling and label-based analytical methods, here we have quantified all the molecules using a validated ELISA method. As such, the reported PK parameters may differ from the one generated using labeled molecules.…”

“…Drug-specific factors include serum half-life, target-mediated drug disposition in the tumor, and protein size. Of these factors, size plays an important role because it affects overall tumor exposure by affecting both systemic PK (Li et al, 2016(Li et al, , 2017 and tumor penetration of protein therapeutics (Beckman et al, 2007;Thurber et al, 2007Thurber et al, , 2008b. To date, however, there is no consensus on whether there is an optimal molecular size for targeting protein therapeutics to solid tumor.…”

Pharmacokinetics of protein and peptide conjugates

“…[55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72]. These engineered antibody fragments retain the binding properties of the full-size antibody, and clear from the systemic circulation rapidly, since there is an inverse relationship between the size of a protein and systemic clearance [73]. This PK property allows them to achieve higher tumor:plasma contrast ratio compared to the full length antibodies.…”