Influence of molecular size on tissue distribution of antibody fragments.
Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be ~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues.
a Department of Pharmaceutical Sciences ; School of Pharmacy and Pharmaceutical Sciences; The State University of New York at Buffalo ; Buffalo ; NY.|d These authors contributed equally.
Zhe
Z
Li
b Roche Pharmaceutical Research and Early Development; Pharmaceutical Sciences; Quantitative Systems Pharmacology; Roche Innovation Center Basel ; CH - 4070; Basel.|d These authors contributed equally.
Ben-Fillippo
BF
Krippendorff
a Department of Pharmaceutical Sciences ; School of Pharmacy and Pharmaceutical Sciences; The State University of New York at Buffalo ; Buffalo ; NY.
Sharad
S
Sharma
b Roche Pharmaceutical Research and Early Development; Pharmaceutical Sciences; Quantitative Systems Pharmacology; Roche Innovation Center Basel ; CH - 4070; Basel.
Antje C
AC
Walz
c Roche Pharmaceutical Research and Early Development; Pharmaceutical Sciences; Project Leaders and M&S; Roche Innovation Center Basel ; CH - 4070 Basel.
Thierry
T
Lavé
a Department of Pharmaceutical Sciences ; School of Pharmacy and Pharmaceutical Sciences; The State University of New York at Buffalo ; Buffalo ; NY.
Dhaval K
DK
Shah
D000818:Animals; D006801:Humans; D007128:Immunoglobulin Fragments / Q000494:pharmacology*; D008954:Models, Biological; D008970:Molecular Weight; D014018:Tissue Distribution
D007128:Immunoglobulin Fragments
Antibody Fragments; Biodistribution Coefficient (BC); Biologics; Monoclonal Antibody (mAb); PBPK Model; QSPKR; Tissue Distribution