Influence of molecular size on tissue distribution of antibody fragments

Abstract

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.

Keywords:

• Antibody Fragments
• Biodistribution Coefficient (BC)
• Biologics
• Monoclonal Antibody (mAb)
• PBPK Model
• QSPKR
• Tissue Distribution

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was in part supported by NIH grant GM114179 to DKS. SS was supported by the post-doctoral fellowship from Roche. We thank the members of the Quantitative and Systems Pharmacology Group at Roche pRed for valuable discussion regarding disposition of large molecules.

Supplementary Material

Supplemental data for this article can be accessed on the publisher's website.