Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins

Abstract

There are many factors that can influence the pharmacokinetics (PK) of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediated recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic antibodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation. Glycosylation of a mAb or Fc-fusion protein can have a significant impact on the PK of these molecules. mAb charge can be important and variants with pI values of 1-2 unit difference are likely to impact PK with lower pI values being favorable for a longer half-life. Most mAbs display target mediated drug disposition (TMDD), which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody (ADA) response and off-target binding, which require careful consideration during the discovery stage. mAbs are primarily absorbed through the lymphatics via convection and can be conveniently administered by the subcutaneous (sc) route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be reasonably estimated using cynomolgus monkey data and allometric scaling methods.

Keywords: Fc-fusion protein; FcRn; anti-drug antibody (ADA); glycosylation; human PK prediction; monoclonal antibody (mAb); pharmacokinetics; target-mediated drug disposition (TMDD).

Figure 1

Antibody features that contribute to PK properties

Figure 2

FcRn mediated IgG recycling pathway and antibody mediated antigen removal via pH dependent binding. (A) IgG circulating in the blood is taken up by endothelial cells or monocytes through either fluid phase pinocytosis or receptor mediated endocytosis. Once inside the cells, IgG binds to FcRn in the acidified endosomes. IgG that binds to FcRn migrates to the cell surface where the IgG encounters a physiological pH environment (~pH 7.4) and is released back into the blood. IgG that is not bound to FcRn (due to competition with other IgG) will be sorted to lysosomes for degradation. (B) mAb (with strong binding at pH 7.4 and no or weak binding at pH 6) binds to antigen at neutral pH in the circulation; once endocytosed into the cell and entered the acidic endosome, the antibody releases the antigen and binds to FcRn. FcRn bound antibody recycles back to the blood stream while the antigen is degraded in the lysosome

Figure 3

Relationship between charge/pI and half-life and clearance in PK of mAbs. Reproduced from Igawa et al., with permission (2010b)

Figure 4

A typical TMDD graph exhibiting the relationship between clearance or t_1/2 and mAb dose. Anti-α_v mAb was infused to cancer patients; clearance or terminal half-life (t_1/2) was plotted against dose (0.1, 0.3, 1, 3, and 10 mg/kg). Adapted from Mullamitha et al., Clin Cancer Res. (2007)

Figure 5

Hypothetical concentration time curves following iv administration of a mAb in animals with or without ADA

Figure 6

Tumor distribution of anti-Her2 mAbs with different affinities. Adapted from Rudnick et al. (2011)

Figure 7

Relationship between MABEL, NOAEL, therapeutic window and toxicity in FIH trial. MABEL: minimally anticipated biological effect level; NOAEL: no observed adverse effect level. Modified from Muller et al., Curr Opin Biotechnol. (2009)