Effect of Dose, Molecular Size, and Binding Affinity on Uptake of Antibodies

Abstract

The huge molecular radius of immunoglobulins would seem to be a major drawback for the targeting of solid tumors, because of slow extravasation into tumor interstitium and along plasma half-life. The permeability of normal continuous capillary endothelia to intravascular solutes of different molecular sizes has been determined in animals, mainly for macromolecules, and different sources give data consistent with the graph in Fig. 1 (1-3). The position of whole antibodies (IgG, mol wt 150 kDa and effective molecular radius 5.5 nm) is well to the right of albumen (66 kDa and 3.5 nm), and they are therefore very slowly extravasated in normal tissues. A F(ab')2 fragment (100 kDa, 5.06 nm) should not extravasate much faster than the intact molecule on this basis and a monomeric Fab' fragment (50 kDa, 3.48 nm) still has quite a high molecular radius (4), so a much smaller molecule would be necessary to equilibrate very quickly with extracellular fluid (ECF). Fig. 1. Relationship between molecular radius and permeability/surface area product for intact capillaries.

Distinct Uptake Kinetics of Alzheimer Disease Amyloid-β 40 and 42 at the Blood-Brain Barrier Endothelium

“…These results indicate that despite the higher affinity of 125 I-Aβ40 to the luminal BBB receptors compared to that of 125 I-Aβ42, the L-A transcytosis of 125 I-Aβ40 was lower. It is not uncommon for macromolecules to demonstrate greater affinity for the receptors (Thomas, 2000) but show ineffective transcytosis; hence, reduction of receptor affinity is often pursued as a strategy to improve the transcytosis of such molecules (Bien-Ly et al, 2014). While it is possible that the lower ability of 125 I-A40 to transcytose across the BBB endothelium is due to its greater receptor affinity, it may also result from the ability of vasculotropic A40 to inhibit its own exocytosis (Agyare et al, 2013), most likely by interfering with the SNARE assemblies (Sharda et al, 2020).…”

Optimization and comparison of CD4‐targeting lipid–polymer hybrid nanoparticles using different binding ligands

“…The fragmented antibody achieved a higher surface density up to 10,000 mAbs/um 2 (~1250 mAb per LCNP of ~200 nm diameter when accounting for the number of full mAb that generated these fragments, total number of fragments would be two- to four-fold more) compared to 6736 mAbs/um 2 for the full antibody conjugation (~842 mAbs per LCNP). Assuming the surface area projection of an antibody is 95 nm 2 (antibody radius ~5.5 nm), 65 approximately 64% of the spherical surface area is occupied by the full antibody and 95% is estimated to be occupied by fragmented antibodies. This calculation supports the hypothesis that the fragmented antibody could cover most of the surface of the LCNPs, thus hindering the nonspecific binding between the dtLCNPs and cells.…”

PET and SPECT Imaging of the EGFR Family (RTK Class I) in Oncology

“…The pharmacokinetics and blood clearance of a potential tracer is, to a large extent, dependent on their size. The capillary permeability decreases with the increasing molecular weight and effective molecular radius of the protein [ 76 ]. Thus, a smaller imaging agent can provide better extravasation, deeper penetration into the tumors, and rapider clearance of the non-bound agent from circulation and may enable high imaging contrast a few hours after injection [ 71 , 77 , 78 , 79 , 80 ].…”

“…Their smaller size overall increases their clearance from the blood, and enables reasonable imaging contrast earlier than in the case of intact antibodies [ 71 ]. Despite the lower molecular weight, the effective molecular radius of F(ab′) 2 fragments is only slightly smaller than full-length antibodies (5.05 nm vs. 5.5 nm), which still limits their extravasation compared with other smaller targeting molecules [ 76 ]. scFvs, which consist of the variable domains of light and heavy chains (VL and VH) linked by a polypeptide linker, have an even smaller size than antibody fragments (25–27 kDa).…”