Abstract
Purpose :
Smaller intermolecular distance (<8 nm) facilitates protein-to-protein interactions and may cause particles in protein solution. Immunogenicity correlates to nature, count and size of particles. Reportedly, proinflammatory reactions were strongly induced by particles about 1 µ in size. Monoclonal–antibodies (mAbs) are subject to QC only up until being filled in vials, then visual inspection and use of filters may make up for it. Aim: to study FDA imposed safety/efficacy balance for 2018-23 approved mAbs, and compare ocular with non-ocular mAbs by using a novel physicochemical approach including converting clinical dose (mg) to count of molecules per dose.
Methods :
Data was extracted from FDA records. We have converted concentrations (mg/mL) to molecule-count/mL, per Avogadro number, 2019 revision: 1 mole contains exactly 6.02214076 E+23 molecules. Molecule diameter was computed from its shape and density. In-vial spacing between molecules (SBM) was calculated by assuming in-vial state of low entropy. Molecule push speed (MPS) was calculated per molecule-count and FDA recommended infusion rate.
Results :
60 FDA mAb approvals were included: 37 IV, 20 SC, 1 IM and 2 IVIT. SBM (nm): Brolucizumab=3.2, Faricimab=5.7; SC vs IV= 7.7±4.2 vs 19.7±15.8/p=.0024; IVIT vs SC/p=.3093; IVIT vs IV/p=.1979; % of scores <8: IVIT=100%, SC=68%, IV=22%. Filters required in 28 (76%) of IV_mAbs; pore size 0.2µ (24/28), 0.2-5µ (3/28), 1.2µ (1/28); size for IVIT_mAbs=5µ. MPS (quadrillion/0.1 min): Brolucizumab=137.3, Faricimab=24.3, SC vs IV= 245.3±202.4 vs 4.95±8.7/p<.0001; IVIT vs SC/p=.2880; IVIT vs IV/p<.0001.
Conclusions :
IVIT_mAb features were skewed to resemble SC_mAbs rather than IV_mAbs. Increased concentration (ie molecule-count) is a way to overcome inferior potency, as in the escalating trend of skyrocketing clinical doses with each launch of a new ocular anti–VEGF: (quadrillion molecule/clinical dose) Brolucizumab=137.3 > AfliberceptHD=41.9 > Faricimab=24.3 > Aflibercept=10.5 > Ranibizumab=6.3 > Bevacizumab=5.1. Yet, a safety hazard is inherent in the dwindling in-vial distance between molecules: (nm) Brolucizumab=3.2 < AfliberceptHD=5.4 < Faricimab=5.7 < Aflibercept=10.4 < Bevacizumab=14.4 < Ranibizumab=15.2. Thus, efficacy gains come at a dire cost of a steep departure from safety zone of IV_mAbs, as embodied by Bevacizumab.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.