Abstract
Purpose :
To provide build insights for future tasks of designing new ocular biopharmaceuticals based on optimal balance of affinity vs. avidity and efficacy vs. potency.
Methods :
List of approved biopharmaceuticals was obtained from FDA records and structure/function data was mined from regulatory evaluations, publications and patents.
Results :
Of 87 approved 67 were monoclonal-antibodies (mAb) – 63/67 full-mAb (145.5±1.5 kDa): 3/63 chimeric, 30/63 humanized, 30/63 human; 8/63 IgG2, 11/63 IgG4, 2/63 hybrid, 42/63 IgG1; 3 bispecific; 6 Fc-modified; 8 mAb-drug conjugates (5 enzyme-, 2 acid- and 1 non-cleavable – drug/mAb ratio of 4.9±1.9). 4/67 non-full: 1 fragment antigen binding (Fab), 1 single-chain variable fragment (scFv), 1 single-domain antibody (sdAb) and 1 Fv-fusion.
Conclusions :
Full-mAb hegemony has yet to be truly contested (typically human/-ized IgG1k). Novelties included bispecific-mAb and Fc-altered amino-acid or fucose to boost avidity. Fab, scFv, sdAb and fusions are emerging – no one a racehorse yet. Eye approvals were cenegermin (nerve GF /Neurotrophic Keratitis), teprotumumab for TED (148 kDa human IgG1k) and brolucizumab for wAMD (26 kDa humanized scFv). With prior approvals, aflibercept (115 kDa Fc-fusion receptor) and ranibizumab (48 kDa humanized Fab), the average MW of ocular anti-VEGFs is 63 kDa, well under all-mAb MW mean and contrast to bevacizumab MW (149 kDa humanized IgG1k). As per the standard IVT doses, 1.2 molecules of ranibizumab, 2.1 of aflibercept and 27.2 of brolucizumab, each has an anti-VEGF potency comparable to just 1 bevacizumab molecule. With molecular-radius roughly twice higher, 1 bevacizumab molecule can still cross the retina and perform an anti-VEGF “work” comparable to that of 27.2 molecules of the smaller brolucizumab – practically setting aside the argument of size-related obstacles to mAb penetration across the retina. A no surprise, since bevacizumab has 2 Fab per 1 molecule and Fc region for FcRn assisted passage across retina barriers. Higher mAb concentrations catalyze a growing risk of unleashing a generic tendency to aggregate (en syringe) that could lead to immune-mediated adverse effects. Thus, despite emerging innovative mAb designs, full-mAb based design (e.g. bevacizumab) is still the molecular design to beat in terms of ocular anti-VEGF potency per 1 molecule.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.