Preventing physical and chemical degradation of the LABL-Fc-MOGR5, a bifunctional peptide inhibitor, with formulation development approaches.

Abstract

Background: LABL-Fc-MOG_R5 is a bifunctional peptide inhibitor designed to modulate immune responses in multiple sclerosis, including primary progressive multiple sclerosis. Although therapeutically promising, its development has been hindered by poor physical stability, particularly rapid precipitation under standard formulation conditions.

Methods: A high-throughput, multi-phase formulation strategy was implemented to improve conformational and colloidal stability. An initial Phase 1 evaluation used intrinsic fluorescence differential scanning fluorometry and polyethylene glycol (PEG) solubility assays to screen 96 formulations spanning a range of pH values, buffer systems, and excipients. Then, a Phase 2 study applied a definitive screening design to evaluate key formulation variables-including buffer type, excipients, and surfactant concentration-at reduced protein concentration in 96-well plates. A final Phase 3 study compared the lead formulation from Phase 2 with the control formulation at higher protein concentration in glass vials.

Results: The Phase 1 study revealed pronounced sensitivity of LABL-Fc-MOG_R5 to pH and ionic strength. Divalent anionic buffers (e.g. citrate, succinate) and excipients such as sucrose and hydroxypropyl-β-cyclodextrin substantially reduced aggregation propensity. In the Phase 2 study, an optimized formulation was identified-10 mM sodium acetate, pH 5.3, 125 mM sucrose, 150 mM HBP-LB-βCD, and 0.025% polysorbate 80-based on statistical modeling. This formulation demonstrated markedly improved resistance to aggregation, fragmentation, and subvisible particle formation under accelerated stress relative to the control.

Conclusions: This work underscores the value of excipient selection and rational design of experiments in stabilizing complex fusion proteins. The optimized formulation provides a significantly enhanced stability profile and supports further development of LABL-Fc-MOG_R5 toward clinical evaluation for primary progressive multiple sclerosis.