(T1230-03-15) Controlled Release of Monoclonal Antibodies from Long-Acting PLGA-Coated Implants

Purpose: Local controlled release of therapeutic monoclonal antibodies (MAbs) has important applications in many diseases such as brain and oral cancer, and macular degeneration. Previous studies in our group have shown that coated poly(lactide-co-glycolide) (PLGA) implants are capable of slowly releasing stabilized anti-angiogenic MAbs with excellent efficacy in rodent models (1). The anti-interleukin-6 (IL-6) receptor tocilizumab (TCZ) was selected as a model MAb for the purpose of optimizing formulation features such as the PLGA coating that allows for high levels of osmotic trehalose in the core implant and promotes both stability and slow release of the MAb.

Methods: Commercial grade TCZ solution was buffer exchanged into sodium phosphate solution to give a MAb/trehalose ratio of 1:1.5 before freeze-drying. The TCZ powder was micronized by grinding or cryo-milling (˂ 90 µm) before mixing with a 50 % w/v PLGA 50/50/acetone polymer solution containing 3% w/w MgCO₃. Core implants were prepared by extrusion of the MAb/polymer suspension into 0.8 mm silicone rubber tubing and then vacuum drying. A 30-50% w/v PLGA 50/50/acetone coating solution was used to coat core implants 1-3 times by re-extruding around the implant in the silicone rubber tubing with pre-mixing with a spatula or dual syringe. After vacuum drying, the prepared TCZ implants were evaluated for drug composition in both the protein powder and the implant, and during in vitro release in PBS+0.02% Tween 80 at 37 °C using size-exclusion (SEC)-UPLC. The moisture content of each TCZ powder and the water uptake of TCZ implants were evaluated by Fischer titration and gravimetry, respectively. The stability of the released TCZ samples was studied using SEC-UPLC, far UV circular dichroism (CD) spectroscopy, and ELISA.

Results: The drug composition in the powder (39.9 ± 2.6%) was very close to theoretical values and contained ~2.2 % moisture. Likewise, drug loading was typically within ~10% of theoretical in core implants and coating caused a slight drop in loading from the additional PLGA added to the implants (e.g., 7.2 ± 0.8%). Without coating TCZ release was rapid and essentially complete within a few days. Coating with pure PLGA of the same type strongly reduced release and decreased water content in the implant (e.g., 64.2% vs. 94.3% after 14 days). Double coating was useful to obtain continuous and complete release, whereas release was too fast or incomplete for single and triple coating, respectively. Dual syringe pre-mixing increased reproducibility of loading and release kinetics. Micronization reduced the initial burst release relative to conventional grinding/sieving. In each case with double coating drug release duration was approximately 4-5 weeks with complete ( >80%) release. Stability of TCZ was excellent with >80% monomer and unchanged CD traces over the first 21-35 days. Immunoreactive content of optimized formulations was high ( >80%) through 4 weeks and dipped slightly at the release end (~60% by 50 weeks).

Conclusion: By loading the TCZ into long-acting coated PLGA implants, the high initial burst and short release duration of TCZ were each prevented, and a 1-month slow and continuous release was attained with minimal instability of the monoclonal antibody. Adjusting the pre-mixing, coating and drug particle size are important to enhance stability and release of the encapsulated MAbs.

References: 1- Schwendeman, S. P. and Chang, R. S., Coated implants for long-term controlled release of antibody therapeutics, EP 3,452,013, 2021.

Acknowledgements: This research was supported in part by the BioInnovations in Brain Cancer (BIBC) program at the University of Michigan.

Figure 1: % loading of TCZ-loaded PLGA implants (A) and in vitro release of TCZ from TCZ-Loaded implants (B).

Figure 2: CD spectra of TCZ in vitro release samples (A) and ELISA assay for TCZ release samples (B).