Kim Shepard*, Molly Adam, John Baumann, Julia Oddo, Amanda Pluntze, Lauren Switala & David Vodak

Co-authors: Philip Kuehl, David Revelli and Yue Zhou (Lovelace Biomedical, Albuquerque, NM)

Shepard et al, “Local Treatment of Non-small cell lung cancer with a spray-dried bevacizumab formulation” AAPS PharmSciTech (2021)

BACKGROUND

Bevacizumab

Bevacizumab is a monoclonal antibody VEGF-inhibitor which is an approved  product for treatment of cancers, as well as age-related macular degeneration. It works by inhibiting the growth of blood vessels, which are essential for growth  of tumors in cancer.

Use for NSCLC

• Treats non-small cell lung cancer (NSCLC)
• IV infusion in clinic every 3 weeks, in combination with chemotherapy
• Serious side effects, such as fatal bleeding
• Many patients must be excluded from treatment due to high risk of bleeding

PURPOSE

Project goals

Demonstrate a platform for inhaled biologics manufactured by spray drying, which can be shared in a peer-reviewed article

Product goals

Develop a formulation of bevacizumab for local delivery to the lung using a dry powder inhaler. Potential to:

• Improve patient compliance & convenience
• Reduce cost of treatment
• Enable prolonged maintenance therapy
• Reduce dose and potential side effects

Formulation goals

Manufacture an SDD using bevacizumab, trehalose and L-leucine which achieves:

• Preserved biological activity
• Physical stability at ambient temperature
• Targeted particle size for lung delivery
• Demonstrated efficacy in NSCLC rat model

MANUFACTURING

SDD formulation:

40/40/20 bevacizumab/ trehalose/ L-leucine by weight

Spray drying parameters

Develop a formulation of bevacizumab for local delivery to the lung using a dry powder inhaler. Potential to:

• Improve patient compliance & convenience
• Reduce cost of treatment
• Enable prolonged maintenance therapy
• Reduce dose & potential side effects

RESULTS

Particle size and respirability

• SDDs have good aerosol properties for delivery to the deep lung, measured by next-generation impactor 
• Mass median aerodynamic diameter = 2.3µm
• Fine particle fraction = 80%

VEGF inhibition

• In luciferase reporter assay, bevacizumab SDD and bevacizumab control inhibit VEGF expression at indistinguishable levels.
• For more details about the assay kit, click here.

Physical state and stability

• L-leucine is crystalline in the SDD, by design
• Trehalose and bevacizumab are a single amorphous phase with a T_g onset of 118°C
• After 6 months at both 5°C and 25°C (closed with desiccant), no changes in state, particle size, or VEGF activity are observed.

Efficacy study in rats

• NSCLC CALU-3 cells were instilled into the lungs of nude rats and allowed to grow for 3 weeks
• Weekly treatment was administered for 5 weeks:

1. 1. 1.5mg/kg bev SDD
   2. 1.5mg/kg bev SDD plus 3mg/kg cisplatin IP
   3. 15mg/kg bev IP plus 3mg/kg cisplatin IP
   4. No treatment

• Bev SDD reduced tumors compared with control
• Bev SDD with cisplatin reduced tumors as much as bev IP with cisplatin, even though the bev SDD dose was 1/10^th smaller
• In maintenance study, treatment was continued for 4 additional weeks with bevacizumab SDD only. Maintenance treatment reduced tumor burden and improved survival compared to control.

CONCLUSIONS

• Monoclonal antibodies can be spray dried resulting in a stable, respirable, and efficacious dry powder formulation for lung delivery
• Inhaled bevacizumab is effective at reducing NSCLC lung tumor burden in a rat model when administered to the lung as a dry powder

Inhalation particle size

Next-Generation Impactor shows a high fine particle fraction, meaning much of the powder will be delivered to the deep lung.

Retains anti-VEGF activity

Bevacizumab retains similar biological anti-VEGF activity to control solution after spray drying, as measured by a Promega luminescence assay kit.

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