Lonza Small Molecules

Inhaled bevacizumab SDDs: Local treatment for non-small cell lung cancer

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)




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


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


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



Batch Size

30g SDD

Liquid flow rate

6 g/min



Atomization pressure


Outlet Temp

50° C

Inlet Temp

~120° C


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 Tg 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. 1.5mg/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 1/10th 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.


  • 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

Breathe Easy: An inhaled SDD formulation of bevacizumab shrinks tumors in rat lung cancer model

Inhalation particle size

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

Inhalation Particle Size

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.

Retains anti-VEGF activity

Effective with cisplatin at 1/10th the IV dose

In vivo results show when dosed with cisplatin (standard of care), inhaled bevacizumab is as effective as injected, even at 1/10th the dose.

Effective with cisplatin at 1/10th the IV dose

Effective for maintenance 

Maintenance treatment is continued when the patient can no longer tolerate chemotherapy. Inhaled bevacizumab helps increase survival times and maintain lower tumor burden during maintenance therapy. Potential for convenient at-home administration

Effective for maintenance 


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