Fate of inhaled monoclonal antibodies after the deposition of aerosolized particles in the respiratory system

Guilleminault, L.; Azzopardi, Nicolas; Arnoult, Christophe; Sobilo, Julien; Hervé, Virginie; Montharu, J.; Guillon, Antoine; Andres, Christian R.; Hérault, Olivier; Pape, Alain Le; Diot, Patrice; Lemarié, É.; Paintaud, Gilles; Gouilleux-Gruart, Valérie; Heuzé-Vourc’h, Nathalie

doi:10.1016/j.jconrel.2014.10.003

Cited by 99 publications

(80 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…33 The feasibility of using nebulized therapeutic antibodies was demonstrated in a study showing that airwaydelivered cetuximab, an anti-EGFR antibody, accumulated rapidly in cancerous lung tissue at concentrations twice those achieved after i.v. delivery 22 and in a study on an anti-influenza virus neutralizing monoclonal antibody (MAb) that revealed higher concentrations of the antibody in the bronchoalveolar lavage fluid (BAL), with low penetration into the bloodstream upon direct delivery to the respiratory tract. 23 Moreover, local delivery of an anti-VEGF MAb to K-ras-induced adenocarcinoma-bearing lungs efficiently reduced tumor burden at »100-fold lower serum concentration of MAb than that after systemic delivery.…”

Section: Discussionmentioning

confidence: 99%

“…The MAb RB6-8C5 was administered endotracheally. 22,24 Briefly, mice were anesthetized and given 25 mg/ mouse of RB6-8C5 MAb using a Microsprayer Aerosolizer Model IA-1C connected to a FMJ-250 high-pressure syringe (Penn-Century, Philadelphia, PA, USA) introduced just before the first trachea bifurcation. 32 In all experiments, mice were weighed twice weekly, euthanized at the end of experiments and macroscopic lung metastases counted.…”

Section: Mice and Experimental Protocolsmentioning

confidence: 99%

See 1 more Smart Citation

Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor

et al. 2016

View full text Add to dashboard Cite

Due to their constant exposure to inhaled antigens, lungs represent a particularly immunosuppressive environment that limits excessive immune responses; however, cancer cells can exploit this unique environment for their growth. We previously described the ability of aerosolized CpG-ODN combined with Poly(I:C) (TLR9 and TLR3 agonists, respectively) to promote antitumor immunity in a B16 melanoma lung metastasis model. Here, we explored the possibility of improving the therapeutic efficacy of TLR9/TLR3 agonist combinations by including in the inhalant either an antibody directed to both Ly6G and Ly6C markers to locally deplete myeloid-derived suppressive cells (MDSCs) or IFNa to directly activate the natural killer (NK) and macrophage innate immune cells in the lung. Addition of nebulized anti-MDSC antibody RB6-8C5 to aerosolized CpG-ODN/Poly(I:C) resulted in reduced mRNA levels of immunsuppressive molecules (IL10, Arg-1, and Nos2), increased activation of resident NK cells and improved treatment outcome, with a significant reduction in established B16 melanoma lung metastases compared to treatment with CpG-ODN/ Poly(I:C) alone. Likewise, addition of aerosolized IFNa led to increased mRNA levels of proinflammatory cytokines (IL15 and IFNg) in the lung and recruitment of highly activated NK cells, with no evident signs of toxicity and with a significantly improved antitumor effect as compared with aerosolized CpG-ODN/Poly(I:C). Combining both IFNa and RB6-8C5 with CpG-ODN/Poly(I:C) did not produce an additive effect compared to IFNa C CpG-ODN/Poly(I:C) or RB6-8C5 C CpG-ODN/Poly(I:C). Our results indicate that the inhalation therapy is a feasible and non-invasive strategy to deliver immunodulatory molecules, including antibodies and cytokines that reprogram the lung tumor microenvironment to foster immune destruction of tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Mice and Experimental Protocolsmentioning

confidence: 99%

Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Similar distribution patterns have been observed in previous studies using fluorescently labeled anticancer monoclonal antibodies that compared systemic administration (i.v.) versus local administration via endotracheal aerosolization (20,21). Larger amounts of the MAb in the BAL fluid of mice that received the antibody intranasally may explain the extended protection observed in mice infected up to 5 days after antibody administration.…”

Section: Discussionmentioning

confidence: 99%

Direct Administration in the Respiratory Tract Improves Efficacy of Broadly Neutralizing Anti-Influenza Virus Monoclonal Antibodies

Leyva-Grado

Tan

Leon

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The emergence of influenza virus strains resistant to approved neuraminidase inhibitors and the time constrains after infection when these drugs can be effective constitute major drawbacks for this class of drugs. This highlights a critical need to discover new therapeutic agents that can be used for the treatment of influenza virus-infected patients. The use of broadly neutralizing anti-influenza monoclonal antibodies (MAbs) has been sought as an alternative immunotherapy against influenza infection. Here, we tested in mice previously characterized broadly neutralizing anti-hemagglutinin (HA) stalk MAbs prophylactically and therapeutically using different routes of administration. The efficacy of treatment against an influenza H1N1 pandemic virus challenge was compared between two systemic routes of administration, intraperitoneal (i.p.) and intravenous (i.v.), and two local routes, intranasal (i.n.) and aerosol (a.e.). The dose of MAb required for prophylactic protection was reduced by 10-fold in animals treated locally (i.n. or a.e.) compared with those treated systemically (i.p. or i.v.). Improved therapeutic protection was observed in animals treated i.n. on day 5 postinfection (60% survival) compared with those treated via the i.p. route (20% survival). An increase in therapeutic efficacy against other influenza virus subtypes (H5N1) was also observed when a local route of administration was used. Our findings demonstrate that local administration significantly decreases the amount of broadly neutralizing monoclonal antibody required for protection against influenza, which highlights the potential use of MAbs as a therapeutic agent for influenza-associated disease.

show abstract

“…Moreover, pharmacokinetics of the different mAbs delivered through the airways in mice and non-human-primates showed a limited lungs-tobloodstream passage and an accumulation of the antibodies in the lungs. 9 This scientific talk convinced the audience that mAb delivery through the airways is therapeutically relevant. The next questions Dr Heuz e-Vourc'h plans to address are the effectiveness of the aerosol delivery of antibodies in pathophysiological conditions (indeed, patients with respiratory diseases do not breathe the same as healthy patients), stability of the antibodies during administration (in particular, specific formulations must be designed to limit aggregation induced by the air-liquid interface) and safety of this administration route.…”

Section: Session 1: Administration Routesmentioning

confidence: 94%

“…The scientific rationale to deliver antibody-based therapeutics through the airways is based on 2 facts: for respiratory diseases, most mAbs operate into the lungs, but these large molecules hardly diffuse passively from the blood vessels into the targeted compartment (for example, there are 500 to 10,000 times less mAb in the lungs than in the systemic circulation). To demonstrate that mAbs delivery through the airways is both feasible and relevant, Dr Heuz e-Vourc'h's team developed 2 animal models of lung cancer to test aerosol delivery of cetuximab (an approved antiepidermal growth factor receptor antibody), 9 and of an antimurine vascular endothelial growth factor antibody. 10 The results of both studies indicated that airway-delivered mAbs reach their target antigen in the tumor and are pharmacologically efficient in limiting tumor growth.…”

Section: Session 1: Administration Routesmentioning

confidence: 99%

MAbDelivery: Administration routes for antibody therapy Third LabEx MAbImprove industrial workshop, July 2, 2015 Tours, France

Bodier-Montagutelli

Respaud

Watier

et al. 2017

mAbs

View full text Add to dashboard Cite

The annual "LabEx MAbImprove Industrial Workshops" are primarily intended to provide a comprehensive view about topics of interest for the pharmaceutical industry to scientists involved in research on therapeutic antibodies. The third workshop in this series, held July 2, 2015 in Tours, was dedicated to the optimization of delivery, namely all processes leading monoclonal antibodies to reach their target site. The commonly used intravenous (IV) route, although advantageous in terms of pharmacokinetics and pharmacodynamics, presents some disadvantages in terms of patients' convenience, therapeutic target access or treatment cost. Such problems led pharmaceutical companies to consider more straightforward and patient-friendly administration routes, bringing the need for specific formulations adapted to the specific inherent physicochemical challenges. In this context, the workshop provided an overview of these advances and opened discussion on new administration routes and formulation development. In the first session, the opportunities and challenges of 3 main routes of administration (IV, subcutaneous (SC), and pulmonary) were discussed, integrating protein stability issues. The next session was dedicated to medical devices intended for SC and pulmonary administration. The last session focused on specific formulations for monoclonal antibodies, particularly to successfully protect antibodies upon aerosolization, to develop highly concentrated formulations for SC administration, and to use formulation as a mean to overcome the barriers to oral protein delivery. As in the previous editions, this workshop gathered people from the academic and industrial spheres and allowed rich debates and discussions.

show abstract

Fate of inhaled monoclonal antibodies after the deposition of aerosolized particles in the respiratory system

Cited by 99 publications

References 52 publications

Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor

Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor

Direct Administration in the Respiratory Tract Improves Efficacy of Broadly Neutralizing Anti-Influenza Virus Monoclonal Antibodies

MAbDelivery: Administration routes for antibody therapy Third LabEx MAbImprove industrial workshop, July 2, 2015 Tours, France

Contact Info

Product

Resources

About