The Airways, a Novel Route for Delivering Monoclonal Antibodies to Treat Lung Tumors

Maillet, Agnès; Guilleminault, L.; Lemarié, É.; Lerondel, Stéphanie; Azzopardi, Nicolas; Montharu, J.; Congy‐Jolivet, Nicolas; Reverdiau, Pascale; Legrain, Brigitte; Parent, Christelle; Douvin, Dominique-Henri; Hureaux, J.; Courty, Yves; Monte, M. De; Diot, Patrice; Paintaud, Gilles; Pape, Alain Le; Watier, Hervé; Heuzé-Vourc’h, Nathalie

doi:10.1007/s11095-011-0442-5

Cited by 65 publications

(53 citation statements)

References 33 publications

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“…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

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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.

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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

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show abstract

“…Advantages to aerosol administration of medications to the lung include a high local concentration by delivery directly to the airways, a reduced distribution to systemic circulation and, for drugs that would otherwise require subcutaneous or intravenous injection, pain-and needle-free delivery. Several therapeutic agents have been explored for inhalation delivery in malignancies, including chemotherapeutic agents, 20,21 cytokines, 22,23 antisense oligonucleotides 24 and monoclonal antibodies, 25 demonstrating the feasibility of aerosol delivery, potential antitumor effects and reduced side-effects compared to systemic treatment.…”

Section: Discussionmentioning

confidence: 99%

Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment

et al. 2015

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The immunostimulatory ability of synthetic oligonucleotides containing CpG motifs (CpG-ODN), agonists of Toll-like receptor 9 (TLR9), can be harnessed to promote antitumor immunity by their application at the tumor site to stimulate local activation of innate immunity; however, particularly in the lung, tumor-associated immunosuppression can subvert such antitumor innate immune responses. To locally maintain continuous activation of innate subpopulations while inhibiting immunosuppressive cells, we evaluated aerosol delivery CpG-ODN combined with Poly(I:C), a TLR3 agonist able to convert tumor-supporting macrophages to tumoricidal effectors, in the treatment of B16 melanoma lung metastases in C57BL/6 mice. Aerosolization of CpG-ODN with Poly(I:C) into the bronchoalveolar space reduced the presence of M2-associated arginase-and IL-10-secreting macrophages in tumor-bearing lungs and increased the antitumor activity of aerosolized CpG-ODN alone against B16 lung metastases without apparent signs of toxicity or injury of the bronchial-bronchiolar structures and alveolar walls. Moreover, CpG-ODN/Poly(I:C) aerosol combined with dacarbazine, a therapeutic agent used in patients with inoperable metastatic melanoma able to exert immunostimulatory effects, led to a significant increase in antitumor activity as compared to treatments with aerosolized CpG-ODN/Poly(I:C) or dacarbazine alone. This effect was related to an enhanced recruitment and cytotoxic activity of tumor-infiltrating NK cells in the lung. Our results point to aerosol delivery as a convenient approach for repeated applications of immunostimulants in patients with lung metastases to maintain a continuous local activation of innate immune cells while suppressing polarization of tumor-infiltrating macrophages to an M2 phenotype.

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“…We previously showed that aerosolized cetuximab passed slowly and poorly in blood in mice [103]. It also significantly decreased tumor growth in an ectopic model of lung tumors.…”

Section: Aerosolized Cetuximabmentioning

confidence: 99%

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

Guilleminault¹,

Lemarié²,

Heuzé-Vourc’h³

2012

JCT

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Lung cancer is the leading cause of cancer-related deaths in industrialized countries and non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Cisplatin doublet based chemotherapy, which is the recommended regimen in first line therapy in advanced or metastatic NSCLC, improves survival but in low proportion. Monoclonal antibodies (mAbs) are a novel promising therapeutic class used with great results in inflammatory diseases such as rheumatoid arthritis. Antibodies are natural proteins with modular structure, specific pharmacodynamics and pharmacokinetics and possibly produced against any antigens, thus giving them several advantages over small drug therapeutics. In solid tumors, therapeutic mAbs improved progression free survival (PFS) and overall survival (OS) of patients with breast and colon cancers and had considerably changed the treatment in clinical practice. In NSCLC, bevacizumab, an anti-VEGF mAb, and cetuximab, an anti-EGFR mAb, are the most studied antibodies. Bevacizumab acts on angiognenesis and improved PFS of non squamous NSCLC but in low proportion as shown in two large phase III trials. It was approved by European Medicines Agency (EMEA) and Food and Drug administration (FDA) as a first line therapy in combination with cisplatin doublet chemotherapy. Cetuximab slightly enhanced OS but did not improve PFS in two large phase III trials. These results added to high adverse effect lead to cetuximab refusal by EMEA and FDA in NSCLC. At first glance, the results of mAbs in NSCLC are somewhat disappointing, in contrast to the benefits obtained with mAb treatments in other solid tumors. However, many other mAbs directed against novel targets, such as IGF1-R or CTLA-4, and new mAbs targeting VEGFR and EGFR pathways with different pharmacodymamical and pharmacokinetic properties are under evaluation and may change our vision of taking care of patients with NSCLC. In conclusion, it seems that mAbs therapy in NSCLC clearly marks the start of a new era in NSCLC treatment, with promises in improving patient survival and quality of life.

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The Airways, a Novel Route for Delivering Monoclonal Antibodies to Treat Lung Tumors

Abstract: Delivery of aerosolized-mAbs via the airways deserves further evaluation for treating lung cancers.

Cited by 65 publications

References 33 publications

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

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

Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

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