VEGF neutralizing aerosol therapy in primary pulmonary adenocarcinoma with K-ras activating-mutations

Abstract

y Nathalie Heuz e-Vourc'h and Marie Wislez equally contributed to the study design and are co-senior authors of this article.Keywords: Non-small cell lung cancer, lung adenocarcinoma, anti-VEGF, monoclonal antibody, aerosol, K-ras mutation, anti-angiogenic agent, airways delivery, pharmacokinetics K-ras mutations promote angiogenesis in lung cancer and contribute to the drug resistance of cancer cells. It is not clear whether K-ras mutated adenocarcinomas are sensitive to anti-angiogenic therapy with monoclonal antibodies (mAbs) that target vascular endothelial growth factor (VEGF). Anti-angiogenic mAbs are usually delivered systemically, but only a small proportion reaches the lung after intravenous injection. We investigated the relevance of a noninvasive pulmonary route for the delivery of anti-VEGF mAbs in the mouse K-ras LA1 model. We found that pulmonary delivery of these mAbs significantly reduced the number of tumor lesions and inhibited malignant progression. The antitumor effect involves the VEGFR2-dependent inhibition of blood vessel growth, which impairs tumor proliferation. Pharmacokinetic analysis of aerosolized anti-VEGF showed its low rate of passage into the bloodstream, suggesting that this delivery route is associated with reduced systemic side effects. Our findings highlight the value of the aerosol route for administration of anti-angiogenic mAbs in pulmonary adenocarcinoma with K-ras activating-mutations.

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

“…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. 24 To our knowledge, ours is the first study to evaluate this route in administering an antibody to deplete a suppressive immune population. Our data indicate that while MDSC depletion by the nebulized antibody did not enhance NK cell recruitment induced by CpG-ODN/Poly(I:C), depletion did lead to increased NK cell activation, possibly by minimizing direct inhibition of these effector cells and/or by enhancing the ability of aerosolized CpG-ODN/Poly(I:C)-activated macrophages to promote NK cell cytotoxicity.…”

“…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.…”

Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

“…anti-cancer agents and anti-fungals) or excipients at single or repeated doses, to assess efficacy, tolerance and PK (Chandenier et al, 2009;Frédéric Gagnadoux et al, 2005;Gagnadoux et al, 2008;Maillet et al, 2011;Montharu et al, 2010). The Microsprayer™ device has been used with success to assess the efficacy of several mAbs in murine models Hervé et al, 2014;Maillet et al, 2011). It should be noted however that tolerability issues have been raised concerning intratracheal administration with these devices in small rodents (slight and transitory lung inflammation (Dubois et al, 2013;Montharu et al, 2010) and lung lesions (Guillon et al, 2012)).…”

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

“…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. 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.…”