American Journal of Respiratory and Critical Care Medicine

There are several new available biological treatments such as the anti–IL-5 monoclonal antibodies (mAbs) mepolizumab and reslizumab and the IL-5rα (IL-5 receptor α) blocker, benralizumab, for the treatment of severe eosinophilic asthma (1, 2). Dupilumab, which targets IL-4rα blocking the IL-4/IL-13 signaling pathways, is moving through the approvals process (3). Lebrikizumab and tralokinumab are anti–IL-13 mAbs that improved lung function in patients with poorly controlled asthma, yet the development of these drugs was ultimately halted because of a lack of clinical efficacy in phase 3 clinical trials (4, 5). IL-13 is produced in the airways after exposure to allergens and is involved in mucous hypersecretion, bronchial hyperresponsiveness, epithelial metaplasia, and airway remodeling (6, 7). Given its pivotal role in many of the key pathophysiological processes in acute and chronic allergic inflammation, it is somewhat surprising that mAbs targeting IL-13 were not more clinically effective in patients with this asthma phenotype. One potential explanation is that these mAbs do not achieve sufficient concentrations to effectively target receptors in the bronchial airway epithelium, mast cells, and mononuclear cells in the lung (8); in fact, mAB transport from the serum to the lung is poor in all species, with serum levels of mAbs 500–10,000 times higher than those in BAL after intravenous administration (9, 10). Therefore, to determine whether direct airway delivery is an effective and safe alternative to systemic administration, in this issue of the Journal, Lightwood and colleagues (pp. 610–619) evaluated the effectiveness of CDP7766 in a model of allergic asthma in cynomolgus macaques naturally sensitized to Ascaris suum. CDP7766 is an inhaled mAb Fab fragment that acts by blocking IL-13 binding to IL-13rα1 and IL-13rα2 (11). This was administered via an eFlow nebulizer, producing particles with median aerodynamic diameter of 3.2 μm (SD, 1.5), which fall within the respirable fraction capable of reaching the terminal bronchioles. The target dose was delivered over the course of 6 minutes, using a breath simulation algorithm. The experiment consisted of allocating 32 macaques to five daily consecutive treatments with vehicle or varying CDP7766 concentrations (60, 10, or 1 mg/d). Sensitization was performed via 15 breaths of ultrasonic nebulized A. summ at screening 4–6 weeks before any treatment, and during Days 3 and 4 of the CDP7766 treatment protocol. BAL was collected 24 hours after the last sensitization dose.

Sensitization increased airway resistance, eosinophil numbers, and cytokine levels, particularly IL-5, which had marked more than 10-fold elevation. Treatment with CDP7766, regardless of dose, did not significantly reduce airway eosinophilia when compared with vehicle. However, relative to the eosinophilia induced during the screening 4–6 weeks before treatment, the 60 mg/day dose significantly reduced the degree of sensitization-induced airway eosinophilia. CDP7766 markedly lowered the levels of all cytokines measured in the BAL, with the exception of eotaxin-1, TARC (thymus- and activation-regulated chemokine), IP-10 (IFN-γ–induced protein 10), MCP-1 (monocyte chemoattractant protein 1), and IL-4, IL-2, and IL-1β. It also blunted the increase in airway resistance measured on Day 2.

Overall, there are many reasons why to feel excited about the possibilities that can potentially arise from the results of this study. Although performed in nonhuman primates, it clearly demonstrates that nebulized IL-13 mAbs Fab fragments can effectively lower airway eosinophilia by ∼30%, while reducing T2-related cytokines by ∼78% and preventing increased airway resistance. Blocking the effect of IL-13 directly in airway epithelium could potentially result in stronger MUC5AB inhibition (6), leading to better mucous secretion control, and long-term use could reduce epithelial remodeling and subepithelial fibrosis. Also, it could have stronger effects on airway smooth cells, and thus explain why CDP7766 was able to reduce airway resistance, whereas previous clinical studies of anti-IL13 mAbs in patients with mild asthma failed to prevent allergen-induced bronchial hyperresponsiveness (12). The use of Fab fragments instead of full-length mAbs is an exciting proposition, as these are smaller, could have better lung deposition, are potentially less immunogenic, and have a high affinity and specificity for IL-13 (10, 12). Further, using a vibrating membrane nebulizer ensures that the particles generated are mostly in the respirable fraction, ensuring more distal airway deposition (12). In addition, given that Fab fragments have low systemic bioavailability when delivered into the airways, this limits the potential for systemic toxicity (10). For example, CDP7766 did not affect peripheral blood cell counts, whereas clinical studies have shown that anti–IL-3 mAbs can be associated with increased peripheral blood eosinophilia (4).

There are significant limitations to the study and many questions that still need to be answered. The study is was of very short duration, and thus it is not known whether CDP7766 would be effective for longer periods, including whether it could potentially reduce exacerbations. In addition, mAbs Fab fragments were delivered using a tidal breathing algorithm in the absence of any underlying airway disease; however, in patients with severe asthma, underlying changes in ventilation parameters and airway function and structure could significantly affect the physical properties of the aerosol (size, density, and shape) particles and their deposition rate, potentially affecting its clinical effectiveness (10). Regardless of these limitations and uncertainties, the data presented in this study strongly support the development of phase 1 clinical studies in patients with severe eosinophilic asthma and the potential to deliver biological therapies directly into the target organ while reducing the potential for adverse systemic effects.

1. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al.; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014;371:11981207.
2. Öztürk Aktaş Ö, Şekerel BE, Kalyoncu AF. Glucocorticoid sparing of benralizumab in asthma. N Engl J Med 2017;377:12041205.
3. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018;378:24862496.
4. Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med 2016;4:781796.
5. Chung KF. Tralokinumab unsuccessful for management of severe, uncontrolled asthma. Lancet Respir Med 2018;6:480481.
6. Seibold MA. Interleukin-13 stimulation reveals the cellular and functional plasticity of the airway epithelium. Ann Am Thorac Soc 2018;15:S98S102.
7. Firszt R, Francisco D, Church TD, Thomas JM, Ingram JL, Kraft M. Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma. Eur Respir J 2014;43:464473.
8. Huang SK, Xiao HQ, Kleine-Tebbe J, Paciotti G, Marsh DG, Lichtenstein LM, et al. IL-13 expression at the sites of allergen challenge in patients with asthma. J Immunol 1995;155:26882694.
9. Hart TK, Cook RM, Zia-Amirhosseini P, Minthorn E, Sellers TS, Maleeff BE, et al. Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immunol 2001;108:250257.
10. Respaud R, Vecellio L, Diot P, Heuzé-Vourc’h N. Nebulization as a delivery method for mAbs in respiratory diseases. Expert Opin Drug Deliv 2015;12:10271039.
11. Lightwood D, Tservistas M, Zehentleitner M, Sarkar K, Turner A, Bracher M, et al. Efficacy of an inhaled IL-13 antibody fragment in a model of chronic asthma. Am J Respir Crit Care Med 2018;198:610619.
12. Gauvreau GM, Boulet LP, Cockcroft DW, Fitzgerald JM, Carlsten C, Davis BE, et al. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am J Respir Crit Care Med 2011;183:10071014.

Originally Published in Press as DOI: 10.1164/rccm.201807-1205ED on July 11, 2018

Author disclosures are available with the text of this article at www.atsjournals.org.

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