Although severe asthma afflicts a relatively small percentage of individuals with asthma, it affects millions of individuals in the United States. Despite the numerous therapies available for patients with this disabling diseas, severe asthma remains difficult to control in many patients due in part to pathobiologc and clinical heterogeneity. YKL-40 is a chitinase-like protein that is encoded by the Chitinase-3-Like-1 (CHI3L1) gene in humans. Our laboratories discovered that YKL-40 is elevated in the circulation and lung of a subgroup of severe asthmatics. In addition, we determined that the levels in the blood correlate with YKL-40 expression in the airway, reduced lung function, and pathologic airway remodeling. These studies suggested that YKL-40 levels could serve as a biomarker for selecting a subset of patients with asthma and be useful for asthma management. We also conducted a genome wide association study of serum YKL-40 levels and discovered that variation in the CHI3L1 gene, including a single nucleotide polymorphism in the gene's core promoter region, influences serum YKL-40 levels, asthma prevalence, and lung function. Our group and others then discovered that YKL-40 functions as a critical mediator of inflammation and remodeling by controlling apoptosis, modulating innate and adaptive immune responses, and mediating repair responses in the lung via binding to IL-13 receptor ?2 (IL-13R?2). This leads to activation of mitogen-activated protein kinase (MAPK), protein kinase B/AKT, and Wnt/?-catenin-signaling a cascade of events that regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF- ? production in vivo. Furthermore, multiple studies have shown that inhibition of YKL-40 in knockout mice or using antibodies against YKL-40 inhibits inflammation in animal models of asthma and downstream of transgenic expression of IL-13. These studies demonstrate that a therapeutic against YKL-40 has the potential to be an effective therapy for severe asthma. In this proposal, our multidisciplinary team in translational research, genomics, drug development, and immunology will complete the pre-clinical development of humanized monoclonal antibodies against YKL-40.
In Aim 1, the UH2 Phase, we will develop a humanized clinical lead candidate monoclonal antibody against YKL-40 that inhibits allergic airway inflammation with a favorable safety and, pharmacokinetic profiles. In the Aim 2/UH3 Phase, with a commercial partner Covance, we will conduct ADME studies.
In Aim 3, we will develop a companion diagnostic test using intermediate anti- YKL-40 monoclonal antibodies clones for the measurement of free and drug-bound YKL-40 for patient selection and therapeutic monitoring. We will prepare to submit an Investigational New Drug (IND) application for a humanized anti-YKL-40 antibody for the treatment of severe asthma. Ultimately, targeted blockade of YKL-40 will be a critical addition to the astma physician's armamentarium to treat patients with this chronic severe disease and could prove useful in other disease where inflammation is modulated by YKL-40.

Public Health Relevance

In this application, we will complete the pre-clinical development of a humanized monoclonal antibody against the chitinase-like-protein, YKL-40, for the treatment of severe asthma. A companion diagnostic test will also be developed to measure YKL-40 in the serum that is drug-bound or free for monitoring the bioavailability, dosing, and biologic effect. The results will generate a novel therapeutic against a validated mediator of inflammation and remodeling in asthma and will lead to an Investigational New Drug (IND) application following the conclusion of the award.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
1UH2HL123876-01
Application #
8758113
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Program Officer
Noel, Patricia
Project Start
2014-09-22
Project End
2016-06-30
Budget Start
2014-09-22
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$1,663,151
Indirect Cost
$376,863
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510