Development of a Fully Humanized Antibody for Treating Lung Emphysema

Project Summary COPD is a common and serious disease with no cure that is characterized by chronicprogressive lung damagea decline in pulmonary function and quality of lifeand often deathThe two major clinical features of COPD are emphysema and chronic bronchitisCOPD is mainly associated with exposure to cigarette smokeCShoweveraboutof COPD patients have a genetic deficiency of alphaantitrypsinAATDAATD patients represent an orphan disease population for which emphysema is the primary cause of deathand is a relatively homogenous group with a more efficient and less costly clinical development path compared to the broad COPD populationAllinaire TherapeuticsLLChas demonstrated that EMAP IIendothelial monocyte activating proteinis a novel therapeutic target for emphysematous COPD that plays a central role in driving the underlying pathology of the diseaseincluding lung inflammation and alveolar destructionEMAP II levels in the lungs of patients positively correlate with the severity of COPD and remain elevated even after smoking cessationFurthermorelung specific overexpression of EMAP II induces emphysematous changes in miceand a tool rat antibody to EMAP IIMblocks the progression of chronic CS induced lung emphysema in miceWork supported by the phaseSBIR grant resulted in the synthesis of fully humanized versions of the rat MmAbSeveral leads were identified with appropriate potency and developability properties to be considered for optimizationIn additionpreliminary data presented in the application demonstrates that treatment with one of the humanized EMAP II mAbs prevented lung macrophage infiltration in a sub chronicweekCS exposure modelThe specific aims of this Phase II research plan areAimSelection of an optimizedhigh affinity EMAP II mAb development candidateThe most potent of thecurrent leads will be identifiedby SPRand used to perform lead optimizationaffinity maturationand stable cell line development to produce a clinical candidate with sub nanomolar affinity and suitable manufacturability propertiesAimIn vivo testing of the lead mAb in a chronic CS exposure model of emphysema in mouseThe dose response effects of the clinical development candidate mAb will be tested in a model of chronic CS exposure to confirm a reduction in emphysema endpointsThe mAb will be administered therapeutically via the clinically relevant subcutaneous routeAimTarget validation for EMAP II in AATD patient samplesmouse elastase modeland human lung cellsSerum EMAP II will be measured in individuals with COPD of different severities with or without AATD to determine the correlation between EMAP II and disease severityFurther target validation of EMAP II in the context of AATD will be determined by testing the effects of the mAb in the mouse model of elastaseinduced emphysema and human lung cellsCompletion of the Phase II milestones will provide Allinaire with a strong pre clinical data package to enable either partnering of the project with a Pharmaceutical company or additional fund raising to support progression of the project to manufacturing and IND enabling studiesas critical steps towards clinical trials with an EMAP II mAb in AATD patients initiallyand subsequently in the broader COPD population with emphysema