Preclinical Development of LCTG-001, a Human Secretory IgA Replacement Therapy for CVID Patients

PROJECT SUMMARY Common variable immune deficiency (CVID) is a type of primary immunodeficiency, defined as an immune system dysfunction typically caused by a mutation in a gene or genes. The World Health Organization recognizes more than 400 primary immunodeficiencies (PID) ranging from relatively common to quite rare. CVID is one of the most prevalent symptomatic PID and manifests a wide variability of symptoms and range of severity. CVID is characterized by low levels of immunoglobulins, resulting in a decreased ability to counteract invading microorganisms, toxins, or other foreign substances, with the respiratory tract as a major site of severe, recurring infection. CVID is a chronic, lifelong disease, and symptom management (prevention of infection) is the mainstay of therapy. Currently, the primary treatment for CVID is plasma-derived immunoglobulin replacement therapy (Ig- RT), which can be administered IV or SC to restore systemic antibody concentration to reduce infection. Although it has been demonstrated that intravenous Ig-RT can achieve adequate serum IgG levels and reduce the number of respiratory infections, hospitalization, and antibiotic use, there are considerable shortcomings to current formulations of Ig-RT. For example, currently available Ig-RT is not delivered to the nasal cavity or respiratory tract, which is the most prevalent area of infection in CVID patients. Furthermore, commercially available Ig preparations primarily contain IgG, with little to no IgA, and have limited effectiveness in mucosal compartments, particularly in the airway. In contrast to IgG, the dimeric secretory IgA (sIgA) form of human antibodies is more stable in mucosal compartments, such as those that line the airways and gastrointestinal tract. Because Ig-RT does not deliver IgA to the respiratory tract, CVID patients still experience severe morbidity (e.g., bronchiectasis) and mortality due to respiratory infections. sIgA is the abundant form of antibody found in human milk and represents a novel therapeutic modality. Lactiga has therefore determined that (1) polyclonal sIgA can be reproducibly purified from donated human milk (an abundant natural source of sIgA) and (2) sIgA can bind and neutralize respiratory pathogens of concern to CVID patients. Because IgA also plays an active anti-inflammatory role in the body, a decrease in secretory IgA results in a weakened mucosal barrier overall which can also manifest as allergic or autoimmune conditions. This underscores the severe consequences of IgA deficiency in CVID patients. This proposal supports the Applicant’s overall goal of delivering sIgA replacement therapies to mucosal compartments to address unmet, life-threatening medical needs, especially in vulnerable populations, such as the pediatric CVID population. This proposal specifically supports the development of a nonclinical intranasal pharmacokinetic (PK) profile and formulation framework for our lead asset, LCTG-001, as the first formulation to deliver high molecular weight, human, polyclonal secretory antibodies directly to mucosal compartments to normalize the nasal concentrations of secretory IgA in CVID patients.